Darell Bigner

Overview:

The Causes, Mechanisms of Transformation and Altered Growth Control and New Therapy for Primary and Metastatic Tumors of the Central Nervous System (CNS).

There are over 16,000 deaths in the United States each year from primary brain tumors such as malignant gliomas and medulloblastomas, and metastatic tumors to the CNS and its covering from systemic tumors such as carcinoma of the lung, breast, colon, and melanoma. An estimated 80,000 cases of primary brain tumors were expected to be diagnosed last year. Of that number, approximately 4,600 diagnosed will be children less than 19 years of age. During the last 20 years, however, there has been a significant increase in survival rates for those with primary malignant brain tumors.

For the last 44 years my research has involved the investigation of the causes, mechanism of transformation and altered growth control, and development of new methods of therapy for primary brain tumors and those metastasizing to the CNS and its coverings. In collaboration with my colleagues in the Preston Robert Tisch Brain Tumor Center, new drugs and those not previously thought to be active against CNS tumors have been identified. Overcoming mechanisms of drug resistance in primary brain tumors are also being pursued.

As the founding Director of the Preston Robert Tisch Brain Tumor Center, I help coordinate the research activities of all 37 faculty members in the Brain Tumor Center. These faculty members have projects ranging from very basic research into molecular etiology, molecular epidemiology, signal transduction; translational research performing pre-clinical evaluation of new therapies, and many clinical investigative efforts. I can describe any of the Brain Tumor Center faculty member’s research to third year students and then direct them to specific faculty members with whom the students would like a discussion.

We have identified through genome-wide screening methodology several new target molecules selectively expressed on malignant brain tumors, but not on normal brain. These include EGFRwt, EGFRvIII, and two lacto series gangliosides, 3'-isoLM1 and 3',6'-isoLD1 and chondroitin proteoglycan sulfate. We raised conventional and fully human monoclonal antibodies against most of these targets as well as having developed single fragment chain molecules from naïve human libraries.

My personal research focuses on molecularly targeted therapies of primary and metastatic CNS tumors with monoclonal antibodies and their fragments. Our study we conducted was with a molecule we discovered many years ago, the extracellular matrix molecule, Tenascin. We have treated over 150 malignant brain tumor patients with excellent results with a radiolabeled antibody we developed against Tenascin. We are collaborating with Dr. Ira Pastan at NIH to develop tumor-targeted therapies by fusing single fragment chain molecules from monoclonal antibodies or from naïve human libraries to the truncated fragment of pseudomonas exotoxin A. One example of this is the pseudomonas exotoxin conjugated to a single fragment chain antibody that reacts with wild type EGFR and EGFRvIII, two overexpressed proteins on glioblastoma. The immunotoxin, called D2C7-IT, is currently being investigated in an FDA dose-escalation study, in which patients undergoing treatment of this investigational new drug are showing positive responses. My laboratory is also working with Matthias Gromeier, creator of the oncolytic poliovirus - a re-engineered poliovirus that is lethal to cancer cells, but not lethal to normal cells. The oncolytic poliovirus therapeutic approach has shown such promising results in patients with glioblastoma, that it was recently featured on a on a special two-segment program of 60 Minutes. The next clinical step will be to combine both the virus and the immunotoxin with anti-PD1, an immune checkpoint blockade inhibitor and with anti-CD40, a fully human monoclonal antibody which converts tumor stimulant macrophages into tumor suppressive macrophages. We believe that regional tumor-targeted cytotoxic therapies, such as oncolytic poliovirus and the D2C7 immunotoxin, not only specifically target and destroy tumor cells, but in the process, initiate immune events that promote an in situ vaccine effect. That immune response can be amplified by human checkpoint blockade to engender a long-term systemic immune response that effectively eliminates recurrent and disseminated GBM cells. Ultimately, all three agents may be used together, providing different antigenic targets and cytotoxicity mechanisms.

We have identified through genome-wide screening methodology several new target molecules selectively expressed on malignant brain tumors, but not on normal brain. These include glycoprotein non-metastatic B (GPNMB), a molecule shared with malignant melanoma; MRP3, a member of the multidrug resistant family; and two lacto series gangliosides, 3'-isoLM1 and 3',6'-isoLD1 and chondroitin proteoglycan sulfate. We are raising conventional monoclonal antibodies against all of these targets as well as developing single fragment chain molecules from naïve human libraries. When necessary, affinity maturation in vitro is carried out and the antibodies and fragments are armed either with radioactive iodine, radioactive lutetium, or radioactive Astatine-211. Other constructs are evaluated for unarmed activity and some are armed with Pseudomonas exotoxin. After development of the constructs, they are evaluated in human malignant glioma xenograft systems and then all studies necessary for Investigational New Drug Permits from the Food and Drug Administration are carried out prior to actual clinical trial.

I was senior author on a New England Journal of Medicine paper that was the first to show markedly increased survival in low to intermediate grade gliomas with an isocitrate dehydrogenase mutation.

The first fully funded Specialized Research Center on Primary and Metastatic Tumors to the CNS funded by the National Institutes of Health, of which I was Principal Investigator, was funded for 30 years at which time the type of grant was discontinued. My NCI MERIT Award, which ranked in the upper 1.2 percentile of all NIH grants at the time of its last review, is currently in its 40th year of continuous funding. It is one of the few MERIT awards awarded three consecutive times, and it is the longest continually funded grant of the NCI Division of Cancer Diagnosis and Treatment. My last NCI Award was an Outstanding Investigator Award from 2014 to 2022.

In addition to the representative publications listed, I have made national presentations and international presentations during the past year.

My laboratory has trained over 50 third year medical students, residents, Ph.D. students, and postdoctoral fellows and I have a great deal of experience in career development with some students having advanced all the way from fellowship status to endowed professorships. A major goal with third year medical students is to perform work that can be presented in abstract form at national or international meetings and to obtain publication in major peer-reviewed journals.

Positions:

E. L. and Lucille F. Jones Cancer Distinguished Research Professor, in the School of Medicine

Neurosurgery
School of Medicine

Professor of Neurosurgery

Neurosurgery
School of Medicine

Chief, Division of Experimental Pathology

Pathology
School of Medicine

Professor of Surgery

Surgery
School of Medicine

Professor of Pathology

Pathology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1965

Duke University

Ph.D. 1971

Duke University

Intern, Surgery

Duke University

Fellow, Neurological Surgery

Duke University

Clinical Associate, Medical Neurology

National Institutes of Health

Grants:

Nuclear EGFR Signaling Network in Human Cancer

Administered By
Surgery, Surgical Sciences
Awarded By
National Institutes of Health
Role
Mentor
Start Date
End Date

Anti-tumor efficacy of EGFR-targeting immunotoxin in combination with CCNU or PD-L1 blockade in glioma mouse models

Administered By
Neurosurgery, Neuro-Oncology
Awarded By
National Cancer Center
Role
Principal Investigator
Start Date
End Date

Vaccine Immunotoxin and Radioimmunotherapy of Primary and Metastatic CNS Tumors

Administered By
Pathology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

SRC on Primary Tumors of the CNS

Administered By
Pathology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Meningioma: Risk Factors and Quality of Life

Administered By
Duke Cancer Institute
Awarded By
National Institutes of Health
Role
Co-Principal Investigator
Start Date
End Date

Publications:

Epigenetic STING silencing is developmentally conserved in gliomas and can be rescued by methyltransferase inhibition.

Authors
Low, JT; Chandramohan, V; Bowie, ML; Brown, MC; Waitkus, MS; Briley, A; Stevenson, K; Fuller, R; Reitman, ZJ; Muscat, AM; Hariharan, S; Hostettler, J; Danehower, S; Baker, A; Khasraw, M; Wong, NC; Gregory, S; Nair, SK; Heimberger, A; Gromeier, M; Bigner, DD; Ashley, DM
MLA Citation
Low, Justin T., et al. “Epigenetic STING silencing is developmentally conserved in gliomas and can be rescued by methyltransferase inhibition.Cancer Cell, vol. 40, no. 5, May 2022, pp. 439–40. Pubmed, doi:10.1016/j.ccell.2022.04.009.
URI
https://scholars.duke.edu/individual/pub1519621
PMID
35487217
Source
pubmed
Published In
Cancer Cell
Volume
40
Published Date
Start Page
439
End Page
440
DOI
10.1016/j.ccell.2022.04.009

Polio Virotherapy of Malignant Glioma Engages the Tumor Myeloid Infiltrate and Induces Diffuse Microglia Activation

Authors
Yang, Y; Brown, M; Zhang, G; Stevenson, K; Mohme, M; Kornahrens, R; Bigner, D; Ashley, D; López, G; Gromeier, M
MLA Citation
Yang, Yuanfan, et al. “Polio Virotherapy of Malignant Glioma Engages the Tumor Myeloid Infiltrate and Induces Diffuse Microglia Activation.” BioRxiv, 20 Apr. 2022. Epmc, doi:10.1101/2022.04.19.488771.
URI
https://scholars.duke.edu/individual/pub1517945
Source
epmc
Published Date
DOI
10.1101/2022.04.19.488771

CTIM-10. REPRODUCIBILITY OF CLINICAL TRIALS USING CMV-TARGETED DENDRITIC CELL VACCINES IN PATIENTS WITH GLIOBLASTOMA

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>INTRODUCTION</jats:title> <jats:p>Vaccination with dendritic cells (DCs) fares poorly in primary and recurrent glioblastoma (GBM). Moreover, GBM vaccine trials are often underpowered due to limited sample size.</jats:p> </jats:sec> <jats:sec> <jats:title>METHODS</jats:title> <jats:p>To address these limitations, we conducted three sequential clinical trials utilizing Cytomegalovirus (CMV)-specific DC vaccines in patients with primary GBM. Autologous DCs were generated and electroporated with mRNA encoding for the CMV protein pp65. Serial vaccination was given throughout adjuvant temozolomide cycles, and 111Indium radiolabeling was implemented to assess migration efficiency of DC vaccines. Patients were followed for median overall survival (mOS) and OS.</jats:p> </jats:sec> <jats:sec> <jats:title>RESULTS</jats:title> <jats:p>Our initial study was the phase II ATTAC study (NCT00639639; total n=12) with 6 patients randomized to vaccine site preconditioning with tetanus-diphtheria (Td) toxoid. This led to an expanded cohort trial (ATTAC-GM; NCT00639639) of 11 patients receiving CMV DC vaccines containing granulocyte-macrophage colony-stimulating factor (GM-CSF). Follow-up data from ATTAC and ATTAC-GM revealed 5-year OS rates of 33.3% (mOS 38.3 months; CI95 17.5-undefined) and 36.4% (mOS 37.7 months; CI95 18.2-109.1), respectively. ATTAC additionally revealed a significant increase in DC migration to draining lymph nodes following Td preconditioning (P=0.049). Increased DC migration was associated with OS (Cox proportional hazards model, HR=0.820, P=0.023). Td-mediated increased migration has been recapitulated in our larger confirmatory trial ELEVATE (NCT02366728) of 43 patients randomized to preconditioning (Wilcoxon rank sum, Td n=24, unpulsed DC n=19; 24h, P=0.031 and 48h, P=0.0195). In ELEVATE, median follow-up of 42.2 months revealed significantly longer OS in patients randomized to Td (P=0.026). The 3-year OS for Td-treated patients in ELEVATE was 34% (CI95 19-63%) compared to 6% given unpulsed DCs (CI95 1-42%).</jats:p> </jats:sec> <jats:sec> <jats:title>CONCLUSION</jats:title> <jats:p>We report reproducibility of our findings across three sequential clinical trials using CMV pp65 DCs. Despite their small numbers, these successive trials demonstrate consistent survival outcomes, thus supporting the efficacy of CMV DC vaccine therapy in GBM.</jats:p> </jats:sec>
Authors
Batich, K; Mitchell, D; Healy, P; Herndon, J; Broadwater, G; Michael, G; Huang, M-N; Hotchkiss, K; Sanchez-Perez, L; Nair, S; Congdon, K; Norberg, P; Weinhold, K; Archer, G; Reap, E; Xie, W; Shipes, S; Albrecht, E; Peters, K; Randazzo, D; Johnson, M; Landi, D; Desjardins, A; Friedman, H; Vlahovic, G; Reardon, D; Vredenburgh, J; Bigner, D; Khasraw, M; McLendon, R; Thompson, E; Cook, S; Fecci, P; Codd, P; Floyd, S; Reitman, Z; Kirkpatrick, J; Friedman, A; Ashley, DM; Sampson, J
MLA Citation
Batich, Kristen, et al. “CTIM-10. REPRODUCIBILITY OF CLINICAL TRIALS USING CMV-TARGETED DENDRITIC CELL VACCINES IN PATIENTS WITH GLIOBLASTOMA.” Neuro Oncology, vol. 23, no. Supplement_6, Oxford University Press (OUP), 2021, pp. vi51–vi51. Manual, doi:10.1093/neuonc/noab196.202.
URI
https://scholars.duke.edu/individual/pub1502906
Source
manual
Published In
Neuro Oncology
Volume
23
Published Date
Start Page
vi51
End Page
vi51
DOI
10.1093/neuonc/noab196.202

Phase I trial of intratumoral PVSRIPO in patients with unresectable, treatment-refractory melanoma.

While programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) antagonists have improved the prognosis for many patients with melanoma, around 60% fail therapy. PVSRIPO is a non-neurovirulent rhinovirus:poliovirus chimera that facilitates an antitumor immune response following cell entry via the poliovirus receptor CD155, which is expressed on tumor and antigen-presenting cells. Preclinical studies show that oncolytic virus plus anti-PD-1 therapy leads to a greater antitumor response than either agent alone, warranting clinical investigation. An open-label phase I trial of intratumoral PVSRIPO in patients with unresectable melanoma (American Joint Committee on Cancer V.7 stage IIIB, IIIC, or IV) was performed. Eligible patients had disease progression on anti-PD-1 and V-raf murine sarcoma viral oncogene homolog B (BRAF)/mitogen activated protein kinase kinase (MEK) inhibitors (if BRAF mutant). The primary objective was to characterize the safety and tolerability of PVSRIPO. Twelve patients in four cohorts received a total of 1, 2 or 3 injections of PVSRIPO monotherapy, with 21 days between injections. PVSRIPO injections were well tolerated with no serious adverse events (SAEs) or dose-limiting toxicities (DLTs) reported. All adverse events (AEs) were grade (G) 1 or G2 (G1 pruritus most common at 58%); all but two PVSRIPO-treatment related AEs were localized to the injected or adjacent lesions (n=1 G1 hot flash, n=1 G1 fatigue). Four out of 12 patients (33%) achieved an objective response per immune-related response criteria (two observations, 4 weeks apart), including 4/6 (67%) who received three injections. In the four patients with in-transit disease, a pathological complete response (pCR) was observed in two (50%) patients. Following study completion, 11/12 patients (92%) reinitiated immune checkpoint inhibitor-based therapy, and 6/12 patients (50%) remained without progression at a median follow-up time of 18 months. Intratumoral PVSRIPO was well tolerated. Despite the limited number of PVSRIPO treatments relative to the overall lesion burden (67% patients>5 lesions), intratumoral PVSRIPO showed promising antitumor activity, with pCR in injected as well as non-injected lesions in select patients. NCT03712358.
Authors
Beasley, GM; Nair, SK; Farrow, NE; Landa, K; Selim, MA; Wiggs, CA; Jung, S-H; Bigner, DD; True Kelly, A; Gromeier, M; Salama, AK
MLA Citation
Beasley, Georgia M., et al. “Phase I trial of intratumoral PVSRIPO in patients with unresectable, treatment-refractory melanoma.Journal for Immunotherapy of Cancer, vol. 9, no. 4, Apr. 2021, p. e002203. Epmc, doi:10.1136/jitc-2020-002203.
URI
https://scholars.duke.edu/individual/pub1480357
PMID
33875611
Source
epmc
Published In
Journal for Immunotherapy of Cancer
Volume
9
Published Date
Start Page
e002203
DOI
10.1136/jitc-2020-002203

GENETICALLY STABLE POLIOVIRUS VECTOR CARRYING H3.3K27M ANTIGEN FOR TREATMENT OF DIFFUSE MIDLINE GLIOMA BY INTRAMUSCULAR INJECTION

Authors
Mosaheb, M; Landi, D; Dobrikova, E; Brown, M; Yang, Y; Cable, J; Okada, H; Nair, S; Bigner, D; Ashley, D; Gromeier, M
MLA Citation
URI
https://scholars.duke.edu/individual/pub1473629
Source
wos-lite
Published In
Neuro Oncology
Volume
22
Published Date
Start Page
472
End Page
472