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AACR17 Update: Taking Immunotherapy to the Next Level

April 01, 2017

Day one of the annual meeting of the American Association for Cancer Research kicked off with expert-led educational sessions focused on a variety of topics including, “Cancer Immunology for the Non-Immunologist.”

Hideho Okada, Ellen Pure, Robert Vonderheide, and Sacha GnjaticImmunotherapy’s newfound prevalence in the clinic means that sessions like this—which allowed attendees to converse with immunology experts in an informal, roundtable format—will help scientists and doctors become more familiar with immune responses against cancer and the factors that influence them. This will be crucial to enhancing the effectiveness of treatments and improving patient outcomes.

Hideho Okada, M.D., Ph.D., who leads a Cancer Research Institute (CRI) Clinical Team Grant at the University of California in San Francisco, discussed latest advances in immunotherapy for brain cancer. Dr. Okada echoed the session’s importance and stressed the necessity of “integrating experts from different areas to understand what happens in the brain during immunotherapy.”

Dominating talk at that table was a question about the potential side effects of immunotherapy in the brain. Since these treatments “unleash” the immune system, could they contribute to neurodegenerative diseases that are associated with immune responses against healthy cells?

Dr. Okada acknowledged the possibility, but pointed out that current treatments like chemotherapy and radiation surgery are already quite toxic. He also emphasized that as more is learned about how immunotherapy influences immune activity in the brain, and as current efforts progress to provide the immune system with more precise targets, steps can be taken to minimize potential damage.

At another table, Ellen Puré, Ph.D., was in the middle of a lively discussion on how the connective tissues—the stroma—that make up the tumor environment influence the immune system’s ability to eliminate tumors. Dr. Puré, whose work at the Penn Vet Cancer Center at the University of Pennsylvania and the Wistar Institute focuses on inflammation, is an associate director of CRI’s Scientific Advisory Council and chair of our Postdoctoral Fellowship Review Committee.

Dr. Puré mentioned how tumors often have a dense, stiff network of fibers around them that can keep anti-tumor T cells from getting close to the tumor. To address this, her team engineered CAR (chimeric antigen receptor) T cells to target the fiber-producing stromal cells, which are characterized by their expression of FAP (fibrolast activation protein).

These FAP-targeting CAR T cells “act like Pac-Man and chew their way in,” which then allows other immune cells to come in and go after the cancer cells. While thus far the approach has only been tried in mice, it could potentially be used in humans to make hard-to-treat cancers, such as pancreatic cancer, more responsive to immunotherapy.

histology slide showing pancreatic cancer cells and tumor stromaSpeaking of pancreatic cancer, at another table, Robert H. Vonderheide, M.D., D.Phil., of the University of Pennsylvania and a member of CRI’s Scientific Advisory Council, led a talk titled, “Taming the Tumor Microenvironment in Pancreatic Cancer.” He spoke on the importance of pre-existing immune responses in pancreatic cancer. By examining expression of various genes involved in promoting and dampening immune activity—especially those that encode the immune checkpoint molecules PD-L1, CTLA-4, IDO1, LAG-3, and TIM-3—doctors can identify patients with pre-existing responses who are more likely to benefit from checkpoint immunotherapy.

Dr. Vonderheide and his team have also developed a vaccine to help stimulate immune responses in patients whose immune systems do not appear to be responding to the cancer.

The vaccine, which targets an enzyme called telomerase that helps cancer cells stay “immortal,” has been shown to improve overall survival in mice by 40 percent. Now, it’s being tested in pancreatic cancer patients at high-risk of relapse. If it’s shown to stimulate the intended immune response safely, it might then be used to stave off cancer’s potential return in treated patients, improve patient responses to checkpoint blockade therapy, and even has the potential to “help patients who are not yet patients” by preventing pancreatic cancer development in the first place.

Finally, Sacha Gnjatic, Ph.D., a leader of two separate CRI Clinical Team Grants at the Icahn School of Medicine at Mount Sinai, discussed tools his team has developed to overcome technical barriers and enable a better understanding of the interactions between cancer and the immune system, especially in the context of immunotherapy. This is important because, as several CRI scientists noted today, there is a need for predictive biomarkers that can help clinicians determine which immunotherapies will benefit which patients.

Dr. Gnjatic first discussed a technique dubbed MICSSS (multiplex immunohistochemical consecutive staining on single slide), which allows tumors to be analyzed for the presence of up to 10 immune markers simultaneously. With this, his team can characterize the different types of immune cells within tumors as well as determine their location. After checkpoint blockade, this analysis provided them with important insights into how the immunotherapy regimen impacted the immune cell activity within the tumor.

Lastly, Dr. Gnjatic covered his team’s use of mass cytometry (CyTOF) to cast an even wider analysis net for immune cells. While CyTOF doesn’t provide location information, with it his team can monitor up to 35 immune markers simultaneously and get a more comprehensive picture of the tumor-immune environment. They were also able to analyze immune cells in the blood, which have been shown to reflect immune activity in the tumor itself, but can be acquired much more non-invasively.

Today’s talks provided a great overview of the most pressing challenges remaining in immunotherapy, as well how scientists are addressing them. As the prologue of the conference, they indicate that much more interesting ideas and data in cancer immunotherapy will be revealed over the next four days. Check back tomorrow for our coverage of day two at #AACR17!

 

Photo credit: Pancreatic adenocarcinoma histology, The Human Protein Atlas

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