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October 03, 2016

The Future of Immunotherapy Is Not Stopping at the Checkpoints

Session Notes from the Second International Cancer Immunotherapy Conference

The Future of Immunotherapy Is Not Stopping at the Checkpoints

At the Second International Cancer Immunotherapy Conference, researchers discussed their current work in cancer immunotherapy that goes beyond the class of checkpoint inhibitor compounds [elvanegra/Getty]

  • Given the marketing onslaught by the pharmaceutical industry for drugs such as Keytruda, Opdivo, Tecentriq, and Yervoy it would be natural to assume that cancer immunotherapy falls into either the category of immune checkpoint inhibitor compounds or everything else. Yet, there is quite a broad range of therapeutic modalities that can be classified as immunotherapeutic, with history describing William B. Coley—an American surgeon and cancer researchers—using a mixture of bacteria and bacterial lysates to successfully treat malignant tumors as early as 1893.

    In the ensuing century since “Coley’s Toxins” were first used, research has become more sophisticated, and our knowledge of the immune system has expanded exponentially, allowing investigators to develop some truly unique and clever ways to “jump start” immune cells into seek-and-destroy mode. Recently, at the Second International Cancer Immunotherapy Conference, organized by the Cancer Research Institute (CRI), Cancer Immunotherapy (CIMT), the European Academy of Tumor Immunology (EATI), and the American Association for Cancer Research (AACR), researchers gathered to discuss the current state of cancer immunotherapy, with this year’s theme being “Translating Science into Survival.”

    In particular, one session at the conference stood out, as it sought to address immunotherapy approaches that lie outside of the immune checkpoint strategy approach—the session was aptly named Non-Checkpoint Immunotherapies.

    The session was chaired by Glenn Dranoff, M.D., global head of immune-oncology at the Novartis Institutes for Biomedical Research, and Axel Hoos, M.D., Ph.D., svp and head of Immuno-Oncology at GlaxoSmithKline. Dr. Hoos lead the sessions with a brief summary of immunotherapy development strategies from generation one, which begin with the approval of Ipilimumab (Yervoy) in 2011, into generation three, which constituted many therapies currently under development and the basis for many of the presentations at the session.

    Exploiting the activation of T-cell receptors (TCR) has been an area of interest with immunologists for a number of years, particularly in respect to cancer, as the disease has been known to suppress the activation of cytotoxic T-cell responses to allow tumor proliferation. Christina Coughlin, M.D., chief medical officer at Immunocore, presented her company’s work on TCR activation through the use of bispecific antibodies. Specifically, Dr. Coughlin described a new class of bispecific therapeutics called ImmTACs (immune-mobilizing monoclonal TCRs against cancer), which utilizes a TCR fused to an anti-CD3 domain, which provides extremely high affinity for their targets. Dr. Coughlin also spoke about preliminary results from IMCgp100, the first ImmTAC tested clinically, which has a TCR recognizing the gp100 melanoma antigen.

    Early clinical studies show that IMCgp100 has a favorable safety profile and a durable response against both cutaneous and uveal melanomas. Tumor biopsy revealed that IMCgp100 induced T-cell infiltration into tumors and provided evidence for combining the drug along with anti-PDL1 and anti-CTLA4 therapies for cutaneous melanoma. Conversely, efficacy data supported monotherapy use in uveal melanoma cases.           

    Next up was Patrick Mayes, Ph.D., director and early development leader at GSK, who gave a presentation entitled “Targeting inducible T cell co-stimulator (ICOS) promotes effector T cell function and antitumor response.”  ICOS is a T cell-restricted co-stimulatory receptor that belongs to the CD28/CTLA immunoglobulin superfamily, which is highly induced on CD4+ and CD8+ T cells, upon TCR activation. Dr. Mayes described his team’s development of a humanized monoclonal antibody (mAb) that has high affinity to human ICOS, delivering agonistic activity while stimulating effector CD4+ and cytotoxic CD8+ T cell activation, expansion, and function. Preclinical studies with this antibody (H2L5) showed a well-tolerated safety profile and strong rational to combine the mAb with other anticancer agents. Due to encouraging preclinical data, GSK has initiated a Phase I trial to test H2L5 alone and in combination with anti-PD1 against solid tumors.

    Finally, another area where researchers are looking to gain a better understanding, so as to control the immune response against cancer, is the tumor microenvironment (TME). The TME is the cellular environment in which a tumor resides—typically consisting of fibroblasts, blood vessels, immune cells, and extracellular matrix molecules. Interestingly, resistance to immunotherapies such as PD-1 has been shown to be associated with the presence of transcripts from genes associated with angiogenesis and wound healing—suggesting that targeting the TME could improve various immunotherapy compounds.

    In a presentation given by Viviana Cremasco, Ph.D., an investigator at the Novartis Institutes for Biomedical Research, Dr. Cremasco revealed how her group’s work has shown that the reticular matrix secreted by myofibroblasts promotes the compartmentalization of tumor-infiltrating leukocytes, establishing an incredibly dynamic interaction between T cells and the stroma. These interactions promote the secretion of nitric oxide, which impedes the proliferation of lymphocytes. This data further supports the hypothesis that fibroblasts contribute to immunosuppression by creating nonpermissive immune cell domains within the TME. Most interestingly, Dr. Cremasco explained how her group’s work supports the notion of targeting the tumor collagen networks to augment T cell tumor penetration and increase anti-tumor immunity. This may prove to be a valuable approach to improving and extending the clinical benefits of current immunotherapy regimens.

    The session continued with other exciting talks about distinct approaches toward cancer immunotherapy from the use of oncolytic viruses to target tumors and generate a massive immune response, to integrin-targeted immunotherapies. The information provided in this session was extensive and encouraging, as the next few years should deliver some exciting new results and possibly entire new classes of drugs to combat a multitude of cancers.

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