8th Annual Cancer Immunotherapy Conference

Wednesday, May 30, 2018

In April, the William Blair Biotechnology Research Team co-hosted the Eighth Annual Cancer Immunotherapy Conference in New York with Maidstone Life Sciences.  The two-day event was divided into four themes: Adoptive Cell Therapies, Jump-Starting the Immune System, Next-Generation Approaches, and Immunotherapy Combinations.

William Blair analyst Katherine Xu, Ph.D., stated, “The emergence of immunotherapy represents a paradigm shift in cancer treatment, which we expect to continue to evolve rapidly.” She continued, “the conference pulled together leaders from academia and industry to discuss a series of carefully selected topics to capture the current hot areas of development and point to future directions.”  The conference featured presentations from eight leading academicians, two seasoned industry consultants, and 29 companies including large pharma and biotech companies.

Following the groundbreaking approvals of Kymriah and Yescarta, adoptive T-cell therapies continue to rapidly evolve and these initially approved therapies are just the tip of the iceberg. Several companies at the conference discussed the next-generation programs being developed including dual-targeting CARs, TCRs, and NK cells. Dr. Renier Brentjens, M.D., Ph.D., director of Cellular Therapies at Memorial Sloan Kettering (MSK) spoke extensively on the ‘armored’ CARs being developed in his lab to address solid tumors. These next-generation CARs utilize a variety of mechanisms to increase persistence, such as the secretion of IL12, IL18, or specific single chain variable fragments (scFvs).

“The scientific advances in the field of CAR-Ts have garnered significant attention from both the industry and investors,” stated William Blair analyst Raj Prasad, Ph.D. Dr. Sergio Giralt, chief of the Adult Bone Marrow Transplant Service at MSK discussed some headwinds from the commercial launch of CAR-T products, notably the cost of care on top of the CAR-T therapy itself, including nights in the intensive care unit. “Although there have been initial challenges in establishing broad commercial infrastructure, these may be addressed through further experience gained from treatment centers as well as anticipated progress in manufacturing processes and continued innovation in the adoptive T cell field, including potential “off the shelf” products,” Dr. Prasad noted.

A focus throughout the conference was on how to turn “cold” tumors “hot.” Ira Mellman, Ph.D., vice president of Cancer Immunology at Genentech eloquently outlined three different types of immune phenotypes: an “inflamed” in which T cells are infiltrated into the tumor but non-functional primarily due to high PD-L1 expression on tumor cells, an ‘immune exclusion’ in which T-cells are blocked from effectively infiltrating a tumor, and an ‘immune desert’ in which no immune response is observed at all and tumor PD-L1 expression is the lowest. The latter two phenotypes represent patients unlikely to respond to PD-(L)1 monotherapy, but likely require different strategies for combinations.

In the case of an ‘immune exclusion,’ additional immunosuppressive mechanism, such as tumor stroma, MDSCs, TAMs or Tregs, may be blocking T-cell infiltration, and therefore combinations targeting these cell types may prove effective. Several companies at the conference discussed possible mechanisms, including Infinity’s PI3Ky (gamma) inhibitor to switch macrophage fate from M2 (pro-tumor) to M1 (anti-tumor), and other targets for development including CSFR-1 and Tim3.

In the case of an ‘immune desert,’ robust signals must jump-start an immune response, and Dr. Xu highlighted data upcoming this year from Dynavax’s TLR9 agonist and Aduro’s STING agonist, in addition to other approaches such as oncolytic viruses and neoantigen vaccines in development by several companies as potential combination options. Further, William Blair analyst Matt Phipps, Ph.D., stated, “given the significant and growing number of patients who become resistant to checkpoint inhibitors, several companies are specifically designing clinical trials in these patient populations.” He highlighted Idera's recently initiated Phase III with IMO-2125, a TLR9 agonist, in combination with Yervoy in PD-1 refractory melanoma patients; Aduro's recently expanded trial of ADUS100, a STING agonist, to include a combination with Yervoy in similar patients; and Calithera's combining of CB-839, a glutaminase inhibitor, plus Opdivo in attempt to 'rescue' patients who have disease progression on prior PD-1 regimen across several different tumor types.

There is a growing focus on tyrosine kinase inhibitors (TKIs). More so than in years past, clinicians and scientists from several companies highlighted the synergies observed when combining established therapies such as tyrosine kinase inhibitors, PARP inhibitors, and chemotherapy regimens with PD-(L)1 inhibitors to extend the number of patients who achieve clinical benefit. TKIs have shown promise, particularly in RCC and bladder cancer, when used in combination with PD-(L)1 antibodies. Although a specific mechanism may be unclear for each TKI depending on the kinases inhibited, there is evidence for altering the tumor microenvironment and immunosuppressive cell types. William Blair analyst Andy Hsieh, Ph.D., noted that “several ongoing Phase III studies are testing these combinations, including Keytruda plus Inlyta in RCC, Exelixis’s Cabometyx plus Opdivo in RCC, and Exelixis’s Cotellic plus Tecentriq in colorectal cancer.”

Chemotherapy also can achieve synergistic effects with anti-PD-(L)1 agents. Ruslan Novosiadly, M.D., Ph.D., senior research advisor of Experimental & Translational Immuno-oncology at Eli Lilly & Company presented detailed work outlining the ability of pemetrexed to induce immunologic tumor cell death, which can facilitate an anti-tumor immune response, particularly when combined with checkpoint antibodies. This may be particularly interesting when comparing Merck’s KEYNOTE-189 results, combining Keytruda plus pemetrexed and cisplatin/carboplatin versus other chemotherapy plus PD-(L)1 regimens in non-small cell lung cancer, such as Roche’s Tecentriq plus carboplatin and paclitaxel.

Scientist-clinicians are placing a greater focus on mechanisms of resistance to PD-(L)1 monotherapy, addressing the “excluded” and the “desert” phenotypes: Dr. Roy Herbst and his team at Yale have an extensive program ongoing to try to analyze patients who relapse on checkpoint inhibitors, noting that up to 50% of patients with non-small cell lung cancer become resistant after showing benefit. Although the program is still in the early stages of gathering patient data, Dr. Herbst noted that they have seen multiple patients who lose MHC Class I expression through beta-2-microglobulin knock out in tumor cells. This would preclude the ability to generate a T-cell response, and therefore Dr. Herbst is evaluating mechanisms preclinically to potentially treat these patients, including with NK cell therapies.

This is the longest standing cancer immunotherapy conference for the investment community and industry.  William Blair started co-hosting the conference in 2016, when the four major themes were Checkpoint/Immune Modulators, Vaccines, Cell Therapy, and Combo Approaches. In 2017, we expanded the conference to two days and more topics were added, including tumor microenvironment, neoantigens, and overcoming PD-1 resistance.

For a copy of the full review of this year’s Cancer Immunotherapy Conference or for more information on companies from the William Blair Biotech Team’s coverage list, please contact your William Blair sales rep.

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