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Sanchez-Perez, Luis Ariel

Overview:

My overall research interests include the elucidation of immune mechanisms underlying the efficacy of novel immunotherapeutic strategies for the treatment of malignant brain tumors. I am currently evaluating the mechanisms of Chimeric Antigen Receptor (CAR) gene-modified T-cells mediated immune tumor cell destruction and the induction of endogenous immunity to individual tumor specific mutations. 

Positions:

Assistant Professor of Neurosurgery

Neurosurgery
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2005

Ph.D. — Mayo Graduate School

Grants:

EGFRvIII-targeted Bispecific T cell Engagers for brain tumors

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Investigator
Start Date
September 30, 2013
End Date
May 31, 2018

Brain tumors with regulatory T-cells treated with EGFRvIII-specific T-cells

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Research Scientist
Start Date
April 05, 2013
End Date
March 31, 2018

Precision BioSciences/Duke Brain Tumor Center Collaboration

Administered By
Neurosurgery
AwardedBy
Precision BioSciences , Inc.
Role
Associate in Research
Start Date
November 03, 2015
End Date
October 31, 2017

A clinically-relevant anti-CD27 agonist antibody as a vaccine adjuvant for brain tumor immunotherapy

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
August 01, 2016
End Date
July 31, 2017

Use of YH24931 in combination with antigen-specific DC vaccines for antitumor efficacy

Administered By
Neurosurgery
AwardedBy
Yuhan Corporation
Role
Principal Investigator
Start Date
December 20, 2016
End Date
June 19, 2017

Gene-engineered adoptive T cell immunotherapy of GBM

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Postdoc Scholar
Start Date
September 12, 2012
End Date
December 31, 2012
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Publications:

Systemic activation of antigen-presenting cells via RNA-loaded nanoparticles.

While RNA-pulsed dendritic cell (DC) vaccines have shown promise, the advancement of cellular therapeutics is fraught with developmental challenges. To circumvent the challenges of cellular immunotherapeutics, we developed clinically translatable nanoliposomes that can be combined with tumor-derived RNA to generate personalized tumor RNA-nanoparticles (NPs) with considerable scale-up capacity. RNA-NPs bypass MHC restriction, are amenable to central distribution, and can provide near immediate immune induction. We screened commercially available nanoliposomal preparations and identified the cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) as an efficient mRNA courier to antigen-presenting cells (APCs). When administered intravenously, RNA-NPs mediate systemic activation of APCs in reticuloendothelial organs such as the spleen, liver, and bone marrow. RNA-NPs increase percent expression of MHC class I/II, B7 co-stimulatory molecules, and maturation markers on APCs (all vital for T-cell activation). RNA-NPs also increase activation markers on tumor APCs and elicit potent expansion of antigen-specific T-cells superior to peptide vaccines formulated in complete Freund's adjuvant. We demonstrate that both model antigen-encoding and physiologically-relevant tumor-derived RNA-NPs expand potent antitumor T-cell immunity. RNA-NPs were shown to induce antitumor efficacy in a vaccine model and functioned as a suitable alternative to DCs in a stringent cellular immunotherapy model for a radiation/temozolomide resistant invasive murine high-grade glioma. Although cancer vaccines have suffered from weak immunogenicity, we have advanced a RNA-NP formulation that systemically activates host APCs precipitating activated T-cell frequencies necessary to engender antitumor efficacy. RNA-NPs can thus be harnessed as a more feasible and effective immunotherapy to re-program host-immunity.

Authors
Sayour, EJ; De Leon, G; Pham, C; Grippin, A; Kemeny, H; Chua, J; Huang, J; Sampson, JH; Sanchez-Perez, L; Flores, C; Mitchell, DA
MLA Citation
Sayour, EJ, De Leon, G, Pham, C, Grippin, A, Kemeny, H, Chua, J, Huang, J, Sampson, JH, Sanchez-Perez, L, Flores, C, and Mitchell, DA. "Systemic activation of antigen-presenting cells via RNA-loaded nanoparticles." Oncoimmunology 6.1 (January 2017): e1256527-.
PMID
28197373
Source
epmc
Published In
OncoImmunology
Volume
6
Issue
1
Publish Date
2017
Start Page
e1256527
DOI
10.1080/2162402x.2016.1256527

Emerging immunotherapies for glioblastoma.

Immunotherapy for brain cancer has evolved dramatically over the past decade, owed in part to our improved understanding of how the immune system interacts with tumors residing within the central nervous system (CNS). Glioblastoma (GBM), the most common primary malignant brain tumor in adults, carries a poor prognosis (<15 months) and only few advances have been made since the FDA's approval of temozolomide (TMZ) in 2005. Importantly, several immunotherapies have now entered patient trials based on promising preclinical data, and recent studies have shed light on how GBM employs a slew of immunosuppressive mechanisms that may be targeted for therapeutic gain. Altogether, accumulating evidence suggests immunotherapy may soon earn its keep as a mainstay of clinical management for GBM.Here, we review cancer vaccines, checkpoint inhibitors, adoptive T-cell immunotherapy, and oncolytic virotherapy.Checkpoint blockade induces antitumor activity by preventing negative regulation of T-cell activation. This platform, however, depends on an existing frequency of tumor-reactive T cells. GBM tumors are exceptionally equipped to prevent this, occupying low levels of antigen expression and elaborate mechanisms of immunosuppression. Therefore, checkpoint blockade may be most effective when used in combination with a DC vaccine or adoptively transferred tumor-specific T cells generated ex vivo. Both approaches have been shown to induce endogenous immune responses against tumor antigens, providing a rationale for use with checkpoint blockade where both primary and secondary responses may be potentiated.

Authors
Desai, R; Suryadevara, CM; Batich, KA; Farber, SH; Sanchez-Perez, L; Sampson, JH
MLA Citation
Desai, R, Suryadevara, CM, Batich, KA, Farber, SH, Sanchez-Perez, L, and Sampson, JH. "Emerging immunotherapies for glioblastoma." Expert opinion on emerging drugs 21.2 (June 2016): 133-145.
PMID
27223671
Source
epmc
Published In
Expert Opinion on Emerging Drugs
Volume
21
Issue
2
Publish Date
2016
Start Page
133
End Page
145
DOI
10.1080/14728214.2016.1186643

Serum elevation of B lymphocyte stimulator does not increase regulatory B cells in glioblastoma patients undergoing immunotherapy.

Regulatory B cells that secrete IL-10 (IL-10(+) Bregs) represent a suppressive subset of the B cell compartment with prominent anti-inflammatory capacity, capable of suppressing cellular and humoral responses to cancer and vaccines. B lymphocyte stimulator (BLyS) is a key regulatory molecule in IL-10(+) Breg biology with tightly controlled serum levels. However, BLyS levels can be drastically altered upon chemotherapeutic intervention. We have previously shown that serum BLyS levels are elevated, and directly associated, with increased antigen-specific antibody titers in patients with glioblastoma (GBM) undergoing lymphodepletive temozolomide chemotherapy and vaccination. In this study, we examined corresponding IL-10(+) Breg responses within this patient population and demonstrate that the IL-10(+) Breg compartment remains constant before and after administration of the vaccine, despite elevated BLyS levels in circulation. IL-10(+) Breg frequencies were not associated with serum BLyS levels, and ex vivo stimulation with a physiologically relevant concentration of BLyS did not increase IL-10(+) Breg frequency. However, BLyS stimulation did increase the frequency of the overall B cell compartment and promoted B cell proliferation upon B cell receptor engagement. Therefore, using BLyS as an adjuvant with therapeutic peptide vaccination could promote humoral immunity with no increase in immunosuppressive IL-10(+) Bregs. These results have implications for modulating humoral responses in human peptide vaccine trials in patients with GBM.

Authors
Saraswathula, A; Reap, EA; Choi, BD; Schmittling, RJ; Norberg, PK; Sayour, EJ; Herndon, JE; Healy, P; Congdon, KL; Archer, GE; Sanchez-Perez, L; Sampson, JH
MLA Citation
Saraswathula, A, Reap, EA, Choi, BD, Schmittling, RJ, Norberg, PK, Sayour, EJ, Herndon, JE, Healy, P, Congdon, KL, Archer, GE, Sanchez-Perez, L, and Sampson, JH. "Serum elevation of B lymphocyte stimulator does not increase regulatory B cells in glioblastoma patients undergoing immunotherapy." Cancer immunology, immunotherapy : CII 65.2 (February 2016): 205-211.
PMID
26759007
Source
epmc
Published In
Cancer Immunology, Immunotherapy
Volume
65
Issue
2
Publish Date
2016
Start Page
205
End Page
211
DOI
10.1007/s00262-015-1784-3

RNA NANOPARTICLE VACCINES FACILITATE AND SUSTAIN ADOPTIVE CELLULAR THERAPY TARGETING PEDIATRIC INTRACRANIAL MALIGNANCIES

Authors
Sayour, E; Flores, C; Pham, C; De Leon, G; Kemeny, H; Sanchez-Perez, L; Mitchell, D
MLA Citation
Sayour, E, Flores, C, Pham, C, De Leon, G, Kemeny, H, Sanchez-Perez, L, and Mitchell, D. "RNA NANOPARTICLE VACCINES FACILITATE AND SUSTAIN ADOPTIVE CELLULAR THERAPY TARGETING PEDIATRIC INTRACRANIAL MALIGNANCIES." PEDIATRIC BLOOD & CANCER 62 (June 2015): 24-24.
Source
wos-lite
Published In
Pediatric Blood & Cancer
Volume
62
Publish Date
2015
Start Page
24
End Page
24

Tetanus toxoid conditioning enhances migration and efficacy of dendritic cell vaccines in patients with glioblastoma

Authors
Batich, K; Sampson, JH; Reap, E; Sanchez-Perez, L; Archer, G; Snyder, D; Nair, S; Gunn, M; Mitchell, D
MLA Citation
Batich, K, Sampson, JH, Reap, E, Sanchez-Perez, L, Archer, G, Snyder, D, Nair, S, Gunn, M, and Mitchell, D. "Tetanus toxoid conditioning enhances migration and efficacy of dendritic cell vaccines in patients with glioblastoma." June 2015.
Source
wos-lite
Published In
Journal of neurosurgery
Volume
122
Issue
6
Publish Date
2015
Start Page
A1522
End Page
A1522

Are BiTEs the "missing link" in cancer therapy?

Conventional treatment for cancer routinely includes surgical resection and some combination of chemotherapy and radiation. These approaches are frequently accompanied by unintended and highly toxic collateral damage to healthy tissues, which are offset by only marginal prognostic improvements in patients with advanced cancers. This unfortunate balance has driven the development of novel therapies that aim to target tumors both safely and efficiently. Over the past decade, mounting evidence has supported the therapeutic utility of T-cell-centered cancer immunotherapy, which, in its various iterations, has been shown capable of eliciting highly precise and robust antitumor responses both in animal models and human trials. The identification of tumor-specific targets has further fueled a growing interest in T-cell therapies given their potential to circumvent the non-specific nature of traditional treatments. Of the several strategies geared toward achieving T-cell recognition of tumor, bispecific antibodies (bsAbs) represent a novel class of biologics that have garnered enthusiasm in recent years due to their versatility, specificity, safety, cost, and ease of production. Bispecific T-cell Engagers (BiTEs) are a subclass of bsAbs that are specific for CD3 on one arm and a tumor antigen on the second. As such, BiTEs function by recruiting and activating polyclonal populations of T-cells at tumor sites, and do so without the need for co-stimulation or conventional MHC recognition. Blinatumomab, a well-characterized BiTE, has emerged as a promising recombinant bscCD19×CD3 construct that has demonstrated remarkable antitumor activity in patients with B-cell malignancies. This clinical success has resulted in the rapid extension of BiTE technology against a greater repertoire of tumor antigens and the recent US Food and Drug Administration's (FDA) accelerated approval of blinatumomab for the treatment of a rare form of acute lymphoblastic leukemia (ALL). In this review, we dissect the role of T-cell therapeutics in the new era of cancer immunotherapy, appraise the value of CAR T-cells in the context of solid tumors, and discuss why the BiTE platform may rescue several of the apparent deficits and shortcomings of competing immunotherapies to support its widespread clinical application.

Authors
Suryadevara, CM; Gedeon, PC; Sanchez-Perez, L; Verla, T; Alvarez-Breckenridge, C; Choi, BD; Fecci, PE; Sampson, JH
MLA Citation
Suryadevara, CM, Gedeon, PC, Sanchez-Perez, L, Verla, T, Alvarez-Breckenridge, C, Choi, BD, Fecci, PE, and Sampson, JH. "Are BiTEs the "missing link" in cancer therapy?." Oncoimmunology 4.6 (June 2015): e1008339-. (Review)
PMID
26155413
Source
epmc
Published In
OncoImmunology
Volume
4
Issue
6
Publish Date
2015
Start Page
e1008339
DOI
10.1080/2162402x.2015.1008339

Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients.

After stimulation, dendritic cells (DCs) mature and migrate to draining lymph nodes to induce immune responses. As such, autologous DCs generated ex vivo have been pulsed with tumour antigens and injected back into patients as immunotherapy. While DC vaccines have shown limited promise in the treatment of patients with advanced cancers including glioblastoma, the factors dictating DC vaccine efficacy remain poorly understood. Here we show that pre-conditioning the vaccine site with a potent recall antigen such as tetanus/diphtheria (Td) toxoid can significantly improve the lymph node homing and efficacy of tumour-antigen-specific DCs. To assess the effect of vaccine site pre-conditioning in humans, we randomized patients with glioblastoma to pre-conditioning with either mature DCs or Td unilaterally before bilateral vaccination with DCs pulsed with Cytomegalovirus phosphoprotein 65 (pp65) RNA. We and other laboratories have shown that pp65 is expressed in more than 90% of glioblastoma specimens but not in surrounding normal brain, providing an unparalleled opportunity to subvert this viral protein as a tumour-specific target. Patients given Td had enhanced DC migration bilaterally and significantly improved survival. In mice, Td pre-conditioning also enhanced bilateral DC migration and suppressed tumour growth in a manner dependent on the chemokine CCL3. Our clinical studies and corroborating investigations in mice suggest that pre-conditioning with a potent recall antigen may represent a viable strategy to improve anti-tumour immunotherapy.

Authors
Mitchell, DA; Batich, KA; Gunn, MD; Huang, M-N; Sanchez-Perez, L; Nair, SK; Congdon, KL; Reap, EA; Archer, GE; Desjardins, A; Friedman, AH; Friedman, HS; Herndon, JE; Coan, A; McLendon, RE; Reardon, DA; Vredenburgh, JJ; Bigner, DD; Sampson, JH
MLA Citation
Mitchell, DA, Batich, KA, Gunn, MD, Huang, M-N, Sanchez-Perez, L, Nair, SK, Congdon, KL, Reap, EA, Archer, GE, Desjardins, A, Friedman, AH, Friedman, HS, Herndon, JE, Coan, A, McLendon, RE, Reardon, DA, Vredenburgh, JJ, Bigner, DD, and Sampson, JH. "Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients." Nature 519.7543 (March 11, 2015): 366-369.
PMID
25762141
Source
epmc
Published In
Nature
Volume
519
Issue
7543
Publish Date
2015
Start Page
366
End Page
369
DOI
10.1038/nature14320

Novel role of hematopoietic stem cells in immunologic rejection of malignant gliomas.

Adoptive cellular therapy (ACT) after lymphodepletive conditioning can induce dramatic clinical responses, but this approach has been largely limited to melanoma due to a lack of reliable methods for expanding tumor-specific lymphocytes from the majority of other solid cancers. We have employed tumor RNA-pulsed dendritic cells (DCs) to reliably expand CD4(+) and CD8(+) tumor-reactive T lymphocytes for curative ACT in a highly-invasive, chemotherapy- and radiation-resistant malignant glioma model. Curative treatment of established intracranial tumors involved a synergistic interaction between myeloablative (MA) conditioning, adoptively transferred tumor-specific T cells, and tumor RNA-pulsed DC vaccines. Hematopoietic stem cells (HSCs), administered for salvage from MA conditioning, rapidly migrated to areas of intracranial tumor growth and facilitated the recruitment of tumor-specific lymphocytes through HSC-elaborated chemokines and enhanced immunologic rejection of intracranial tumors during ACT. Furthermore, HSC transplant under non-myeloablative (NMA) conditions also enhanced immunologic tumor rejection, indicating a novel role for the use of HSCs in the immunologic treatment of malignant gliomas and possibly other solid tumors.

Authors
Flores, C; Pham, C; Snyder, D; Yang, S; Sanchez-Perez, L; Sayour, E; Cui, X; Kemeny, H; Friedman, H; Bigner, DD; Sampson, J; Mitchell, DA
MLA Citation
Flores, C, Pham, C, Snyder, D, Yang, S, Sanchez-Perez, L, Sayour, E, Cui, X, Kemeny, H, Friedman, H, Bigner, DD, Sampson, J, and Mitchell, DA. "Novel role of hematopoietic stem cells in immunologic rejection of malignant gliomas." Oncoimmunology 4.3 (March 2015): e994374-.
PMID
25949916
Source
epmc
Published In
OncoImmunology
Volume
4
Issue
3
Publish Date
2015
Start Page
e994374
DOI
10.4161/2162402x.2014.994374

Novel role of hematopoietic stem cells in immunologic rejection of malignant gliomas

Authors
Flores, C; Pham, C; Snyder, D; Yang, S; Sanchez-Perez, L; Sayour, E; Cui, X; Kemeny, H; Friedman, H; Bigner, DD; Sampson, J; Mitchell, DA
MLA Citation
Flores, C, Pham, C, Snyder, D, Yang, S, Sanchez-Perez, L, Sayour, E, Cui, X, Kemeny, H, Friedman, H, Bigner, DD, Sampson, J, and Mitchell, DA. "Novel role of hematopoietic stem cells in immunologic rejection of malignant gliomas." ONCOIMMUNOLOGY 4.3 (March 2015).
Source
wos-lite
Published In
OncoImmunology
Volume
4
Issue
3
Publish Date
2015
DOI
10.4161/2162402X.2014.9943741

Generation of CAR T cells for adoptive therapy in the context of glioblastoma standard of care.

Adoptive T cell immunotherapy offers a promising strategy for specifically targeting and eliminating malignant gliomas. T cells can be engineered ex vivo to express chimeric antigen receptors specific for glioma antigens (CAR T cells). The expansion and function of adoptively transferred CAR T cells can be potentiated by the lymphodepletive and tumoricidal effects of standard of care chemotherapy and radiotherapy. We describe a method for generating CAR T cells targeting EGFRvIII, a glioma-specific antigen, and evaluating their efficacy when combined with a murine model of glioblastoma standard of care. T cells are engineered by transduction with a retroviral vector containing the anti-EGFRvIII CAR gene. Tumor-bearing animals are subjected to host conditioning by a course of temozolomide and whole brain irradiation at dose regimens designed to model clinical standard of care. CAR T cells are then delivered intravenously to primed hosts. This method can be used to evaluate the antitumor efficacy of CAR T cells in the context of standard of care.

Authors
Riccione, K; Suryadevara, CM; Snyder, D; Cui, X; Sampson, JH; Sanchez-Perez, L
MLA Citation
Riccione, K, Suryadevara, CM, Snyder, D, Cui, X, Sampson, JH, and Sanchez-Perez, L. "Generation of CAR T cells for adoptive therapy in the context of glioblastoma standard of care." Journal of visualized experiments : JoVE 96 (February 16, 2015).
PMID
25741761
Source
epmc
Published In
Journal of Visualized Experiments
Issue
96
Publish Date
2015
DOI
10.3791/52397

Immunotherapy for malignant glioma.

Malignant gliomas (MG) are the most common type of primary malignant brain tumor. Most patients diagnosed with glioblastoma (GBM), the most common and malignant glial tumor, die within 12-15 months. Moreover, conventional treatment, which includes surgery followed by radiation and chemotherapy, can be highly toxic by causing nonspecific damage to healthy brain and other tissues. The shortcomings of standard-of-care have thus created a stimulus for the development of novel therapies that can target central nervous system (CNS)-based tumors specifically and efficiently, while minimizing off-target collateral damage to normal brain. Immunotherapy represents an investigational avenue with the promise of meeting this need, already having demonstrated its potential against B-cell malignancy and solid tumors in clinical trials. T-cell engineering with tumor-specific chimeric antigen receptors (CARs) is one proven approach that aims to redirect autologous patient T-cells to sites of tumor. This platform has evolved dramatically over the past two decades to include an improved construct design, and these modern CARs have only recently been translated into the clinic for brain tumors. We review here emerging immunotherapeutic platforms for the treatment of MG, focusing on the development and application of a CAR-based strategy against GBM.

Authors
Suryadevara, CM; Verla, T; Sanchez-Perez, L; Reap, EA; Choi, BD; Fecci, PE; Sampson, JH
MLA Citation
Suryadevara, CM, Verla, T, Sanchez-Perez, L, Reap, EA, Choi, BD, Fecci, PE, and Sampson, JH. "Immunotherapy for malignant glioma." Surgical neurology international 6.Suppl 1 (January 2015): S68-S77.
PMID
25722935
Source
epmc
Published In
Surgical Neurology International
Volume
6
Issue
Suppl 1
Publish Date
2015
Start Page
S68
End Page
S77
DOI
10.4103/2152-7806.151341

Bridging infectious disease vaccines with cancer immunotherapy: a role for targeted RNA based immunotherapeutics.

Tumor-specific immunotherapy holds the promise of eradicating malignant tumors with exquisite precision without additional toxicity to standard treatments. Cancer immunotherapy has conventionally relied on cell-mediated immunity while successful infectious disease vaccines have been shown to induce humoral immunity. Efficacious cancer immunotherapeutics likely require both cellular and humoral responses, and RNA based cancer vaccines are especially suited to stimulate both arms of the immune system. RNA is inherently immunogenic, inducing innate immune responses to initiate cellular and humoral adaptive immunity, but has limited utility based on its poor in vivo stability. Early work utilized 'naked' RNA vaccines, whereas more recent efforts have attempted to encapsulate RNA thereby protecting it from degradation. However, feasibility has been limited by a lack of defined and safe targeting mechanisms for the in vivo delivery of stabilized RNA. As new cancer antigens come to the forefront with novel RNA encapsulation and targeting techniques, RNA vaccines may prove to be a vital, safe and robust method to initiate patient-specific anti-tumor efficacy.

Authors
Sayour, EJ; Sanchez-Perez, L; Flores, C; Mitchell, DA
MLA Citation
Sayour, EJ, Sanchez-Perez, L, Flores, C, and Mitchell, DA. "Bridging infectious disease vaccines with cancer immunotherapy: a role for targeted RNA based immunotherapeutics." Journal for immunotherapy of cancer 3 (January 2015): 13-.
PMID
25901285
Source
epmc
Published In
Journal for ImmunoTherapy of Cancer
Volume
3
Publish Date
2015
Start Page
13
DOI
10.1186/s40425-015-0058-0

IT-10 * SYNERGISTIC CELLULAR INTERACTIONS IN ADOPTIVE IMMUNOTHERAPY LEADS TO IMMUNOLOGIC REJECTION OF MALIGNANT GLIOMA

Authors
Flores, C; Pham, C; Snyder, D; Yang, S; Sanchez-Perez, L; Sayour, E; Cui, X; Kemeny, H; Friedman, H; Bigner, D; Sampson, J; Mitchell, D
MLA Citation
Flores, C, Pham, C, Snyder, D, Yang, S, Sanchez-Perez, L, Sayour, E, Cui, X, Kemeny, H, Friedman, H, Bigner, D, Sampson, J, and Mitchell, D. "IT-10 * SYNERGISTIC CELLULAR INTERACTIONS IN ADOPTIVE IMMUNOTHERAPY LEADS TO IMMUNOLOGIC REJECTION OF MALIGNANT GLIOMA." Neuro-Oncology 16.suppl 5 (November 1, 2014): v111-v111.
Source
crossref
Published In
Neuro-Oncology
Volume
16
Issue
suppl 5
Publish Date
2014
Start Page
v111
End Page
v111
DOI
10.1093/neuonc/nou258.8

IT-31 * HARNESSING THE IMMUNOLOGIC CAPACITY OF THE LIVER AGAINST GLIOBLASTOMA MULTIFORME

Authors
Sayour, E; De Leon, G; Pham, C; Sanchez-Perez, L; Snyder, D; Kemeny, H; Flores, C; Mitchell, D
MLA Citation
Sayour, E, De Leon, G, Pham, C, Sanchez-Perez, L, Snyder, D, Kemeny, H, Flores, C, and Mitchell, D. "IT-31 * HARNESSING THE IMMUNOLOGIC CAPACITY OF THE LIVER AGAINST GLIOBLASTOMA MULTIFORME." Neuro-Oncology 16.suppl 5 (November 1, 2014): v116-v116.
Source
crossref
Published In
Neuro-Oncology
Volume
16
Issue
suppl 5
Publish Date
2014
Start Page
v116
End Page
v116
DOI
10.1093/neuonc/nou258.29

RANDOMIZATION OF PATIENTS WITH GLIOBLASTOMA TO VACCINE SITE PRE-CONDITIONING WITH TETANUS-DIPHTHERIA TOXOID SYSTEMICALLY ENHANCES MIGRATION AND THERAPEUTIC EFFECT OF CYTOMEGALOVIRUS PP65-PULSED DENDRITIC CELL VACCINE IN A MIP-1α-DEPENDENT FASHION.

Dendritic cell (DC) vaccine efficacy is limited by suboptimal migration to vaccine site-draining lymph nodes (VDLNs). In mice, vaccine site conditioning with inflammatory cytokines or mature DCs increases DC trafficking and the induction of antigen-specific T cells. We assessed the impact of DC migration to VDLNs on clinical outcomes in patients with newly-diagnosed glioblastoma (GBM) by randomizing patients to one of two vaccine site conditioning strategies.

Authors
Sampson, J; Mitchell, DA; Batich, KA; Snyder, D; Xie, W; Reap, E; Cui, X; Sanchez-Perez, L; Archer, GE; Nair, SK; Gunn, MD
MLA Citation
Sampson, J, Mitchell, DA, Batich, KA, Snyder, D, Xie, W, Reap, E, Cui, X, Sanchez-Perez, L, Archer, GE, Nair, SK, and Gunn, MD. "RANDOMIZATION OF PATIENTS WITH GLIOBLASTOMA TO VACCINE SITE PRE-CONDITIONING WITH TETANUS-DIPHTHERIA TOXOID SYSTEMICALLY ENHANCES MIGRATION AND THERAPEUTIC EFFECT OF CYTOMEGALOVIRUS PP65-PULSED DENDRITIC CELL VACCINE IN A MIP-1α-DEPENDENT FASHION." England. July 2014.
PMID
25165316
Source
pubmed
Published In
Neuro-Oncology
Volume
16 Suppl 3
Publish Date
2014
Start Page
iii39
End Page
iii40
DOI
10.1093/neuonc/nou208.63

EGFRvIII mCAR-modified T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss

Purpose: Chimeric antigen receptor (CAR) transduced T cells represent a promising immune therapy that has been shown to successfully treat cancers in mice and humans. However, CARs targeting antigens expressed in both tumors and normal tissues have led to significant toxicity. Preclinical studies have been limited by the use of xenograft models that do not adequately recapitulate the immune system of a clinically relevant host. A constitutively activated mutant of the naturally occurring epidermal growth factor receptor (EGFRvIII) is antigenically identical in both human and mouse glioma, but is also completely absent from any normal tissues. Experimental Design: We developed a third-generation, EGFRvIII-specific murine CAR (mCAR), and performed tests to determine its efficacy in a fully immunocompetent mouse model of malignant glioma. Results: At elevated doses, infusion with EGFRvIIImCART cells led to cures in all mice with brain tumors. In addition, antitumor efficacy was found to be dependent on lymphodepletive host conditioning. Selective blockade with EGFRvIII soluble peptide significantly abrogated the activity of EGFRvIII mCAR T cells in vitro and in vivo, and may offer a novel strategy to enhance the safety profile for CAR-based therapy. Finally, mCAR-treated, cured mice were resistant to rechallenge with EGFRvIIINEG tumors, suggesting generation of host immunity against additional tumor antigens. Conclusion: All together, these data support that third-generation, EGFRvIII-specific mCARs are effective against gliomas in the brain and highlight the importance of syngeneic, immunocompetent models in the preclinical evaluation of tumor immunotherapies. © 2014 American Association for Cancer Research.

Authors
Sampson, JH; Choi, BD; Sanchez-Perez, L; Suryadevara, CM; Snyder, DJ; Flores, CT; Schmittling, RJ; Nair, SK; Reap, EA; Norberg, PK; Herndon, JE; Kuan, CT; Morgan, RA; Rosenberg, SA; Johnson, LA
MLA Citation
Sampson, JH, Choi, BD, Sanchez-Perez, L, Suryadevara, CM, Snyder, DJ, Flores, CT, Schmittling, RJ, Nair, SK, Reap, EA, Norberg, PK, Herndon, JE, Kuan, CT, Morgan, RA, Rosenberg, SA, and Johnson, LA. "EGFRvIII mCAR-modified T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss." Clinical Cancer Research 20.4 (February 26, 2014): 972-984.
Source
scopus
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
20
Issue
4
Publish Date
2014
Start Page
972
End Page
984
DOI
10.1158/1078-0432.CCR-13-0709

EGFRvIII mCAR-modified T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss.

PURPOSE: Chimeric antigen receptor (CAR) transduced T cells represent a promising immune therapy that has been shown to successfully treat cancers in mice and humans. However, CARs targeting antigens expressed in both tumors and normal tissues have led to significant toxicity. Preclinical studies have been limited by the use of xenograft models that do not adequately recapitulate the immune system of a clinically relevant host. A constitutively activated mutant of the naturally occurring epidermal growth factor receptor (EGFRvIII) is antigenically identical in both human and mouse glioma, but is also completely absent from any normal tissues. EXPERIMENTAL DESIGN: We developed a third-generation, EGFRvIII-specific murine CAR (mCAR), and performed tests to determine its efficacy in a fully immunocompetent mouse model of malignant glioma. RESULTS: At elevated doses, infusion with EGFRvIII mCAR T cells led to cures in all mice with brain tumors. In addition, antitumor efficacy was found to be dependent on lymphodepletive host conditioning. Selective blockade with EGFRvIII soluble peptide significantly abrogated the activity of EGFRvIII mCAR T cells in vitro and in vivo, and may offer a novel strategy to enhance the safety profile for CAR-based therapy. Finally, mCAR-treated, cured mice were resistant to rechallenge with EGFRvIII(NEG) tumors, suggesting generation of host immunity against additional tumor antigens. CONCLUSION: All together, these data support that third-generation, EGFRvIII-specific mCARs are effective against gliomas in the brain and highlight the importance of syngeneic, immunocompetent models in the preclinical evaluation of tumor immunotherapies.

Authors
Sampson, JH; Choi, BD; Sanchez-Perez, L; Suryadevara, CM; Snyder, DJ; Flores, CT; Schmittling, RJ; Nair, SK; Reap, EA; Norberg, PK; Herndon, JE; Kuan, C-T; Morgan, RA; Rosenberg, SA; Johnson, LA
MLA Citation
Sampson, JH, Choi, BD, Sanchez-Perez, L, Suryadevara, CM, Snyder, DJ, Flores, CT, Schmittling, RJ, Nair, SK, Reap, EA, Norberg, PK, Herndon, JE, Kuan, C-T, Morgan, RA, Rosenberg, SA, and Johnson, LA. "EGFRvIII mCAR-modified T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss." Clin Cancer Res 20.4 (February 15, 2014): 972-984.
PMID
24352643
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
20
Issue
4
Publish Date
2014
Start Page
972
End Page
984
DOI
10.1158/1078-0432.CCR-13-0709

Intracerebral delivery of a third generation EGFRvIII-specific chimeric antigen receptor is efficacious against human glioma

Chimeric antigen receptors (CAR)-transduced T cells hold great promise in the treatment of malignant disease. Here, we demonstrate that intracerebral injection with a human, epidermal growth factor receptor variant III (EGFRvIII)-specific, third generation CAR successfully treats glioma in mice. Importantly, these results endorse clinical translation of this CAR in patients with EGFRvIII-expressing brain tumors. © 2013 Elsevier Ltd. All rights reserved.

Authors
Choi, BD; Suryadevara, CM; Gedeon, PC; Herndon, JE; Sanchez-Perez, L; Bigner, DD; Sampson, JH
MLA Citation
Choi, BD, Suryadevara, CM, Gedeon, PC, Herndon, JE, Sanchez-Perez, L, Bigner, DD, and Sampson, JH. "Intracerebral delivery of a third generation EGFRvIII-specific chimeric antigen receptor is efficacious against human glioma." Journal of Clinical Neuroscience 21.1 (January 1, 2014): 189-190.
Source
scopus
Published In
Journal of Clinical Neuroscience
Volume
21
Issue
1
Publish Date
2014
Start Page
189
End Page
190
DOI
10.1016/j.jocn.2013.03.012

EGFRvIII-specific chimeric antigen receptor T cells migrate to and kill tumor deposits infiltrating the brain parenchyma in an invasive xenograft model of glioblastoma.

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and is uniformly lethal. T-cell-based immunotherapy offers a promising platform for treatment given its potential to specifically target tumor tissue while sparing the normal brain. However, the diffuse and infiltrative nature of these tumors in the brain parenchyma may pose an exceptional hurdle to successful immunotherapy in patients. Areas of invasive tumor are thought to reside behind an intact blood brain barrier, isolating them from effective immunosurveillance and thereby predisposing the development of "immunologically silent" tumor peninsulas. Therefore, it remains unclear if adoptively transferred T cells can migrate to and mediate regression in areas of invasive GBM. One barrier has been the lack of a preclinical mouse model that accurately recapitulates the growth patterns of human GBM in vivo. Here, we demonstrate that D-270 MG xenografts exhibit the classical features of GBM and produce the diffuse and invasive tumors seen in patients. Using this model, we designed experiments to assess whether T cells expressing third-generation chimeric antigen receptors (CARs) targeting the tumor-specific mutation of the epidermal growth factor receptor, EGFRvIII, would localize to and treat invasive intracerebral GBM. EGFRvIII-targeted CAR (EGFRvIII+ CAR) T cells demonstrated in vitro EGFRvIII antigen-specific recognition and reactivity to the D-270 MG cell line, which naturally expresses EGFRvIII. Moreover, when administered systemically, EGFRvIII+ CAR T cells localized to areas of invasive tumor, suppressed tumor growth, and enhanced survival of mice with established intracranial D-270 MG tumors. Together, these data demonstrate that systemically administered T cells are capable of migrating to the invasive edges of GBM to mediate antitumor efficacy and tumor regression.

Authors
Miao, H; Choi, BD; Suryadevara, CM; Sanchez-Perez, L; Yang, S; De Leon, G; Sayour, EJ; McLendon, R; Herndon, JE; Healy, P; Archer, GE; Bigner, DD; Johnson, LA; Sampson, JH
MLA Citation
Miao, H, Choi, BD, Suryadevara, CM, Sanchez-Perez, L, Yang, S, De Leon, G, Sayour, EJ, McLendon, R, Herndon, JE, Healy, P, Archer, GE, Bigner, DD, Johnson, LA, and Sampson, JH. "EGFRvIII-specific chimeric antigen receptor T cells migrate to and kill tumor deposits infiltrating the brain parenchyma in an invasive xenograft model of glioblastoma." PloS one 9.4 (January 2014): e94281-.
PMID
24722266
Source
epmc
Published In
PloS one
Volume
9
Issue
4
Publish Date
2014
Start Page
e94281
DOI
10.1371/journal.pone.0094281

Leveraging chemotherapy-induced lymphopenia to potentiate cancer immunotherapy.

First-line chemotherapy to combat primary malignant brain cancer is often accompanied by lymphopenic immunologic deficiency. Although counterintuitive, chemotherapy-induced lymphopenia can provide excellent host conditioning that may actually be leveraged to potentiate antitumor immunotherapy. We discuss here our preclinical and clinical experiences applying immunotherapy against glioblastoma, the most common and lethal primary malignant brain tumor, as well as the use of immunotherapeutics in the setting of standard-of-care temozolomide chemotherapy.

Authors
Sanchez-Perez, L; Suryadevara, CM; Choi, BD; Reap, EA; Sampson, JH
MLA Citation
Sanchez-Perez, L, Suryadevara, CM, Choi, BD, Reap, EA, and Sampson, JH. "Leveraging chemotherapy-induced lymphopenia to potentiate cancer immunotherapy." Oncoimmunology 3.7 (January 2014): e944054-.
PMID
25610727
Source
epmc
Published In
OncoImmunology
Volume
3
Issue
7
Publish Date
2014
Start Page
e944054
DOI
10.4161/21624011.2014.944054

Chimeric antigen receptor engineered T cells can eliminate brain tumors and initiate long-term protection against recurrence.

CAR therapy has shown promise in treating cancer, but at the cost of unexpected toxicity against normal tissues, not predicted by preclinical testing. We are working to generate more physiologically relevant models for preclinical CAR toxicity testing, and in doing so, have discovered that CAR therapy induces immunogenic cell death, with the potential for cures.

Authors
Johnson, LA; Sanchez-Perez, L; Suryadevara, CM; Sampson, JH
MLA Citation
Johnson, LA, Sanchez-Perez, L, Suryadevara, CM, and Sampson, JH. "Chimeric antigen receptor engineered T cells can eliminate brain tumors and initiate long-term protection against recurrence." Oncoimmunology 3.7 (January 2014): e944059-.
PMID
25610729
Source
epmc
Published In
OncoImmunology
Volume
3
Issue
7
Publish Date
2014
Start Page
e944059
DOI
10.4161/21624011.2014.944059

Intracerebral delivery of a third generation EGFRvIII-specific chimeric antigen receptor is efficacious against human glioma.

Chimeric antigen receptors (CAR)-transduced T cells hold great promise in the treatment of malignant disease. Here, we demonstrate that intracerebral injection with a human, epidermal growth factor receptor variant III (EGFRvIII)-specific, third generation CAR successfully treats glioma in mice. Importantly, these results endorse clinical translation of this CAR in patients with EGFRvIII-expressing brain tumors.

Authors
Choi, BD; Suryadevara, CM; Gedeon, PC; Herndon, JE; Sanchez-Perez, L; Bigner, DD; Sampson, JH
MLA Citation
Choi, BD, Suryadevara, CM, Gedeon, PC, Herndon, JE, Sanchez-Perez, L, Bigner, DD, and Sampson, JH. "Intracerebral delivery of a third generation EGFRvIII-specific chimeric antigen receptor is efficacious against human glioma." J Clin Neurosci 21.1 (January 2014): 189-190.
PMID
24054399
Source
pubmed
Published In
Journal of Clinical Neuroscience
Volume
21
Issue
1
Publish Date
2014
Start Page
189
End Page
190
DOI
10.1016/j.jocn.2013.03.012

Regulatory T cells are redirected to kill glioblastoma by an EGFRviii-targeted bispecific antibody

Regulatory T cells (Tregs) play a central role in in tumor escape from immunosurveillance. We report that a bispecific T-cell engager (BiTE) targeting a mutated form of the epidermal growth factor receptor, i.e., EGFRvIII, potently redirects Tregs to kill glioblastoma through the granzyme-perforin pathway. © 2013 Landes Bioscience.

Authors
Choi, BD; Gedeon, PC; Sanchez-Perez, L; Bigner, DD; Sampson, JH
MLA Citation
Choi, BD, Gedeon, PC, Sanchez-Perez, L, Bigner, DD, and Sampson, JH. "Regulatory T cells are redirected to kill glioblastoma by an EGFRviii-targeted bispecific antibody." OncoImmunology 2.12 (December 1, 2013): 1-2.
Source
scopus
Published In
OncoImmunology
Volume
2
Issue
12
Publish Date
2013
Start Page
1
End Page
2
DOI
10.4161/onci.26757

Regulatory T cells are redirected to kill glioblastoma by an EGFRvIII-targeted bispecific antibody.

Regulatory T cells (Tregs) play a central role in in tumor escape from immunosurveillance. We report that a bispecific T-cell engager (BiTE) targeting a mutated form of the epidermal growth factor receptor, i.e., EGFRvIII, potently redirects Tregs to kill glioblastoma through the granzyme-perforin pathway.

Authors
Choi, BD; Gedeon, PC; Sanchez-Perez, L; Bigner, DD; Sampson, JH
MLA Citation
Choi, BD, Gedeon, PC, Sanchez-Perez, L, Bigner, DD, and Sampson, JH. "Regulatory T cells are redirected to kill glioblastoma by an EGFRvIII-targeted bispecific antibody." Oncoimmunology 2.12 (December 2013): e26757-.
PMID
24475376
Source
epmc
Published In
OncoImmunology
Volume
2
Issue
12
Publish Date
2013
Start Page
e26757
DOI
10.4161/onci.26757

TARGETING IDH1 MUTATIONS USING PEPTIDE VACCINES IN BRAIN TUMORS

Authors
Reap, E; Archer, G; Sanchez-Perez, L; Norberg, P; Schmittling, R; Nair, S; Cui, X; Snyder, D; Chandramohan, V; Choi, B; Kuan, C-T; Mitchell, D; Bigner, D; Yan, H; Sampson, J
MLA Citation
Reap, E, Archer, G, Sanchez-Perez, L, Norberg, P, Schmittling, R, Nair, S, Cui, X, Snyder, D, Chandramohan, V, Choi, B, Kuan, C-T, Mitchell, D, Bigner, D, Yan, H, and Sampson, J. "TARGETING IDH1 MUTATIONS USING PEPTIDE VACCINES IN BRAIN TUMORS." November 2013.
Source
wos-lite
Published In
Neuro-Oncology
Volume
15
Publish Date
2013
Start Page
71
End Page
71

A BISPECIFIC ANTIBODY REDIRECTS REGULATORY T CELLS TO KILL TUMOR CELLS THROUGH GRANZYME-DEPENDENT CYTOTOXICITY

Authors
Choi, B; Gedeon, PC; Herndon, J; Sanchez-Perez, L; Mitchell, D; Bigner, D; Sampson, J
MLA Citation
Choi, B, Gedeon, PC, Herndon, J, Sanchez-Perez, L, Mitchell, D, Bigner, D, and Sampson, J. "A BISPECIFIC ANTIBODY REDIRECTS REGULATORY T CELLS TO KILL TUMOR CELLS THROUGH GRANZYME-DEPENDENT CYTOTOXICITY." November 2013.
Source
wos-lite
Published In
Neuro-Oncology
Volume
15
Publish Date
2013
Start Page
68
End Page
69

Rational design and generation of recombinant control reagents for bispecific antibodies through CDR mutagenesis.

Developments in the field of bispecific antibodies have progressed rapidly in recent years, particularly in their potential role for the treatment of malignant disease. However, manufacturing stable molecules has proven to be costly and time-consuming, which in turn has hampered certain aspects of preclinical evaluation including the unavailability of appropriate "negative" controls. Bispecific molecules (e.g., bispecific tandem scFv) exhibit two specificities, often against a tumor antigen as well as an immune-activation ligand such as CD3. While for IgG antibodies, isotype-matched controls are well accepted, when considering smaller antibody fragments it is not possible to adequately control for their biological activity through the use of archetypal isotypes, which differ dramatically in affinity, size, structure, and design. Here, we demonstrate a method for the rapid production of negative control tandem scFvs through complementarity determining region (CDR) mutagenesis, using a recently described bispecific T-cell engager (BiTE) targeting a tumor-specific mutation of the epidermal growth factor receptor (EGFRvIII) as an example. Four independent control constructs were developed by this method through alteration of residues spanning individual CDR domains. Importantly, while target antigen affinity was completely impaired, CD3 binding affinity was conserved in each molecule. These results have a potential to enhance the sophistication by which bispecific antibodies can be evaluated in the preclinical setting and may have broader applications for an array of alternative antibody-derived therapeutic platforms.

Authors
Choi, BD; Gedeon, PC; Kuan, C-T; Sanchez-Perez, L; Archer, GE; Bigner, DD; Sampson, JH
MLA Citation
Choi, BD, Gedeon, PC, Kuan, C-T, Sanchez-Perez, L, Archer, GE, Bigner, DD, and Sampson, JH. "Rational design and generation of recombinant control reagents for bispecific antibodies through CDR mutagenesis." J Immunol Methods 395.1-2 (September 30, 2013): 14-20.
PMID
23806556
Source
pubmed
Published In
Journal of Immunological Methods
Volume
395
Issue
1-2
Publish Date
2013
Start Page
14
End Page
20
DOI
10.1016/j.jim.2013.06.003

Human regulatory T cells kill tumor cells through granzyme-dependent cytotoxicity upon retargeting with a bispecific antibody.

A major mechanism by which human regulatory T cells (T(regs)) have been shown to suppress and kill autologous immune cells is through the granzyme-perforin pathway. However, it is unknown whether T(regs) also possess the capacity to kill tumor cells using similar mechanisms. Bispecific antibodies (bscAbs) have emerged as a promising class of therapeutics that activate T cells against tumor antigens without the need for classical MHC-restricted TCR recognition. Here, we show that a bscAb targeting the tumor-specific mutation of the epidermal growth factor receptor, EGFRvIII, redirects human CD4(+)CD25(+)FoxP3(+) T(regs) to kill glioblastoma (GBM) cells. This activity was significantly abrogated by inhibitors of the granzyme-perforin pathway. Notably, analyses of human primary GBM also displayed diffuse infiltration of granzyme-expressing FoxP3(+) T cells. Together, these data suggest that despite their known suppressive functions, tumor-infiltrating T(regs) possess potent cytotoxic mechanisms that can be co-opted for efficient tumor cell lysis.

Authors
Choi, BD; Gedeon, PC; Herndon, JE; Archer, GE; Reap, EA; Sanchez-Perez, L; Mitchell, DA; Bigner, DD; Sampson, JH
MLA Citation
Choi, BD, Gedeon, PC, Herndon, JE, Archer, GE, Reap, EA, Sanchez-Perez, L, Mitchell, DA, Bigner, DD, and Sampson, JH. "Human regulatory T cells kill tumor cells through granzyme-dependent cytotoxicity upon retargeting with a bispecific antibody." Cancer immunology research 1.3 (September 2013): 163-.
PMID
24570975
Source
epmc
Published In
Cancer Immunology Research
Volume
1
Issue
3
Publish Date
2013
Start Page
163
DOI
10.1158/2326-6066.cir-13-0049

ENGINEERING RNA NANOPARTICLE VACCINES TO TARGET MALIGNANT PEDIATRIC BRAIN TUMORS

Authors
Sayour, E; Sanchez-Perez, L; Pham, C; Snyder, D; Flores, C; Kemeny, H; Xie, W; Cui, X; Bigner, D; Sampson, J; Mitchell, D
MLA Citation
Sayour, E, Sanchez-Perez, L, Pham, C, Snyder, D, Flores, C, Kemeny, H, Xie, W, Cui, X, Bigner, D, Sampson, J, and Mitchell, D. "ENGINEERING RNA NANOPARTICLE VACCINES TO TARGET MALIGNANT PEDIATRIC BRAIN TUMORS." PEDIATRIC BLOOD & CANCER 60 (June 2013): S4-S4.
Source
wos-lite
Published In
Pediatric Blood & Cancer
Volume
60
Publish Date
2013
Start Page
S4
End Page
S4

BLyS levels correlate with vaccine-induced antibody titers in patients with glioblastoma lymphodepleted by therapeutic temozolomide.

B lymphocyte stimulator (BLyS) is a cytokine involved in differentiation and survival of follicular B cells along with humoral response potentiation. Lymphopenia is known to precipitate dramatic elevation in serum BLyS; however, the use of this effect to enhance humoral responses following vaccination has not been evaluated. We evaluated BLyS serum levels and antigen-specific antibody titers in 8 patients undergoing therapeutic temozolomide (TMZ)-induced lymphopenia, with concomitant vaccine against a tumor-specific mutation in the epidermal growth factor receptor (EGFRvIII). Our studies demonstrate that TMZ-induced lymphopenia corresponded with spikes in serum BLyS that directly preceded the induction of anti-EGFRvIII antigen-specific antibody titers, in some cases as high as 1:2,000,000. Our data are the first clinical observation of BLyS serum elevation and greatly enhanced humoral immune responses as a consequence of chemotherapy-induced lymphopenia. These observations should be considered for the development of future vaccination strategies in the setting of malignancy.

Authors
Sanchez-Perez, L; Choi, BD; Reap, EA; Sayour, EJ; Norberg, P; Schmittling, RJ; Archer, GE; Herndon, JE; Mitchell, DA; Heimberger, AB; Bigner, DD; Sampson, JH
MLA Citation
Sanchez-Perez, L, Choi, BD, Reap, EA, Sayour, EJ, Norberg, P, Schmittling, RJ, Archer, GE, Herndon, JE, Mitchell, DA, Heimberger, AB, Bigner, DD, and Sampson, JH. "BLyS levels correlate with vaccine-induced antibody titers in patients with glioblastoma lymphodepleted by therapeutic temozolomide." Cancer Immunol Immunother 62.6 (June 2013): 983-987.
PMID
23591978
Source
pubmed
Published In
Cancer Immunology, Immunotherapy
Volume
62
Issue
6
Publish Date
2013
Start Page
983
End Page
987
DOI
10.1007/s00262-013-1405-y

Characterization of a human CD27 agonistic monoclonal antibody for use as an agent in glioblastoma therapy

Authors
Riccione, K; Sanchez-Perez, L; Flores, C; Sampson, J
MLA Citation
Riccione, K, Sanchez-Perez, L, Flores, C, and Sampson, J. "Characterization of a human CD27 agonistic monoclonal antibody for use as an agent in glioblastoma therapy." May 1, 2013.
Source
wos-lite
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
190
Publish Date
2013

RNA NANOPARTICLE VACCINES RE-DIRECT HOST-IMMUNITY AGAINST INTRACRANIAL MALIGNANCIES

Authors
Sayour, E; Pham, C; Sanchez-Perez, L; Snyder, D; Flores, C; Kemeny, H; Xie, W; Cui, X; Bigner, D; Sampson, J; Mitchell, D
MLA Citation
Sayour, E, Pham, C, Sanchez-Perez, L, Snyder, D, Flores, C, Kemeny, H, Xie, W, Cui, X, Bigner, D, Sampson, J, and Mitchell, D. "RNA NANOPARTICLE VACCINES RE-DIRECT HOST-IMMUNITY AGAINST INTRACRANIAL MALIGNANCIES." April 2013.
Source
wos-lite
Published In
Neuro-Oncology
Volume
15
Publish Date
2013
Start Page
36
End Page
36

NOVEL ROLE FOR ENHANCING IMMUNOTHERAPY AGAINST PEDIATRIC BRAIN TUMORS USING HEMATOPOIETIC STEM CELLS

Authors
Flores, C; Pham, C; Snyder, D; Sanchez-Perez, L; Bigner, D; Sampson, J; Mitchell, D
MLA Citation
Flores, C, Pham, C, Snyder, D, Sanchez-Perez, L, Bigner, D, Sampson, J, and Mitchell, D. "NOVEL ROLE FOR ENHANCING IMMUNOTHERAPY AGAINST PEDIATRIC BRAIN TUMORS USING HEMATOPOIETIC STEM CELLS." April 2013.
Source
wos-lite
Published In
Neuro-Oncology
Volume
15
Publish Date
2013
Start Page
42
End Page
42

Systemic administration of a bispecific antibody targeting EGFRvIII successfully treats intracerebral glioma.

Bispecific antibodies (bscAbs), particularly those of the bispecific T-cell engager (BiTE) subclass, have been shown to effectively redirect T cells against cancer. Previous efforts to target antigens expressed in both tumors and normal tissues have produced significant toxicity, however. Moreover, like other large molecules, bscAbs may be restricted from entry into the "immunologically privileged" CNS. A tumor-specific mutation of the epidermal growth factor receptor, EGFRvIII, is a constitutively activated tyrosine kinase not found in normal tissues but frequently expressed in glioblastomas and many other neoplasms. Because it is localized solely to tumor tissue, EGFRvIII presents an ideal target for immunotherapy. Here we report the preclinical evaluation of an EGFRvIII-targeted BiTE, bscEGFRvIIIxCD3. Our results show that bscEGFRvIIIxCD3 activates T cells to mediate potent and antigen-specific lysis of EGFRvIII-expressing gliomas in vitro (P < 0.001) at exceedingly low concentrations (10 ng/mL) and effector-to-target ratios (2.5:1). Treatment with i.v. bscEGFRvIIIxCD3 yielded extended survival in mice with well-established intracerebral tumors (P < 0.05) and achieved durable complete cure at rates up to 75%. Antitumor efficacy was significantly abrogated on blockade of EGFRvIII binding, demonstrating the need for target antigen specificity both in vitro and in vivo. These results demonstrate that BiTEs can be used to elicit functional antitumor immunity in the CNS, and that peptide blockade of BiTE-mediated activity may greatly enhance the safety profile for antibody-redirected T-cell therapies. Finally, bscEGFRvIIIxCD3 represents a unique advancement in BiTE technology given its exquisite tumor specificity, which enables precise elimination of cancer without the risk of autoimmune toxicity.

Authors
Choi, BD; Kuan, C-T; Cai, M; Archer, GE; Mitchell, DA; Gedeon, PC; Sanchez-Perez, L; Pastan, I; Bigner, DD; Sampson, JH
MLA Citation
Choi, BD, Kuan, C-T, Cai, M, Archer, GE, Mitchell, DA, Gedeon, PC, Sanchez-Perez, L, Pastan, I, Bigner, DD, and Sampson, JH. "Systemic administration of a bispecific antibody targeting EGFRvIII successfully treats intracerebral glioma." Proc Natl Acad Sci U S A 110.1 (January 2, 2013): 270-275.
PMID
23248284
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
110
Issue
1
Publish Date
2013
Start Page
270
End Page
275
DOI
10.1073/pnas.1219817110

Myeloablative temozolomide enhances CD8⁺ T-cell responses to vaccine and is required for efficacy against brain tumors in mice.

Temozolomide (TMZ) is an alkylating agent shown to prolong survival in patients with high grade glioma and is routinely used to treat melanoma brain metastases. A prominent side effect of TMZ is induction of profound lymphopenia, which some suggest may be incompatible with immunotherapy. Conversely, it has been proposed that recovery from chemotherapy-induced lymphopenia may actually be exploited to potentiate T-cell responses. Here, we report the first demonstration of TMZ as an immune host-conditioning regimen in an experimental model of brain tumor and examine its impact on antitumor efficacy of a well-characterized peptide vaccine. Our results show that high-dose, myeloablative (MA) TMZ resulted in markedly reduced CD4(+), CD8(+) T-cell and CD4(+)Foxp3(+) TReg counts. Adoptive transfer of naïve CD8(+) T cells and vaccination in this setting led to an approximately 70-fold expansion of antigen-specific CD8(+) T cells over controls. Ex vivo analysis of effector functions revealed significantly enhanced levels of pro-inflammatory cytokine secretion from mice receiving MA TMZ when compared to those treated with a lower lymphodepletive, non-myeloablative (NMA) dose. Importantly, MA TMZ, but not NMA TMZ was uniquely associated with an elevation of endogenous IL-2 serum levels, which we also show was required for optimal T-cell expansion. Accordingly, in a murine model of established intracerebral tumor, vaccination-induced immunity in the setting of MA TMZ-but not lymphodepletive, NMA TMZ-led to significantly prolonged survival. Overall, these results may be used to leverage the side-effects of a clinically-approved chemotherapy and should be considered in future study design of immune-based treatments for brain tumors.

Authors
Sanchez-Perez, LA; Choi, BD; Archer, GE; Cui, X; Flores, C; Johnson, LA; Schmittling, RJ; Snyder, D; Herndon, JE; Bigner, DD; Mitchell, DA; Sampson, JH
MLA Citation
Sanchez-Perez, LA, Choi, BD, Archer, GE, Cui, X, Flores, C, Johnson, LA, Schmittling, RJ, Snyder, D, Herndon, JE, Bigner, DD, Mitchell, DA, and Sampson, JH. "Myeloablative temozolomide enhances CD8⁺ T-cell responses to vaccine and is required for efficacy against brain tumors in mice." PLoS One 8.3 (2013): e59082-.
PMID
23527092
Source
pubmed
Published In
PloS one
Volume
8
Issue
3
Publish Date
2013
Start Page
e59082
DOI
10.1371/journal.pone.0059082

BLyS levels correlate with vaccine-induced antibody titers in patients with glioblastoma lymphodepleted by therapeutic temozolomide

B lymphocyte stimulator (BLyS) is a cytokine involved in differentiation and survival of follicular B cells along with humoral response potentiation. Lymphopenia is known to precipitate dramatic elevation in serum BLyS; however, the use of this effect to enhance humoral responses following vaccination has not been evaluated. We evaluated BLyS serum levels and antigen-specific antibody titers in 8 patients undergoing therapeutic temozolomide (TMZ)-induced lymphopenia, with concomitant vaccine against a tumor-specific mutation in the epidermal growth factor receptor (EGFRvIII). Our studies demonstrate that TMZ-induced lymphopenia corresponded with spikes in serum BLyS that directly preceded the induction of anti-EGFRvIII antigen-specific antibody titers, in some cases as high as 1:2,000,000. Our data are the first clinical observation of BLyS serum elevation and greatly enhanced humoral immune responses as a consequence of chemotherapy-induced lymphopenia. These observations should be considered for the development of future vaccination strategies in the setting of malignancy. © 2013 Springer-Verlag Berlin Heidelberg.

Authors
Sanchez-Perez, L; Choi, BD; Reap, EA; Sayour, EJ; Norberg, P; Schmittling, RJ; Archer, GE; II, JEH; Mitchell, DA; Heimberger, AB; Bigner, DD; Sampson, JH
MLA Citation
Sanchez-Perez, L, Choi, BD, Reap, EA, Sayour, EJ, Norberg, P, Schmittling, RJ, Archer, GE, II, JEH, Mitchell, DA, Heimberger, AB, Bigner, DD, and Sampson, JH. "BLyS levels correlate with vaccine-induced antibody titers in patients with glioblastoma lymphodepleted by therapeutic temozolomide." Cancer Immunology, Immunotherapy 62.6 (2013): 983-987.
Source
scival
Published In
Cancer Immunology, Immunotherapy
Volume
62
Issue
6
Publish Date
2013
Start Page
983
End Page
987
DOI
10.1007/s00262-013-1405-y

Rational design and generation of recombinant control reagents for bispecific antibodies through CDR mutagenesis

Developments in the field of bispecific antibodies have progressed rapidly in recent years, particularly in their potential role for the treatment of malignant disease. However, manufacturing stable molecules has proven to be costly and time-consuming, which in turn has hampered certain aspects of preclinical evaluation including the unavailability of appropriate "negative" controls. Bispecific molecules (e.g., bispecific tandem scFv) exhibit two specificities, often against a tumor antigen as well as an immune-activation ligand such as CD3. While for IgG antibodies, isotype-matched controls are well accepted, when considering smaller antibody fragments it is not possible to adequately control for their biological activity through the use of archetypal isotypes, which differ dramatically in affinity, size, structure, and design. Here, we demonstrate a method for the rapid production of negative control tandem scFvs through complementarity determining region (CDR) mutagenesis, using a recently described bispecific T-cell engager (BiTE) targeting a tumor-specific mutation of the epidermal growth factor receptor (EGFRvIII) as an example. Four independent control constructs were developed by this method through alteration of residues spanning individual CDR domains. Importantly, while target antigen affinity was completely impaired, CD3 binding affinity was conserved in each molecule. These results have a potential to enhance the sophistication by which bispecific antibodies can be evaluated in the preclinical setting and may have broader applications for an array of alternative antibody-derived therapeutic platforms. © 2013 Elsevier B.V.

Authors
Choi, BD; Gedeon, PC; Kuan, CT; Sanchez-Perez, L; Archer, GE; Bigner, DD; Sampson, JH
MLA Citation
Choi, BD, Gedeon, PC, Kuan, CT, Sanchez-Perez, L, Archer, GE, Bigner, DD, and Sampson, JH. "Rational design and generation of recombinant control reagents for bispecific antibodies through CDR mutagenesis." Journal of Immunological Methods 395.1-2 (2013): 14-20.
Source
scival
Published In
Journal of Immunological Methods
Volume
395
Issue
1-2
Publish Date
2013
Start Page
14
End Page
20
DOI
10.1016/j.jim.2013.06.003

Immunotherapy with tumor vaccines for the treatment of malignant gliomas.

With an average life expectancy of 14 months, Glioblastoma multiforme (GBM), is the most aggressive primary brain tumor. Our growing understanding of the immune system and its role in oncogenesis has helped develop cancer vaccines as a promising treatment modality against this disease. What follows is a comprehensive discussion on the history of immunotherapy and the various vaccine based therapies being developed and utilized for the treatment of malignant gliomas.

Authors
Ajay, D; Sanchez-Perez, L; Choi, BD; De Leon, G; Sampson, JH
MLA Citation
Ajay, D, Sanchez-Perez, L, Choi, BD, De Leon, G, and Sampson, JH. "Immunotherapy with tumor vaccines for the treatment of malignant gliomas." Curr Drug Discov Technol 9.4 (December 2012): 237-255. (Review)
PMID
22339070
Source
pubmed
Published In
Current drug discovery technologies
Volume
9
Issue
4
Publish Date
2012
Start Page
237
End Page
255

DEVELOPING RNA NANOPARTICLE VACCINES TARGETING PEDIATRIC AND ADULT BRAIN TUMORS

Authors
Sayour, EJ; Sanchez-Perez, L; Pham, C; Snyder, D; Xie, W; Cui, X; Bigner, DD; Sampson, JH; Mitchell, DA
MLA Citation
Sayour, EJ, Sanchez-Perez, L, Pham, C, Snyder, D, Xie, W, Cui, X, Bigner, DD, Sampson, JH, and Mitchell, DA. "DEVELOPING RNA NANOPARTICLE VACCINES TARGETING PEDIATRIC AND ADULT BRAIN TUMORS." October 2012.
Source
wos-lite
Published In
Neuro-Oncology
Volume
14
Publish Date
2012
Start Page
39
End Page
39

MYELOABLATIVE TEMOZOLOMIDE INCREASES ANTIGEN-SPECIFIC CD8(+) T-CELL VACCINE RESPONSES AND IS REQUIRED FOR EFFICACIOUS IMMUNOTHERAPY AGAINST INTRACEREBRAL TUMORS

Authors
Sanchez-Perez, L; Choi, B; Snyder, D; Cui, X; Schmittling, RJ; Flores, C; Johnson, L; Archer, GA; Bigner, DD; Mitchell, DA; Sampson, JH
MLA Citation
Sanchez-Perez, L, Choi, B, Snyder, D, Cui, X, Schmittling, RJ, Flores, C, Johnson, L, Archer, GA, Bigner, DD, Mitchell, DA, and Sampson, JH. "MYELOABLATIVE TEMOZOLOMIDE INCREASES ANTIGEN-SPECIFIC CD8(+) T-CELL VACCINE RESPONSES AND IS REQUIRED FOR EFFICACIOUS IMMUNOTHERAPY AGAINST INTRACEREBRAL TUMORS." October 2012.
Source
wos-lite
Published In
Neuro-Oncology
Volume
14
Publish Date
2012
Start Page
40
End Page
40

ROLE OF HEMATOPOIETIC STEM CELLS IN ENHANCING THE ANTI-TUMOR EFFICACY OF ADOPTIVE CELLULAR THERAPY

Authors
Flores, CT; Snyder, D; Sanchez-Perez, L; Pham, C; Friedman, H; Bigner, DD; Sampson, JH; Mitchell, DA
MLA Citation
Flores, CT, Snyder, D, Sanchez-Perez, L, Pham, C, Friedman, H, Bigner, DD, Sampson, JH, and Mitchell, DA. "ROLE OF HEMATOPOIETIC STEM CELLS IN ENHANCING THE ANTI-TUMOR EFFICACY OF ADOPTIVE CELLULAR THERAPY." October 2012.
Source
wos-lite
Published In
Neuro-Oncology
Volume
14
Publish Date
2012
Start Page
35
End Page
35

RNA NANOPARTICLE VACCINES TARGETING MEDULLOBLASTOMA

Authors
Sayour, E; Pham, C; Sanchez-Perez, L; Snyder, D; Mitchell, D
MLA Citation
Sayour, E, Pham, C, Sanchez-Perez, L, Snyder, D, and Mitchell, D. "RNA NANOPARTICLE VACCINES TARGETING MEDULLOBLASTOMA." PEDIATRIC BLOOD & CANCER 58.7 (July 2012): 1078-1078.
Source
wos-lite
Published In
Pediatric Blood & Cancer
Volume
58
Issue
7
Publish Date
2012
Start Page
1078
End Page
1078

Th17 cells are long lived and retain a stem cell-like molecular signature.

Th17 cells have been described as short lived, but this view is at odds with their capacity to trigger protracted damage to normal and transformed tissues. We report that Th17 cells, despite displaying low expression of CD27 and other phenotypic markers of terminal differentiation, efficiently eradicated tumors and caused autoimmunity, were long lived, and maintained a core molecular signature resembling early memory CD8(+) cells with stem cell-like properties. In addition, we found that Th17 cells had high expression of Tcf7, a direct target of the Wnt and β-catenin signaling axis, and accumulated β-catenin, a feature observed in stem cells. In vivo, Th17 cells gave rise to Th1-like effector cell progeny and also self-renewed and persisted as IL-17A-secreting cells. Multipotency was required for Th17 cell-mediated tumor eradication because effector cells deficient in IFN-γ or IL-17A had impaired activity. Thus, Th17 cells are not always short lived and are a less-differentiated subset capable of superior persistence and functionality.

Authors
Muranski, P; Borman, ZA; Kerkar, SP; Klebanoff, CA; Ji, Y; Sanchez-Perez, L; Sukumar, M; Reger, RN; Yu, Z; Kern, SJ; Roychoudhuri, R; Ferreyra, GA; Shen, W; Durum, SK; Feigenbaum, L; Palmer, DC; Antony, PA; Chan, C-C; Laurence, A; Danner, RL; Gattinoni, L; Restifo, NP
MLA Citation
Muranski, P, Borman, ZA, Kerkar, SP, Klebanoff, CA, Ji, Y, Sanchez-Perez, L, Sukumar, M, Reger, RN, Yu, Z, Kern, SJ, Roychoudhuri, R, Ferreyra, GA, Shen, W, Durum, SK, Feigenbaum, L, Palmer, DC, Antony, PA, Chan, C-C, Laurence, A, Danner, RL, Gattinoni, L, and Restifo, NP. "Th17 cells are long lived and retain a stem cell-like molecular signature." Immunity 35.6 (December 15, 2011): 972-985.
PMID
22177921
Source
epmc
Published In
Immunity
Volume
35
Issue
6
Publish Date
2011
Start Page
972
End Page
985
DOI
10.1016/j.immuni.2011.09.019

Monoclonal antibody blockade of IL-2 receptor α during lymphopenia selectively depletes regulatory T cells in mice and humans.

Lymphodepletion augments adoptive cell transfer during antitumor immunotherapy, producing dramatic clinical responses in patients with malignant melanoma. We report that the lymphopenia induced by the chemotherapeutic agent temozolomide (TMZ) enhances vaccine-driven immune responses and significantly reduces malignant growth in an established model of murine tumorigenesis. Unexpectedly, despite the improved antitumor efficacy engendered by TMZ-induced lymphopenia, there was a treatment related increase in the frequency of immunosuppressive regulatory T cells (T(Regs); P = .0006). Monoclonal antibody (mAb)-mediated inhibition of the high-affinity IL-2 receptor α (IL-2Rα/CD25) during immunotherapy in normal mice depleted T(Regs) (73% reduction; P = .0154) but also abolished vaccine-induced immune responses. However, during lymphodepletion, IL-2Rα blockade decreased T(Regs) (93% reduction; P = .0001) without impairing effector T-cell responses, to augment therapeutic antitumor efficacy (66% reduction in tumor growth; P = .0024). Of clinical relevance, we also demonstrate that anti-IL-2Rα mAb administration during recovery from lymphodepletive TMZ in patients with glioblastoma reduced T(Reg) frequency (48% reduction; P = .0061) while permitting vaccine-stimulated antitumor effector cell expansion. To our knowledge, this is the first report of systemic antibody-mediated T(Reg) depletion during lymphopenia and the consequent synergistic enhancement of vaccine-driven cellular responses, as well as the first demonstration that anti-IL-2Rα mAbs function differentially in nonlymphopenic versus lymphopenic contexts.

Authors
Mitchell, DA; Cui, X; Schmittling, RJ; Sanchez-Perez, L; Snyder, DJ; Congdon, KL; Archer, GE; Desjardins, A; Friedman, AH; Friedman, HS; Herndon, JE; McLendon, RE; Reardon, DA; Vredenburgh, JJ; Bigner, DD; Sampson, JH
MLA Citation
Mitchell, DA, Cui, X, Schmittling, RJ, Sanchez-Perez, L, Snyder, DJ, Congdon, KL, Archer, GE, Desjardins, A, Friedman, AH, Friedman, HS, Herndon, JE, McLendon, RE, Reardon, DA, Vredenburgh, JJ, Bigner, DD, and Sampson, JH. "Monoclonal antibody blockade of IL-2 receptor α during lymphopenia selectively depletes regulatory T cells in mice and humans." Blood 118.11 (September 15, 2011): 3003-3012.
PMID
21768296
Source
pubmed
Published In
Blood
Volume
118
Issue
11
Publish Date
2011
Start Page
3003
End Page
3012
DOI
10.1182/blood-2011-02-334565

Genetic engineering of murine CD8+ and CD4+ T cells for preclinical adoptive immunotherapy studies.

T-cell receptor (TCR) gene therapy enables for the rapid creation of antigen-specific T cells from mice of any strain and represents a valuable tool for preclinical immunotherapy studies. Here, we describe the superiority of γ-retroviral vectors compared with lentiviral vectors for transduction of murine T cells and surprisingly illustrate robust gene-transfer into phenotypically naive/memory-stem cell like (TN/TSCM; CD62L(hi)/CD44(low)) and central memory (TCM; CD62L(hi)/CD44(hi)) CD8+ T cells using murine stem cell-based γ-retroviral vectors (MSGV1). We created MSGV1 vectors for a major histocompatibility complex-class I-restricted TCR specific for the melanocyte-differentiation antigen, glycoprotein 100 (MSGV1-pmel-1), and a major histocompatibility complex-class II-restricted TCR specific for tyrosinase-related protein-1 (MSGV1-TRP-1), and found that robust gene expression required codon optimization of TCR sequences for the pmel-1 TCR. To test for functionality, we adoptively transferred TCR-engineered T cells into mice bearing B16 melanomas and observed delayed growth of established tumors with pmel-1 TCR engineered CD8+ T cells and significant tumor regression with TRP-1 TCR transduced CD4 T cells. We simultaneously created lentiviral vectors encoding the pmel-1 TCR, but found that these vectors mediated low TCR expression in murine T cells, but robust gene expression in other murine and human cell lines. These results indicate that preclinical murine models of adoptive immunotherapies are more practical using γ-retroviral rather than lentiviral vectors.

Authors
Kerkar, SP; Sanchez-Perez, L; Yang, S; Borman, ZA; Muranski, P; Ji, Y; Chinnasamy, D; Kaiser, ADM; Hinrichs, CS; Klebanoff, CA; Scott, CD; Gattinoni, L; Morgan, RA; Rosenberg, SA; Restifo, NP
MLA Citation
Kerkar, SP, Sanchez-Perez, L, Yang, S, Borman, ZA, Muranski, P, Ji, Y, Chinnasamy, D, Kaiser, ADM, Hinrichs, CS, Klebanoff, CA, Scott, CD, Gattinoni, L, Morgan, RA, Rosenberg, SA, and Restifo, NP. "Genetic engineering of murine CD8+ and CD4+ T cells for preclinical adoptive immunotherapy studies." J Immunother 34.4 (May 2011): 343-352.
PMID
21499127
Source
pubmed
Published In
Journal of Immunotherapy
Volume
34
Issue
4
Publish Date
2011
Start Page
343
End Page
352
DOI
10.1097/CJI.0b013e3182187600

Effect of orthodontic treatment on saliva, plaque and the levels of Streptococcus mutans and Lactobacillus.

OBJECTIVES: The aim of this study was to identify changes in the oral environment with clinical, salivary and bacterial risk markers after placement of fixed orthodontic appliances on permanent dentition. MATERIAL AND METHODS: With ethical approval, we used different techniques to analyzed clinical, salivary and bacterial risk markers in 34 patients (mean age, 16.7+5.2 years), 14 males and 20 females; before starting orthodontic treatment and 1 month after. Clinical risk markers (decayed, missing, and filled surfaces [DMFS], O'Leary's plaque index, and plaque pH); salivary markers (unstimulated and stimulated saliva flow rate, buffer capacity, pH, and occult blood in saliva) and bacterial counts (Streptococcus mutans and Lactobacillus). Data were analyzed by paired t-test and X2 test. RESULTS: This study showed that orthodontic appliances increased the stimulated salivary flow rate (p=0.0001), buffer capacity (p=0.0359), salivary pH (p=0.0246) and occult blood in saliva (p=0.0305). Bacterial levels increased slightly after 1 month of treatment, without statistical significance. Between genders, initially we observed differences in: stimulated saliva (p=0.0019), buffer capacity (p=0.0381) and plaque pH (p=0.0430); after treatment the unstimulated saliva (p=0.0026) showed differences. CONCLUSIONS: Orthodontic treatment changes the oral environmental factors, promotes an increase in stimulated flow rate, buffer capacity and salivary pH, which augment the anti caries activity of saliva. In contrast, increased occult blood indicated more gingival inflammation, apparently because augmented the retentive plaque surfaces and the difficult to maintain a good oral hygiene, rinsed the bleeding in saliva by periodontal damage.

Authors
Lara-Carrillo, E; Montiel-Bastida, N-M; Sánchez-Pérez, L; Alanís-Tavira, J
MLA Citation
Lara-Carrillo, E, Montiel-Bastida, N-M, Sánchez-Pérez, L, and Alanís-Tavira, J. "Effect of orthodontic treatment on saliva, plaque and the levels of Streptococcus mutans and Lactobacillus." Medicina oral, patologia oral y cirugia bucal 15.6 (November 2010): e924-e929.
PMID
20383105
Source
epmc
Published In
Medicina oral, patologia oral y cirugia bucal
Volume
15
Issue
6
Publish Date
2010
Start Page
e924
End Page
e929

Tumor-specific CD8+ T cells expressing interleukin-12 eradicate established cancers in lymphodepleted hosts.

T-cell-based immunotherapies can be effective in the treatment of large vascularized tumors, but they rely on adoptive transfer of substantial numbers ( approximately 20 million) of tumor-specific T cells administered together with vaccination and high-dose interleukin (IL)-2. In this study, we report that approximately 10,000 T cells gene-engineered to express a single-chain IL-12 molecule can be therapeutically effective against established tumors in the absence of exogenous IL-2 and vaccine. Although IL-12-engineered cells did not perist long-term in hosts, they exhibited enhanced functionality and were detected in higher numbers intratumorally along with increased numbers of endogenous natural killer and CD8(+) T cells just before regression. Importantly, transferred T cells isolated from tumors stably overproduced supraphysiologic amounts of IL-12, and the therapeutic effect of IL-12 produced within the tumor microenvironment could not be mimicked with high doses of exogenously provided IL-12. Furthermore, antitumor effects could be recapitulated by engineering wild-type open-repertoire splenocytes to express both the single-chain IL-12 and a recombinant tumor-specific T-cell receptor (TCR), but only when individual cells expressed both the TCR and IL-12, indicating that arrested migration of T cells at the tumor site was required for their activities. Successful tumor eradication was dependent on a lymphodepleting preconditioning regimen that reduced the number of intratumoral CD4(+) Foxp3(+) T regulatory cells. Our findings reveal an approach to genetically modify T cells to reduce the cell number needed, eliminate the need for vaccines or systemic IL-2, and improve immunotherapy efficacy based on adoptive transfer of gene-engineered T cells.

Authors
Kerkar, SP; Muranski, P; Kaiser, A; Boni, A; Sanchez-Perez, L; Yu, Z; Palmer, DC; Reger, RN; Borman, ZA; Zhang, L; Morgan, RA; Gattinoni, L; Rosenberg, SA; Trinchieri, G; Restifo, NP
MLA Citation
Kerkar, SP, Muranski, P, Kaiser, A, Boni, A, Sanchez-Perez, L, Yu, Z, Palmer, DC, Reger, RN, Borman, ZA, Zhang, L, Morgan, RA, Gattinoni, L, Rosenberg, SA, Trinchieri, G, and Restifo, NP. "Tumor-specific CD8+ T cells expressing interleukin-12 eradicate established cancers in lymphodepleted hosts." Cancer research 70.17 (September 2010): 6725-6734.
PMID
20647327
Source
epmc
Published In
Cancer Research
Volume
70
Issue
17
Publish Date
2010
Start Page
6725
End Page
6734
DOI
10.1158/0008-5472.can-10-0735

A promising approach for treatment of tumor-induced bone diseases: utilizing bisphosphonate derivatives of nucleoside antimetabolites.

Despite palliative treatments, tumor-induced bone disease (TIBD) remains highly debilitating for many cancer patients and progression typically results in death within two years. Therefore, more effective therapies with enhanced anti-resorptive and cytotoxic characteristics are needed. We developed bisphosphonate-chemotherapeutic conjugates designed to bind bone and hydrolyze, releasing both compounds, thereby targeting both osteoclasts and tumor cells. This study examined the effects of our lead compound, MBC-11 (the anhydride formed between arabinocytidine (AraC)-5'-phosphate and etidronate), on bone tumor burden, bone volume, femur bone mineral density (BMD), and overall survival using two distinct mouse models of TIBD, the 4T1/luc breast cancer and the KAS-6/1-MIP1alpha multiple myeloma models. In mice orthotopically inoculated with 4T1/luc mouse mammary cells, MBC-11 (0.04 microg/day; s.c.) reduced the incidence of bone metastases to 40% (4/10), compared to 90% (9/10; p=0.057) and 100% (5/5; p=0.04) of PBS- or similarly-dosed, zoledronate-treated mice, respectively. MBC-11 also significantly decreased bone tumor burden compared to PBS- or zoledronate-treated mice (p=0.021, p=0.017, respectively). MBC-11 and zoledronate (0.04 microg/day) significantly increased bone volume by two- and four-fold, respectively, compared to PBS-treated mice (p=0.005, p<0.001, respectively). In mice systemically injected with human multiple myeloma KAS-6/1-MIP1alpha cells, 0.04 and 4.0 microg/day MBC-11 improved femur BMD by 13% and 16%, respectively, compared to PBS (p=0.025, p=0.017, respectively) at 10 weeks post-tumor cell injection and increased mean survival to 95 days compared to 77 days in mice treated with PBS (p=0.047). Similar doses of zoledronate also improved femur BMD (p< or =0.01 vs PBS) and increased mean survival to 86 days, but this was not significantly different than in PBS-treated mice (p=0.53). These results demonstrate that MBC-11 decreases bone tumor burden, maintains bone structure, and may increase overall survival, warranting further investigation as a treatment for TIBD.

Authors
Reinholz, MM; Zinnen, SP; Dueck, AC; Dingli, D; Reinholz, GG; Jonart, LA; Kitzmann, KA; Bruzek, AK; Negron, V; Abdalla, AK; Arendt, BK; Croatt, AJ; Sanchez-Perez, L; Sebesta, DP; Lönnberg, H; Yoneda, T; Nath, KA; Jelinek, DF; Russell, SJ; Ingle, JN; Spelsberg, TC; Dixon, HBFH; Karpeisky, A; Lingle, WL
MLA Citation
Reinholz, MM, Zinnen, SP, Dueck, AC, Dingli, D, Reinholz, GG, Jonart, LA, Kitzmann, KA, Bruzek, AK, Negron, V, Abdalla, AK, Arendt, BK, Croatt, AJ, Sanchez-Perez, L, Sebesta, DP, Lönnberg, H, Yoneda, T, Nath, KA, Jelinek, DF, Russell, SJ, Ingle, JN, Spelsberg, TC, Dixon, HBFH, Karpeisky, A, and Lingle, WL. "A promising approach for treatment of tumor-induced bone diseases: utilizing bisphosphonate derivatives of nucleoside antimetabolites." Bone 47.1 (July 2010): 12-22.
PMID
20233612
Source
epmc
Published In
BONE
Volume
47
Issue
1
Publish Date
2010
Start Page
12
End Page
22
DOI
10.1016/j.bone.2010.03.006

Phosphotumor antigen-specific CD4 T cells

Authors
Davila, E; Geng, D; Sanchez-Perez, L; Riker, A
MLA Citation
Davila, E, Geng, D, Sanchez-Perez, L, and Riker, A. "Phosphotumor antigen-specific CD4 T cells." Immunotherapy 1.6 (November 1, 2009): 923-.
Source
scopus
Published In
Immunotherapy
Volume
1
Issue
6
Publish Date
2009
Start Page
923
DOI
10.2217/IMT.09.74

PD-1 and impaired antitumor T cell responses in melanoma

Authors
Davila, E; Geng, D; Sanchez-Perez, L; Riker, A
MLA Citation
Davila, E, Geng, D, Sanchez-Perez, L, and Riker, A. "PD-1 and impaired antitumor T cell responses in melanoma." Immunotherapy 1.6 (November 1, 2009): 924-.
Source
scopus
Published In
Immunotherapy
Volume
1
Issue
6
Publish Date
2009
Start Page
924
DOI
10.2217/IMT.09.74

Enhancing melanoma immunotherapy using T-cell clones

Authors
Davila, E; Geng, D; Sanchez-Perez, L; Riker, A
MLA Citation
Davila, E, Geng, D, Sanchez-Perez, L, and Riker, A. "Enhancing melanoma immunotherapy using T-cell clones." Immunotherapy 1.6 (November 1, 2009): 922-.
Source
scopus
Published In
Immunotherapy
Volume
1
Issue
6
Publish Date
2009
Start Page
922
DOI
10.2217/IMT.09.74

Research highlights.

Authors
Davila, E; Geng, D; Sanchez-Perez, L; Riker, A
MLA Citation
Davila, E, Geng, D, Sanchez-Perez, L, and Riker, A. "Research highlights." Immunotherapy 1.6 (November 2009): 921-924.
PMID
20635909
Source
epmc
Published In
Immunotherapy
Volume
1
Issue
6
Publish Date
2009
Start Page
921
End Page
924
DOI
10.2217/imt.09.74

Adoptively transferred effector cells derived from naive rather than central memory CD8+ T cells mediate superior antitumor immunity.

Effector cells derived from central memory CD8(+) T cells were reported to engraft and survive better than those derived from effector memory populations, suggesting that they are superior for use in adoptive immunotherapy studies. However, previous studies did not evaluate the relative efficacy of effector cells derived from naïve T cells. We sought to investigate the efficacy of tumor-specific effector cells derived from naïve or central memory T-cell subsets using transgenic or retrovirally transduced T cells engineered to express a tumor-specific T-cell receptor. We found that naïve, rather than central memory T cells, gave rise to an effector population that mediated superior antitumor immunity upon adoptive transfer. Effector cells developed from naïve T cells lost the expression of CD62L more rapidly than those derived from central memory T cells, but did not acquire the expression of KLRG-1, a marker for terminal differentiation and replicative senescence. Consistent with this KLRG-1(-) phenotype, naïve-derived cells were capable of a greater proliferative burst and had enhanced cytokine production after adoptive transfer. These results indicate that insertion of genes that confer antitumor specificity into naïve rather than central memory CD8(+) T cells may allow superior efficacy upon adoptive transfer.

Authors
Hinrichs, CS; Borman, ZA; Cassard, L; Gattinoni, L; Spolski, R; Yu, Z; Sanchez-Perez, L; Muranski, P; Kern, SJ; Logun, C; Palmer, DC; Ji, Y; Reger, RN; Leonard, WJ; Danner, RL; Rosenberg, SA; Restifo, NP
MLA Citation
Hinrichs, CS, Borman, ZA, Cassard, L, Gattinoni, L, Spolski, R, Yu, Z, Sanchez-Perez, L, Muranski, P, Kern, SJ, Logun, C, Palmer, DC, Ji, Y, Reger, RN, Leonard, WJ, Danner, RL, Rosenberg, SA, and Restifo, NP. "Adoptively transferred effector cells derived from naive rather than central memory CD8+ T cells mediate superior antitumor immunity." Proceedings of the National Academy of Sciences of the United States of America 106.41 (October 2009): 17469-17474.
PMID
19805141
Source
epmc
Published In
Proceedings of the National Academy of Sciences of USA
Volume
106
Issue
41
Publish Date
2009
Start Page
17469
End Page
17474
DOI
10.1073/pnas.0907448106

Antitumor immunity can be uncoupled from autoimmunity following heat shock protein 70-mediated inflammatory killing of normal pancreas.

We have a long-term interest in the connectivity between autoimmunity and tumor rejection. However, outside of the melanocyte/melanoma paradigm, little is known about whether autoimmune responses to normal tissue can induce rejection of tumors of the same histologic type. Here, we induced direct, pathogen-like cytotoxicity to the normal pancreas in association with the immune adjuvant heat shock protein 70. In sharp contrast to our studies with a similar approach for the treatment of prostate cancer, inflammatory killing of the normal pancreas induced a Th1-like, anti-self-response to pancreatic antigens, which was rapidly suppressed by a concomitant suppressive regulatory T cell (Treg) response. Interestingly, even when Treg cells were depleted, the Th1-like response was insufficient to induce significant ongoing autoimmunity. However, the Th1-like response to antigens expressed in the pancreas at the time of damage was sufficient to induce rejection of tumors expressing either a foreign (ova) antigen or fully syngeneic tumor antigens (on Panc02 tumor cells), provided that Treg were depleted before inflammatory killing of the normal pancreas. Taken together, these data indicate that profound differences exist between the immunoprotective mechanisms in place between different tissues (pancreas and prostate) in their response to pathogen-like damage. Moreover, they also show that, although multiple layers of immunologic safeguards are in place to prevent the development of severe autoimmune consequences in the pancreas (in contrast to the prostate), tumor rejection responses can still be decoupled from pathologic autoimmune responses in vivo, which may provide novel insights into the immunotherapeutic treatment of pancreatic cancer.

Authors
Kottke, T; Pulido, J; Thompson, J; Sanchez-Perez, L; Chong, H; Calderwood, SK; Selby, P; Harrington, K; Strome, SE; Melcher, A; Vile, RG
MLA Citation
Kottke, T, Pulido, J, Thompson, J, Sanchez-Perez, L, Chong, H, Calderwood, SK, Selby, P, Harrington, K, Strome, SE, Melcher, A, and Vile, RG. "Antitumor immunity can be uncoupled from autoimmunity following heat shock protein 70-mediated inflammatory killing of normal pancreas." Cancer research 69.19 (October 2009): 7767-7774.
PMID
19738045
Source
epmc
Published In
Cancer Research
Volume
69
Issue
19
Publish Date
2009
Start Page
7767
End Page
7774
DOI
10.1158/0008-5472.can-09-1597

Type 17 CD8+ T cells display enhanced antitumor immunity.

Interleukin-17 (IL-17)-secreting CD8(+) T cells have been described, but they have not been thoroughly studied and they do not have a known role in cancer immunotherapy. We skewed CD8(+) T cells to secrete IL-17 through priming in Th17-polarizing conditions. IL-17-producing CD8(+) T cells demonstrated reduced expression of Eomes and diminished cytolytic differentiation in vitro. However, after adoptive transfer, these cells converted to interferon-gamma-producing effector cells and mediated regression of large, established tumors. This improved antitumor immunity was associated with increased expression of IL-7R-alpha, decreased expression of killer cell lectin-like receptor G1, and enhanced persistence of the transferred cells. This report is the first description of a cancer therapy with IL-17-secreting CD8(+) T cells. These findings have implications for the improvement of CD8(+) T cell-based adoptive immunotherapy.

Authors
Hinrichs, CS; Kaiser, A; Paulos, CM; Cassard, L; Sanchez-Perez, L; Heemskerk, B; Wrzesinski, C; Borman, ZA; Muranski, P; Restifo, NP
MLA Citation
Hinrichs, CS, Kaiser, A, Paulos, CM, Cassard, L, Sanchez-Perez, L, Heemskerk, B, Wrzesinski, C, Borman, ZA, Muranski, P, and Restifo, NP. "Type 17 CD8+ T cells display enhanced antitumor immunity." Blood 114.3 (July 2009): 596-599.
PMID
19471017
Source
epmc
Published In
Blood
Volume
114
Issue
3
Publish Date
2009
Start Page
596
End Page
599
DOI
10.1182/blood-2009-02-203935

Inflammatory Killing of the Pancreas Induces Multiple Immune Checkpoints Which Protect from Autoimmunity but Which Can Be Manipulated To Achieve Anti Tumor Immunity

Authors
Kottke, T; Pulido, J; Thompson, J; Sanchez-Perez, L; Chong, H; Calderwood, SK; Dong, H; Pease, L; Selby, P; Harrington, K; Melcher, A; Vile, RG
MLA Citation
Kottke, T, Pulido, J, Thompson, J, Sanchez-Perez, L, Chong, H, Calderwood, SK, Dong, H, Pease, L, Selby, P, Harrington, K, Melcher, A, and Vile, RG. "Inflammatory Killing of the Pancreas Induces Multiple Immune Checkpoints Which Protect from Autoimmunity but Which Can Be Manipulated To Achieve Anti Tumor Immunity." May 2009.
Source
wos-lite
Published In
Molecular Therapy
Volume
17
Publish Date
2009
Start Page
S154
End Page
S154

Engagement of Toll-like receptor-2 on cytotoxic T-lymphocytes occurs in vivo and augments antitumor activity.

Toll-like receptors (TLRs) are among the fundamental molecules that alert the immune system to the presence of an infection by recognizing pathogen-associated molecules. Much of our understanding regarding TLR function stems from the study of innate immune cells. Recent studies by several groups, including ours, have shown that TLRs can function as costimulatory receptors for antigen-specific T cells, resulting in enhanced T-cell survival and increased expression of effector molecules. We report that the ligation of the TLR1/2 heterodimer on OT-1 cytotoxic T-lymphocytes (CTL) but not TLR2(-/-)OT-1 T cells increased cytolytic activity in vitro and in vivo. On the basis of these data, we tested the hypothesis that TLR1/2 stimulation on CTLs would enhance antitumor activity in a therapeutic model of B16-Ova melanoma. Adoptive OT-1 T-cell transfer into wild-type and MyD88(-/-) mice, followed by injection with TLR1/2 ligand, resulted in a synergistic antitumor effect, which correlated with the induction of CD8 T cells specific to various tumor antigens. In contrast, mice receiving TLR2(-/-)OT-1 T cells and TLR1/2 ligand showed minimal therapeutic efficacy. These findings emphasize the physiological significance of TLR2 engagement on CTLs and could make possible new approaches for the development of effective immunotherapies by manipulating TLR signaling within CTLs.

Authors
Asprodites, N; Zheng, L; Geng, D; Velasco-Gonzalez, C; Sanchez-Perez, L; Davila, E
MLA Citation
Asprodites, N, Zheng, L, Geng, D, Velasco-Gonzalez, C, Sanchez-Perez, L, and Davila, E. "Engagement of Toll-like receptor-2 on cytotoxic T-lymphocytes occurs in vivo and augments antitumor activity." FASEB journal : official publication of the Federation of American Societies for Experimental Biology 22.10 (October 2008): 3628-3637.
PMID
18587008
Source
epmc
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
22
Issue
10
Publish Date
2008
Start Page
3628
End Page
3637
DOI
10.1096/fj.08-108274

Induction of hsp70-mediated Th17 autoimmunity can be exploited as immunotherapy for metastatic prostate cancer.

A close connectivity between autoimmune and tumor rejection responses is known to exist in the case of melanoma immunotherapy. However, relatively little is known about self-antigens on other types of normal cells, their relation to the development of autoimmune disease, and their possible coexistence as potential tumor rejection antigens on associated tumors. In the current study, we induced inflammatory killing of normal prostate tissue in situ using a fusogenic membrane glycoprotein along with the immune adjuvant hsp70. We show here that, in the prostate, hsp70 induces interleukin (IL)-6, which triggers a CD4- and CD8-dependent progressive autoimmune reactivity, associated with IL-17 expression. This autoimmune response was also able to induce the rejection of established prostate tumors, but not other histologic types of tumors, growing elsewhere in the animal. These data show that the intimate connectivity between autoimmune and tumor rejection responses extends beyond the classic melanoma paradigm and may be clinically valuable for the treatment of established metastatic disease of the prostate.

Authors
Kottke, T; Sanchez-Perez, L; Diaz, RM; Thompson, J; Chong, H; Harrington, K; Calderwood, SK; Pulido, J; Georgopoulos, N; Selby, P; Melcher, A; Vile, R
MLA Citation
Kottke, T, Sanchez-Perez, L, Diaz, RM, Thompson, J, Chong, H, Harrington, K, Calderwood, SK, Pulido, J, Georgopoulos, N, Selby, P, Melcher, A, and Vile, R. "Induction of hsp70-mediated Th17 autoimmunity can be exploited as immunotherapy for metastatic prostate cancer." Cancer research 67.24 (December 2007): 11970-11979.
PMID
18089828
Source
epmc
Published In
Cancer Research
Volume
67
Issue
24
Publish Date
2007
Start Page
11970
End Page
11979
DOI
10.1158/0008-5472.can-07-2259

Toll-like receptors in tumor immunotherapy.

Lymphodepletion with chemotherapeutic agents or total body irradiation (TBI) before adoptive transfer of tumor-specific T cells is a critical advancement in the treatment of patients with melanoma. More than 50% of patients that are refractory to other treatments experience an objective or curative response with this approach. Emerging data indicate that the key mechanisms underlying how TBI augments the functions of adoptively transferred T cells include (a) the depletion of regulatory T cells (T(reg)) and myeloid-derived suppressor cells that limit the function and proliferation of adoptively transferred cells; (b) the removal of immune cells that act as "sinks" for homeostatic cytokines, whose levels increase after lymphodepletion; and (c) the activation of the innate immune system via Toll-like receptor 4 signaling, which is engaged by microbial lipopolysaccharide that translocated across the radiation-injured gut. Here, we review these mechanisms and focus on the effect of Toll-like receptor agonists in adoptive immunotherapy. We also discuss alternate regimens to chemotherapy or TBI, which might be used to safely treat patients with advanced disease and promote tumor regression.

Authors
Paulos, CM; Kaiser, A; Wrzesinski, C; Hinrichs, CS; Cassard, L; Boni, A; Muranski, P; Sanchez-Perez, L; Palmer, DC; Yu, Z; Antony, PA; Gattinoni, L; Rosenberg, SA; Restifo, NP
MLA Citation
Paulos, CM, Kaiser, A, Wrzesinski, C, Hinrichs, CS, Cassard, L, Boni, A, Muranski, P, Sanchez-Perez, L, Palmer, DC, Yu, Z, Antony, PA, Gattinoni, L, Rosenberg, SA, and Restifo, NP. "Toll-like receptors in tumor immunotherapy." Clinical cancer research : an official journal of the American Association for Cancer Research 13.18 Pt 1 (September 2007): 5280-5289. (Review)
PMID
17875756
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
13
Issue
18 Pt 1
Publish Date
2007
Start Page
5280
End Page
5289
DOI
10.1158/1078-0432.ccr-07-1378

Synergy of adoptive T-cell therapy and intratumoral suicide gene therapy is mediated by host NK cells.

In situ tumor cell killing by the herpes simplex virus thymidine kinase (HSVtk) gene can effectively prime antitumor T-cell responses, at least in part through local induction of a pro-inflammatory environment. Therefore, we reasoned that tumor-associated HSVtk expression would significantly enhance the efficacy of adoptive T-cell transfer (ACT) of (tumor) antigen-specific T cells into tumor-bearing hosts. When B16ovaHSVtk tumors were treated with ganciclovir (GCV), along with suboptimal numbers of activated OT-1T cells, complete tumor regressions were observed where GCV, or ACT, alone was completely ineffective. To our surprise, analysis of regressing tumors showed no increases in intratumoral OT-1T cell trafficking. However, the intratumoral percentages of both OT-1 and endogenous natural killer (NK) cells were substantially increased over controls. Depletion of endogenous NK cells abrogated the efficacy of the combination therapy and reduced the percentages of interferon-gamma(IFNgamma)-secreting OT-1T cells in mice that received combined therapy to levels similar to those of control mice. These data suggest that even relatively low levels of gene transfer of suicide genes into tumors may have therapeutic value as an adjuvant for other T-cell therapies, by providing immunological signals that support T-cell activation and expansion in vivo.

Authors
Sanchez-Perez, L; Gough, M; Qiao, J; Thanarajasingam, U; Kottke, T; Ahmed, A; Thompson, JM; Maria Diaz, R; Vile, RG
MLA Citation
Sanchez-Perez, L, Gough, M, Qiao, J, Thanarajasingam, U, Kottke, T, Ahmed, A, Thompson, JM, Maria Diaz, R, and Vile, RG. "Synergy of adoptive T-cell therapy and intratumoral suicide gene therapy is mediated by host NK cells." Gene therapy 14.13 (July 2007): 998-1009.
PMID
17443216
Source
epmc
Published In
Gene Therapy
Volume
14
Issue
13
Publish Date
2007
Start Page
998
End Page
1009
DOI
10.1038/sj.gt.3302935

Delivery of CCL21 to metastatic disease improves the efficacy of adoptive T-cell therapy

Authors
Thanarajasingam, U; Sanz, L; Diaz, R; Qiao, J; Sanchez-Perez, L; Kottke, T; Thompson, J; Chester, J; Vile, RG
MLA Citation
Thanarajasingam, U, Sanz, L, Diaz, R, Qiao, J, Sanchez-Perez, L, Kottke, T, Thompson, J, Chester, J, and Vile, RG. "Delivery of CCL21 to metastatic disease improves the efficacy of adoptive T-cell therapy." CANCER RESEARCH 67.1 (January 1, 2007): 300-308.
Source
wos-lite
Published In
Cancer Research
Volume
67
Issue
1
Publish Date
2007
Start Page
300
End Page
308
DOI
10.1158/0008.CAN-06-1017

VSV-G pseudotyped, MuLV-based, semi-replication-competent retrovirus for cancer treatment.

Low levels of gene delivery in vivo using replication-defective retroviral vectors have severely limited their application for clinical protocols. To overcome this problem, we describe here a semi-replication-competent retrovirus (s-RCR) in which the gag-pol and envelope (VSV-G, vesicular stomatitis virus G protein) genes were split into two vectors. This system offers potential advantages over both replication-defective vectors, in terms of efficiency of in vivo spread through a tumor, and all-in-one replication-competent vectors in terms of the payload of therapeutic genes that can be carried. We achieved a viral titer of s-RCR viruses approximately 70-fold higher than VSV-G pseudotyped, replication-defective vectors. In addition, s-RCR vectors induced tumor killing by the cytotoxicity of VSV-G during viral spread. Inclusion of the herpes simplex virus thymidine kinase (HSVtk30) gene into vectors significantly improved tumor killing activity followed by ganciclovir (GCV) treatment in vitro under conditions of low-level viral replication. However, at high levels of viral spread, VSV-G-mediated cytotoxicity predominated. Xenografts of human fibrosarcoma HT1080 cells, preinfected by semi-replicative green fluorescent protein vectors (semi-GFP), were completely non-tumorigenic in nude mice. Implantation of cells preinfected by semi-replicative TK30 vectors (semi-TK30) mixed with parental HT1080 cells at a ratio of 1:1 efficiently prevented tumor growth in mice treated by GCV. Direct intratumoral injection of HT1080 tumors growing in nude mice, or B16 murine melanoma in immunocompetent mice, with semi-TK30 viruses significantly prolonged survival. Injection of autologous cells (B16) producing semi-TK30 vector into B16 tumors prolonged survival only in mice treated with GCV but not with phosphate-buffered saline (PBS). In contrast, when xenogeneic cells (293T) producing semi-TK30 vectors were injected into B16 tumors, an optimal survival advantage was obtained in mice treated with PBS rather than GCV. These data indicate that complex interactions exist between direct cytotoxicity of VSV-G and HSVtk expression when placed in the context of additional immune parameters, which combine to determine the efficacy of the therapy. Taken together, our data suggest that s-RCR vectors have some potential advantages for development to deliver genes into tumors for cancer treatment but that a combination of factors will impact on the decision as to whether the s-RCR strategy is worth developing to full clinical trials.

Authors
Qiao, J; Moreno, J; Sanchez-Perez, L; Kottke, T; Thompson, J; Caruso, M; Diaz, RM; Vile, R
MLA Citation
Qiao, J, Moreno, J, Sanchez-Perez, L, Kottke, T, Thompson, J, Caruso, M, Diaz, RM, and Vile, R. "VSV-G pseudotyped, MuLV-based, semi-replication-competent retrovirus for cancer treatment." Gene therapy 13.20 (October 2006): 1457-1470.
PMID
16724095
Source
epmc
Published In
Gene Therapy
Volume
13
Issue
20
Publish Date
2006
Start Page
1457
End Page
1470
DOI
10.1038/sj.gt.3302782

Killing of normal melanocytes, combined with heat shock protein 70 and CD40L expression, cures large established melanomas.

Previously, we showed that nine intradermal injections of a plasmid in which the HSVtk suicide gene is expressed from a melanocyte-specific promoter (Tyr-HSVtk), combined with a plasmid expressing heat shock protein 70 (CMV-hsp70), along with systemic ganciclovir, kills normal melanocytes and raises a CD8+ T cell response that is potent enough to eradicate small, 3-day established B16 tumors. We show in this study that, in that regimen, hsp70 acts as a potent immune adjuvant through TLR-4 signaling and local induction of TNF-alpha. hsp70 is required for migration of APC resident in the skin to the draining lymph nodes to present Ags, derived from the killing of normal melanocytes, to naive T cells. The addition of a plasmid expressing CD40L increased therapeutic efficacy, such that only six plasmid injections were now required to cure large, 9-day established tumors. Generation of potent immunological memory against rechallenge in cured mice accompanied these therapeutic gains, as did induction of aggressive autoimmune symptoms. Expression of CD40L, along with hsp70, increased both the frequency and activity of T cells activated against melanocyte-derived Ags. In this way, addition of CD40L to the hsp70-induced inflammatory killing of melanocytes can be used to cure large established tumors and to confer immunological memory against tumor cells, although a concomitant increase in autoimmune sequelae also is produced.

Authors
Sanchez-Perez, L; Kottke, T; Daniels, GA; Diaz, RM; Thompson, J; Pulido, J; Melcher, A; Vile, RG
MLA Citation
Sanchez-Perez, L, Kottke, T, Daniels, GA, Diaz, RM, Thompson, J, Pulido, J, Melcher, A, and Vile, RG. "Killing of normal melanocytes, combined with heat shock protein 70 and CD40L expression, cures large established melanomas." Journal of immunology (Baltimore, Md. : 1950) 177.6 (September 2006): 4168-4177.
PMID
16951382
Source
epmc
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
177
Issue
6
Publish Date
2006
Start Page
4168
End Page
4177
DOI
10.4049/jimmunol.177.6.4168

The perforin-dependent immunological synapse allows T-cell activation-dependent tumor targeting by MLV vector particles.

We have reported that retroviral particles adhered to the surface of antigen-specific T cells can be carried to metastases following adoptive transfer in vivo, a process we have called viral hitch hiking. Following antigen-driven T-cell accumulation at tumors, viral particles productively infect tumor cells via envelope/receptor dependent interactions ('hand on' of virus from the T cell to the tumor cell). We describe here a second envelope/receptor independent pathway of viral hand on from T cells, dependent on T-cell activation. We show that the endosomolytic property of perforin promotes release of viral particles from endosomes into which they are co-delivered along with cytotoxic granules from the activated T cell. Therefore, hand on of MLV particles lacking any envelope can be used for in vivo delivery of vectors, where targeting is at the extremely specific level of recognition of antigen by the T-cell receptor, thereby dispensing with the need to engineer viral envelopes. These data reveal a novel pathway by which MLV viral particles exploit a functional immunological synapse and present new opportunities both to improve the efficacy of adoptive T-cell transfer and to target vectors for systemic gene delivery.

Authors
Kottke, T; Qiao, J; Diaz, RM; Ahmed, A; Vroman, B; Thompson, J; Sanchez-Perez, L; Vile, R
MLA Citation
Kottke, T, Qiao, J, Diaz, RM, Ahmed, A, Vroman, B, Thompson, J, Sanchez-Perez, L, and Vile, R. "The perforin-dependent immunological synapse allows T-cell activation-dependent tumor targeting by MLV vector particles." Gene therapy 13.15 (August 2006): 1166-1177.
PMID
16625245
Source
epmc
Published In
Gene Therapy
Volume
13
Issue
15
Publish Date
2006
Start Page
1166
End Page
1177
DOI
10.1038/sj.gt.3302722

Tumor-targeted, systemic delivery of therapeutic viral vectors using hitchhiking on antigen-specific T cells.

Antigen-specific T cells circulate freely and accumulate specifically at sites of antigen expression. To enhance the survival and targeting of systemically delivered viral vectors, we exploited the observation that retroviral particles adhere nonspecifically, or 'hitchhike,' to the surface of T cells. Adoptive transfer of antigen-specific T cells, loaded with viruses encoding interleukin (IL)-12 or Herpes Simplex Virus thymidine kinase (HSVtk), cured established metastatic disease where adoptive T-cell transfer alone was not effective. Productive hand off correlated with local heparanase expression either from malignant tumor cells and/or as a result of T-cell activation by antigen, providing high levels of selectivity for viral transfer to metastatic tumors in vivo. Protection, concentration and targeting of viruses by adsorption to cell carriers represent a new technique for systemic delivery of vectors, in fully immunocompetent hosts, for a variety of diseases in which delivery of genes may be therapeutically beneficial.

Authors
Cole, C; Qiao, J; Kottke, T; Diaz, RM; Ahmed, A; Sanchez-Perez, L; Brunn, G; Thompson, J; Chester, J; Vile, RG
MLA Citation
Cole, C, Qiao, J, Kottke, T, Diaz, RM, Ahmed, A, Sanchez-Perez, L, Brunn, G, Thompson, J, Chester, J, and Vile, RG. "Tumor-targeted, systemic delivery of therapeutic viral vectors using hitchhiking on antigen-specific T cells." Nature medicine 11.10 (October 2005): 1073-1081.
PMID
16170322
Source
epmc
Published In
Nature Medicine
Volume
11
Issue
10
Publish Date
2005
Start Page
1073
End Page
1081
DOI
10.1038/nm1297

Gene therapy to manipulate effector T cell trafficking to tumors for immunotherapy.

Strategies that generate tumor Ag-specific effector cells do not necessarily cure established tumors. We hypothesized that the relative efficiency with which tumor-specific effector cells reach the tumor is critical for therapy. We demonstrate in this study that activated T cells respond to the chemokine CCL3, both in vitro and in vivo, and we further demonstrate that expression of CCL3 within tumors increases the effector T cell infiltrate in those tumors. Importantly, we show that adenoviral gene transfer to cause expression of CCL3 within B16ova tumors in vivo increases the efficacy of adoptive transfer of tumor-specific effector OT1 T cells. We additionally demonstrate that such therapies result in endogenous immune responses to tumor Ags that are capable of protecting animals against subsequent tumor challenge. Strategies that modify the "visibility" of tumors have the potential to significantly enhance the efficacy of both vaccine and adoptive transfer therapies currently in development.

Authors
Gough, M; Crittenden, M; Thanarajasingam, U; Sanchez-Perez, L; Thompson, J; Jevremovic, D; Vile, R
MLA Citation
Gough, M, Crittenden, M, Thanarajasingam, U, Sanchez-Perez, L, Thompson, J, Jevremovic, D, and Vile, R. "Gene therapy to manipulate effector T cell trafficking to tumors for immunotherapy." Journal of immunology (Baltimore, Md. : 1950) 174.9 (May 2005): 5766-5773.
PMID
15843579
Source
epmc
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
174
Issue
9
Publish Date
2005
Start Page
5766
End Page
5773
DOI
10.4049/jimmunol.174.9.5766

Potent selection of antigen loss variants of B16 melanoma following inflammatory killing of melanocytes in vivo.

We have reported that i.d. injection of plasmids encoding hsp70 and a suicide gene transcriptionally targeted to melanocytes generates specific proinflammatory killing of melanocytes. The resulting CD8+ T cell response eradicates systemically established B16 tumors. Here, we studied the consequences of that CD8+ T cell response on the phenotype of preexisting tumor. In suboptimal protocols, the T cell response selected B16 variants, which grow extremely aggressively, are amelanotic and have lost expression of the tyrosinase and tyrosinase-related protein 2 (TRP-2) antigens. However, expression of other melanoma-associated antigens, such as gp100, was not affected. Antigen loss could be reversed by long-term growth in culture away from immune-selective pressures or within 96 hours by treatment with the demethylating agent 5-azacytidine (5-Aza). When transplanted back into syngeneic animals, variants were very poorly controlled by further vaccination. However, a combination of vaccination with 5-Aza to reactivate antigen expression in tumors in situ generated highly significant improvements in therapy over treatment with vaccine or 5-Aza alone. These data show that inflammatory killing of normal cells activates a potent T cell response targeted against a specific subset of self-antigens but can also lead to the immunoselection of tumor variants. Moreover, our data indicate that emergence of antigen loss variants may often be due to reversible epigenetic mechanisms within the tumor cells. Therefore, combination therapy using vaccination and systemic treatment with 5-Aza or other demethylating agents may have significant therapeutic benefits for antitumor immunotherapy.

Authors
Sanchez-Perez, L; Kottke, T; Diaz, RM; Ahmed, A; Thompson, J; Chong, H; Melcher, A; Holmen, S; Daniels, G; Vile, RG
MLA Citation
Sanchez-Perez, L, Kottke, T, Diaz, RM, Ahmed, A, Thompson, J, Chong, H, Melcher, A, Holmen, S, Daniels, G, and Vile, RG. "Potent selection of antigen loss variants of B16 melanoma following inflammatory killing of melanocytes in vivo." Cancer research 65.5 (March 2005): 2009-2017.
PMID
15753401
Source
epmc
Published In
Cancer Research
Volume
65
Issue
5
Publish Date
2005
Start Page
2009
End Page
2017
DOI
10.1158/0008-5472.can-04-3216

A simple method to cure established tumors by inflammatory killing of normal cells.

We describe a simple technology used to cure an established metastatic disease. Intradermal injection of plasmid DNA encoding a transcriptionally targeted cytotoxic gene, along with hsp70, not only promoted tissue-specific, inflammatory killing of normal melanocytes, but also induced a CD8(+) T-cell-dependent, antigen-specific response in mice that eradicated systemically established B16 tumors. This CD8(+) T cell response was subsequently suppressed in vivo within a few days. The data demonstrate that deliberate destruction of normal tissue can be exploited to generate immunity against a malignant disease originating from that tissue. This approach obviates the need to identify tumor antigens and does not require complex isolation of tumor cells or their derivatives. In addition, it provides a model system for studying the mechanisms underlying the etiology and control of autoimmune diseases. Finally, despite targeting normal tissue, therapy could be separated from development of overt autoimmune symptoms, suggesting that the strategy may be valuable against tumors derived from both non-essential and essential tissue types.

Authors
Daniels, GA; Sanchez-Perez, L; Diaz, RM; Kottke, T; Thompson, J; Lai, M; Gough, M; Karim, M; Bushell, A; Chong, H; Melcher, A; Harrington, K; Vile, RG
MLA Citation
Daniels, GA, Sanchez-Perez, L, Diaz, RM, Kottke, T, Thompson, J, Lai, M, Gough, M, Karim, M, Bushell, A, Chong, H, Melcher, A, Harrington, K, and Vile, RG. "A simple method to cure established tumors by inflammatory killing of normal cells." Nature biotechnology 22.9 (September 2004): 1125-1132.
PMID
15300260
Source
epmc
Published In
Nature Biotechnology
Volume
22
Issue
9
Publish Date
2004
Start Page
1125
End Page
1132
DOI
10.1038/nbt1007

Induction of cell stress through gene transfer of an engineered heat shock transcription factor enhances tumor immunogenicity.

Heat shock protein expression and release is closely associated with immunogenic forms of cell death. We show that activation of the stress response within tumor cells during cell death, using an engineered form of the heat shock transcription factor, leads to an immunogenic death. Cells dying through 'stressful death' show decreased phagocytosis by macrophages in vitro. Moreover, cells expressing heat shock proteins during cell death are significantly more protective against subsequent tumor challenge. These data demonstrate the utility of activating cellular stress programs over the course of cytotoxic therapies to enhance immune responses to dying cells.

Authors
Gough, MJ; Melcher, AA; Crittenden, MR; Sanchez-Perez, L; Voellmy, R; Vile, RG
MLA Citation
Gough, MJ, Melcher, AA, Crittenden, MR, Sanchez-Perez, L, Voellmy, R, and Vile, RG. "Induction of cell stress through gene transfer of an engineered heat shock transcription factor enhances tumor immunogenicity." Gene therapy 11.13 (July 2004): 1099-1104.
PMID
15103319
Source
epmc
Published In
Gene Therapy
Volume
11
Issue
13
Publish Date
2004
Start Page
1099
End Page
1104
DOI
10.1038/sj.gt.3302274
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Research Areas:

  • Animals
  • Animals, Genetically Modified
  • Antibody Specificity
  • Antigen-Antibody Complex
  • Antigens
  • Antigens, Neoplasm
  • Autoantigens
  • Autoimmunity
  • Azacitidine
  • Brain
  • Cancer Vaccines
  • Cancer--Immunotherapy
  • Cell Death
  • Cell Line
  • Cell Membrane
  • Cell Movement
  • Cell Survival
  • Chemokines
  • Combined Modality Therapy
  • Cytokines
  • DNA Methylation
  • Disease Models, Animal
  • Drug Evaluation, Preclinical
  • Epitopes
  • Gene Expression
  • Gene Expression Regulation
  • Gene Targeting
  • Gene Transfer Techniques
  • Gene therapy
  • Genetic Engineering
  • Genetic Therapy
  • Genetic Vectors
  • Glioblastoma
  • Immunity, Innate
  • Immunization
  • Immunotherapy, Adoptive
  • Inflammation
  • Inflammation Mediators
  • Lymphocyte Activation
  • Lymphopenia
  • Melanocytes
  • Melanoma, Experimental
  • Models, Molecular
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neoplasm Transplantation
  • Neoplasms, Experimental
  • Oncolytic Virotherapy
  • Organ Specificity
  • Phagocytosis
  • Recombinant Proteins
  • Sensitivity and Specificity
  • Signal Transduction
  • Skin Neoplasms
  • Substrate Specificity
  • Surface Plasmon Resonance
  • T cells
  • Treatment Outcome
  • Tumor Escape
  • Whole-Body Irradiation
  • Xenograft Model Antitumor Assays