Cancer immunotherapy is the use of the immune system to prevent or treat cancer. Unlike chemotherapy or radiation, it is a type of treatment that boosts the body’s natural defenses to fight cancer. It uses substances made by the body or in a laboratory to improve or restore immune system function. Through this therapy, the immune system is guided to attack and kill the cancer cells. Immunotherapy has been very successful in treating other types of cancer, which is why experts believe it has promise in pancreatic cancer.

First Immunotherapy Treatment for Pancreatic Cancer

In May 2017, in an unprecedented fast-tracked review, the FDA approved Keytruda® (pembrolizumab) as the first immunotherapy treatment for advanced pancreatic cancer patients whose tumors are mismatch repair deficient (dMMR) or microsatellite instability – high (MSI-H). These terms are used interchangeably. This deficiency alters their capacity to repair DNA, which is a factor in cancer development. It is estimated that approximately 1 in 50 advanced pancreatic cancer patients have tumors that are mismatch repair deficient, making them candidates for this type of therapy. 

3D illustration of cancer cells

Keytruda is the first cancer drug based on a genetic characteristic, rather than tumor site, to be approved by the FDA for use in pancreatic cancer patients. The Lustgarten Foundation played a critical role in bringing this new treatment to patients by funding the research, encouraging patients to get tested and funding patients’ testing to determine if their tumors are mismatch repair deficient.

“Keytruda is the first example of ‘personalized immunotherapy.’ A specific immune treatment can now be recommended for patients based exclusively on the genetic characteristics of the tumor. If the tumor shows a repair defect, then it is very likely that it will respond to this drug, regardless of how advanced the cancer is at the time of treatment. This is a potential life-saving therapy for these patients.”

Bert Vogelstein, M.D.,co-director of the Ludwig Center at the Johns Hopkins Kimmel Cancer Center

Stimulating the Immune System

Immunotherapies have shown benefits across a range of cancers, but so far have not worked well in pancreatic cancer patients with the exception of Keytruda. Recent evidence suggests one major roadblock for the effective use of immunotherapies in pancreatic cancer patients is that the tumors are effectively hidden, preventing the immune system from recognizing and killing them. 

Daniel D. Von Hoff, M.D., Translational Genomics Research Institute (TGen), and his team believe therapies targeting the vitamin D receptor may “unmask” the pancreatic tumors and allow immune cells to reach them and increase the probability for effective immunotherapies. The goal is to test if targeting the vitamin D receptor will unlock the potential of immunotherapies to kill pancreatic cancer tumor cells and potentially establish a therapeutic combination for controlling advanced pancreatic cancer, extending patient survival and reducing side effects. Additionally, Dr. Von Hoff and his team hope to identify features driving patient responses to immunotherapy and gain insight into additional strategies for converting immunotherapy-resistant tumors.

Douglas Fearon, M.D., of Cold Spring Harbor Laboratory and Weill Cornell Medical Center wanted to understand why immunotherapy has not been very effective in pancreatic cancer. He observed that mice with pancreatic cancer didn’t respond to experimental immunotherapy treatments that have been showing great promise in other types of cancer. The reason is that the T cells, a key component of the immune system, were facing a roadblock and were unable to reach and attack the tumor.

The T cells were blocked by a molecule coating the cancer cells—called CXCL12—and that molecule was being produced by the cancer associated fibroblasts (CAF’s). The team then used a drug called AMD3100 that blocks an interaction between T cells and the CXCL12 coating molecule. This freed up the T cells to target the tumor cells. By combining the immunotherapy treatment with AMD3100, the cancer cells responded to the immunotherapy treatment. Soon, Dr. Fearon will test the drug combination in pancreatic cancer patients to see if the response is the same.

For an immune response against cancer to be effective, cells of the immune system known as T cells must recognize the cancer by means of their T cell receptors. Hidde Ploegh, Ph.D., Children’s Hospital Boston, is working on genetically engineering T cells with new receptors that recognize targets on newly formed blood vessels in growing pancreatic cancers. Additionally, Dr. Ploegh’s team is producing biologically active molecules that can direct T cells toward the location of pancreatic tumors to increase their ability to kill cancer cells. This team is also developing imaging agents to monitor the effectiveness of therapy in a non-invasive way.

We know the immune system can unmask and destroy cancer cells. Elizabeth Jaffee, M.D., Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, has examined an important subset of immune cells that suppress the immune response. The drug Entinostat can decrease these immunosuppressive cells and allow access to tumor-killing T cells. Dr. Jaffee is enrolling patients who have become resistant to chemotherapy and treating them with Entinostat to determine if it can decrease the cells suppressing the immune system.

A renowned research team from the University of Pennsylvania, led by Carl June, M.D., is studying CAR T cell immunotherapy in metastatic pancreatic cancer patients, looking for changes in DNA “on and off switches” (epigenetic changes) following treatment with CAR T. The goal of the research is to identify epigenetic changes that will facilitate better understanding of why certain patients respond to treatment compared to non-responders.

Another team at the University of Pennsylvania, led by Peter O’Dwyer, M.D., is investigating epigenetic variations in patients that influence the response to immunotherapy by using epigenetic therapeutics alone or in combination with immunotherapy to inhibit tumor progression as well as to overcome resistance to immunotherapy. The team is identifying genetic and epigenetic features in CAR T cells and/or cancer cells that will help predict which patients will respond to the immunotherapy, with an eventual goal of initiating clinical trials that employ a combination of approaches to therapy.

David Ryan, M.D., Massachusetts General Hospital, and Alec Kimmelman, M.D., Ph.D., NYU Langone Perlmutter Cancer Center, are collaborating on research aimed at improving patient outcomes. Drs. Ryan and Kimmelman are using a comprehensive approach for patients with borderline resectable (operable) and locally advanced pancreatic cancer. Through a clinical trial, the team will evaluate the addition of losartan, a medication used for high blood pressure thought to “open blood vessels,” combined with FOLFIRINOX. 

The research objective is to demonstrate this treatment combination will shrink the patients’ tumors enough to become eligible for surgery. This will result in their best chances for long-term survival. Additionally, since preliminary data suggest losartan therapy and radiation therapy alter the immune microenvironment, the team also will add immunotherapy to determine if this strategy can provide additional benefit.

Along with the clinical trial, patient biopsies will be grown into tumor organoids and exposed to the same treatment that the patients received to determine if the organoid was successful in indicating how the tumor would respond to therapy.

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