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AACR17 Update: CAR T Cells, Regulatory T Cells, and the Future of Immunotherapy

April 02, 2017

Day two of the annual meeting of the American Association for Cancer Research (AACR17) began with a talk titled “The Cancer-Immune Set Point and the Future of Cancer Immunotherapy” by Genentech’s Daniel S. Chen, M.D., Ph.D., co-chair of the Cancer Research Institute (CRI) Cancer Immunotherapy Consortium (CIC), a think tank focused on industry issues in immunotherapy drug development.

Daniel S. Chen, M.D., Ph.D.Echoing a refrain heard frequently during day one of the conference, Dr. Chen’s talk confronted the fact that, while current checkpoint immunotherapies have benefited many patients, the benefits aren’t always permanent and only extend to a portion of patients.

To provide longer-term relief to more patients, Dr. Chen suggested a three-step process in which other therapies are used to complement existing PD-1/PD-L1 immunotherapies, which typically work best against tumors that have already attracted the immune system’s attention.

The first step is induction, which involves making tumors immunogenic, or in other words, making them more noticeable to the immune system. Then, once the immune system has recognized the tumor, PD-1/PD-L1 immunotherapies are added to prevent cancer cells from de-activating the immune cells. Finally, treatments are applied to help maintain the anti-tumor immune response over time and provide long-term protection.

However, different tumors behave differently, so an induction treatment that works for one tumor might not work for another. Therefore, this approach will need to be personalized for individual patients to achieve optimal effect.

To help simplify this, Dr. Chen proposed a hypothetical algorithm to guide treatment decisions for different patients depending on their specific tumor-immune characteristics, an approach that mirrors the CRI-Fight CRC Blueprint for colorectal cancer that was presented at last year’s AACR annual meeting and could be applied to all cancers.

Stanley Riddell, M.D.Next, Stanley R. Riddell, M.D., of the Fred Hutchinson Cancer Research Center and the University of Washington, gave a talk titled “Understanding Success and Failure of T Cell Therapy for B Cell Malignancies.”

Dr. Riddell, who is a SU2C-CRI Cancer Immunology Translational Research Dream Team grantee as well as a member of the CRI Scientific Advisory Council, discussed how his team is working to improve CAR T cell immunotherapies for patients with leukemia and lymphoma.

Typically, patients undergoing CAR T therapy receive a “gemisch” of T cells, as Dr. Riddell called it, meaning a mix of different types of T cells. However, some T cells are better than others at promoting anti-tumor activity, which led Dr. Riddell to wonder, “could we identify effective T cell subsets and formulate consistent products for all patients?”

Fortunately, his team determined the answer was yes.

By selecting the T cells with the most beneficial properties, they demonstrated the feasibility of this approach in a clinical trial and were able to generate these CAR T cells from all patients, even those with low immune cell counts. Amazingly, all 34 of the patients with ALL (acute lymphoblastic leukemia) who were analyzed after treatment had complete responses, meaning that their tumors had completely disappeared.

larry-fong2.jpgWhile Dr. Riddell’s approach deals with the immune cells directly responsible for targeting and eliminating cancer cells, the strategy employed by University of California, San Francisco’s Lawrence Fong, M.D. goes after cancer indirectly, by targeting immune cells known as regulatory T cells (Tregs) that can help protect tumors from killer T cells.

The approach taken by Dr. Fong, a CRI Clinical Team Leader, targets the Ezh2 enzyme, which helps maintain undesirable Treg activity. By disrupting Ezh2, his team showed that they could subvert the pro-cancer Tregs and enhance anti-cancer activity without impacting the important role of Tregs in preventing damage from autoimmune attacks against healthy tissues.

Roberta Zappasodi, Ph.D.Later, Roberta Zappasodi, Ph.D., discussed another Treg-targeting strategy being explored in the lab of Memorial Sloan Kettering Cancer Center’s Jedd D. Wolchok, M.D., Ph.D., an associate director of the CRI Scientific Advisory Council and director of CRI’s clinical research program.

Their approach uses an antibody called TRX-518 to target the GITR receptor on Tregs. In a CRI-funded clinical trial, they found that treatment was associated with a reduction in the number of circulating Tregs.

Further analysis suggested that, similar to Dr. Fong’s Ezh2-targeting approach, GITR-stimulation via TRX-518 converted Tregs into effector T cells. This, Dr. Zappasodi noted, meant that reduction of circulating Tregs could serve as a potential biomarker of TRX-518 activity in patients, and they are now investigating this effective in a clinical trial to determine its relevance to responses in patients.

The evening concluded with a “town hall” meeting of the Cancer Immunology (CIMM) Working Group, organized by the Society for Immunotherapy of Cancer (SITC). The capacity audience heard presentations on immunotherapy biomarkers from Lisa H. Butterfield, Ph.D., of the University of Pittsburgh Cancer Institute, and an overview of mouse models used in cancer research from Yale University School of Medicine’s Marcus W. Bosenberg, M.D.

Olivera J. Finn, Ph.D.Incoming CIMM chair Jedd D. Wolchok, M.D., Ph.D., also recognized this year’s winner of the Fifth Annual AACR-CRI Lloyd J. Old Award in Cancer Immunology, Olivera J. Finn, Ph.D., of the University of Pittsburgh, in celebration of her pioneering work in cancer vaccination. On Tuesday, Dr. Finn will give a talk titled, “Vaccines for Cancer Prevention: The Risk Worth Taking.”

Be sure to check out our coverage of day three of AACR17.

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