The Duke Cancer Institute Center for Cancer Immunotherapy connects physicians, scientists, and researchers to discover immunotherapies for every cancer type. Immunotherapies boost the immune system's ability to kill cancer. The Center’s mission is to develop and test new immunotherapies, new indications for immunotherapies, and new combinations of drugs that include immunotherapies. They hope to accelerate the journey from animal and cell studies to human clinical trials, and drug manufacturing, when possible.
Chimeric antigen receptor (CAR) T-cell therapy is one example of an immunotherapy that is offering new hope to some lymphoma patients. CAR T-cell therapy involves removing white blood cells called T cells from a patient’s body, genetically modifying the cells in a lab, and then infusing them back into the patient. Unlike a pharmaceutical with a defined chemical formulation, each batch is made from living cells of an individual patient.
This therapy is approved for people who have failed at least two lines of treatment for several kinds of non-Hodgkin’s lymphoma: diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. Duke Cancer Institute was one of the earliest treatment centers certified to administer CAR T-Cell therapy when it was approved by the FDA in October of 2017.
Many Studies Underway
CAR-T therapies for some solid tumors are in clinical trials. The Preston Robert Tisch Brain Tumor Center is studying a CAR-T therapy for glioblastomas, a type of brain cancer.
Duke investigators also have several studies under development to learn how to use immunotherapies to target cancer and to the ramp up the immune system to fight cancer.
The Duke Cancer Institute Center for Cancer Immunotherapy is interested in potential opportunities for collaboration from the bench to the bedside across the entire spectrum of cancer types. We are actively looking for the development of strategic research partnerships to generate scientific synergy. Whether there is interest in translating a concept into a different scientific field or building research teams for future grant proposals, the Duke Center for Cancer Immunotherapy is interested in helping investigators through the process.
The Duke Cancer Institute Center for Cancer Immunotherapy is the nexus for physician-scientists and researchers across DCI who are focused on developing new immunotherapies as well as testing, in clinical trials, new immunotherapies, new combinations of drugs that include immunotherapies, and current immunotherapies for new indications. The center is comprised of known thought leaders in their respective fields who look for cancer immunotherapy discoveries that show promise, no matter the cancer type.
The DCI Center for Cancer Immunotherapy aims to speed up the process that brings immunotherapies for cancer from the bench to the bedside. We’ve been able to accomplish in six months what might take years at another institution by drawing on the collaborative talent of Duke investigators. Our investigators are engaged in every step of the process, from conducting lab studies to designing clinical trials and manufacturing a drug. We are open to collaborating with research partners across the world to broaden the scope of cancer patients who may benefit from immunotherapy treatment.
More research efforts are under development at our center, including new lung cancer immunotherapies and immunotherapies that will fight head and neck cancer, upper gastrointestinal cancer, colorectal cancer with metastasis to the liver, melanoma, and bladder cancer.
The Hanks Lab, run by Brent Hanks, MD, PhD, immunotherapy resistance. Understanding why some patients respond to immunotherapy and others don’t may guide the development of novel strategies to overcome resistance and expand the number of patients who can respond to immunotherapy.
Ongoing research in the Hanks Lab focuses on understanding how malignancies develop their own strategies for evading anti-tumor immunity and becoming resistant to currently available immuno-therapeutics. The lab utilizes both genetically engineered tumor models as well as clinical specimens from patients undergoing immunotherapy to guide their research. The group is currently conducting studies in melanoma, non-small cell lung cancer, and colorectal cancer.
This area of investigation holds great promise for using immunotherapies to treat people with cancer.
Brent Hanks, MD, Ph.D, Andrew Nixon, Ph.D., and Jennifer Choe, MD, Ph.D., are collaborating on a biobank to understand why some patients develop autoimmune responses that inflame the gastrointestinal tract, lungs, and liver, or lead to the destruction of endocrine glands, including the thyroid and pituitary. The biobank collects blood and tissue samples, and data on reactions, from Duke cancer patients treated with immunotherapy for various cancer types. Data from this project will help predict which patients are at risk for side effects so they can be proactively managed or even prevented.
Disease-Specific Research Projects
Several projects are underway to study immunotherapies in breast cancer, gastrointestinal cancers, genitourinary cancers, lung cancer, and melanoma.
Novel Therapeutics Development
The Hanks Lab is working to develop drugs that target and manipulate dendritic cells to boost immune responses to checkpoint inhibitor therapy.
Georgia Beasley, MD, a surgical oncologist, is conducting clinical trials evaluating intra-lesional therapeutics such as oncolytic viral vectors to help manage patients with advanced melanoma. She is conducting clinical studies evaluating these agents that have been developed by other biotech companies.
April K.S. Salama, MD, leads ongoing clinical efforts to improve the management of patients with melanoma that has spread to the brain.
Postdoctoral fellow Binita Chakraborty, PhD, was intrigued: in published analyses of large numbers of patients with melanoma (skin cancer) treated with an immunotherapy that is becoming standard of care, the treatment worked better in men than in women.
“There may be multiple reasons why the response may be different between males and females,” she says. “But one of the biggest differences that stands out was circulating estrogen levels. Estrogen levels are much higher in females than males.”
As a breast cancer researcher, Chakraborty knows a bit about estrogen. When she told her mentor, Donald McDonnell, PhD, that she wanted to explore what was really behind this connection, he told her to run with it.
Her findings are leading to a Duke clinical trial in the works that may make immunotherapy work better for people with melanoma, as well as other cancers.
New to studying skin cancer, Chakraborty knew just who to call—Duke physician-scientist Brent Hanks, MD, PhD, who treats patients with melanoma and studies the disease. Hanks helped her establish tumor cell lines and mouse models that mimic humans with melanoma. The mice have mutations that are present in up to 70 percent of people with the disease—a mutation in a protein called BRAF and a deletion in a different protein known as PTEN.
In all the tests that Chakraborty did with these mice, estrogen increased cancer growth. But not in experiments with isolated tumor cells in culture dishes.
“When we cultured the tumor cells, then put in estrogen, they were not growing faster or doing anything,” Chakraborty says. “None of these tumor cells themselves were actually responding to estrogen.”
That told her that the estrogen must be influencing something in the tumor “microenvironment” – the community of cells that surrounds the tumor and nurtures its growth. “The tumor tries to hijack the environment around it to help itself grow faster,” Chakraborty says.
To find out how estrogen is making melanoma worse, she did experiments in a mouse that doesn’t have a functional immune system. In those mice, whether she treated with estrogen or not, the tumor growth stayed about the same. “That got us to hypothesize, okay, estrogen must be affecting the immune cells in the microenvironment,” she says. “The tumor is growing fast in response to estrogen only when the immune cells are present.”
The tumor microenvironment contains many different types of immune cells, but Chakraborty found that in melanoma, estrogen particularly affects one type—macrophages. She explains that normally there is a balance between “good” macrophages, which can help alert T cells to a tumor so they can kill it, and “bad” macrophages, which help a tumor grow by promoting blood vessel growth and impairing T cell function.
In mice with melanoma, estrogen shifts the balance toward the bad macrophages.
Chakraborty shared these findings with Scott Antonia, MD, director of the Duke Cancer Institute for Cancer Immunotherapy, to get his perspective as a clinician. He was immediately interested. Unbeknownst to Chakraborty, Antonia had been studying lung cancer patients who had stopped responding to an immunotherapy called a PD-1 inhibitor. In these patients, “bad” macrophages were increased in proportion to “good” macrophages. Just like in Chakraborty’s mice with melanoma.
So, Chakraborty did some experiments in mouse models of non-small-cell lung cancer. She found that estrogen increased “bad” macrophages in lung cancer too.
Based on these results, Antonia is now writing a clinical trial to combine a newer anti-estrogen drug used to treat breast cancer with a PD-1 inhibitor, in patients with melanoma, non-small cell lung cancer, and gastric (stomach) cancer. He hopes that inhibiting estrogen will improve patient responses to this type of immunotherapy.
“Binita is firing on all cylinders,” McDonnell says. Even while she and her husband, a scientist at UNC-Chapel Hill, juggle homeschooling their six-year-old son during the COVID-19 pandemic, she is having many of the early successes that can prepare her for becoming a faculty member. And McDonnell is thrilled. “I still get a buzz out of publishing papers, but I get a much bigger buzz out of seeing the next generation of cancer researchers succeed and get on their way,” he says.
DISCLOSURES: Donald McDonnell, PhD, is involved in the company developing the drug that will be used in the clinical trials mentioned in this story.
This article appeared in the Winter 2021 issue of Breakthroughs magazine. Breakthroughs is produced twice yearly by Duke Cancer Institute Office of Development.