Key Industry Topics Discussed at the Ninth Annual Cancer Immunotherapy Conference

Thursday, April 25, 2019

The William Blair Biotechnology Team co-hosted the ninth annual Cancer Immunotherapy Conference on March 20 and 21 in New York. This conference showcases the scientists and clinicians driving the advancements in the field of cancer immunotherapy and is designed to facilitate discussion with the audience to further elucidate underlying mechanisms of biology and promising novel therapies. The field continues to advance at an impressive pace, although setbacks in several clinical trials in 2018 highlight the continued need for a greater understanding of the underlying biology of cancer immunotherapies.

"In the ninth year of this conference," biotech analyst Katherine Xu stated, "we addressed key topics in the landscape of cancer immunotherapy with presentations from academic experts and industry scientists actively working in each specific discipline of cancer immunotherapy." She continues to believe the evolving treatment paradigm creates numerous opportunities for stakeholders in the field to ultimately drive benefit for patients. A number of key questions and themes emerged from presentations and discussions at the conference.

Focus on three key trends in adoptive cell therapies advancing concurrently: 1) increasing efficacy through the addition of genetically engineered constructs, 2) moving beyond CD19 and BCMA to novel targets (particularly in solid tumors), and 3) advancements in off-the-shelf technologies (both T cells and other immune cell types). Significant work is being done in the field to improve on the efficacy established with Yescarta and Kymriah, as it was continually noted that not every patient is cured with these therapies. According to biotech analyst Raj Prasad, "the Key data sets anticipated in 2019 include the Phase III results with Atara's tabelecleucel in post-transplant lymphoproliferative disease and mesothelin CAR in mesothelioma, Celyad's CYAD-001 in AML and CYAD-101 in CRC, Allogene/Servier's UCART-19 in r/r ALL, Tmunity's PSMA CAR-T in prostate cancer and NY-ESO-1 TCR-T in multiple indications, and Autolus's four clinical therapies (AUTO1 through AUTO4)."

Searching for synergy: Following setbacks with PD-(L)1 combinations over the past year, namely the ECHO-301 Phase III trial of epacadostat plus Keytruda in metastatic melanoma, the industry continues to search for PD-(L)1 combinations that have the potential to provide synergistic benefit to patients. Dr. Emmett Schmidt, M.D., Ph.D., scientific associate vice president of oncology clinical research at Merck, provided an interesting perspective on the results of combination studies to date and used mathematical modeling to demonstrate that most PD-(L)1 combination studies have not shown true synergistic benefit. While the data relied heavily on cross-trial comparisons from uncontrolled Phase I studies, it highlights that non-overlapping mechanisms of action, such as platinum chemotherapy or tyrosine kinase inhibitors plus immunotherapies, have the potential to provide greater benefit to an unselected patient population (i.e., some patients respond to the TKI and some to the immunotherapy). In addition, non-overlapping mechanisms of action reduce the risk of one mutation leading to tumor cells developing resistance. For instance, knockout of beta-2 microglobulin will prevent the ability of T cells to recognize antigens on a tumor, and therefore any combination therapies designed to boost T cells will be unlikely to be able to overcome this.

However, Dr. Schmidt maintains the importance of fully evaluating novel PD-(L)1 combinations, and highlighted the initial results of Keytruda plus Lenvima as showing very impressive response rates and potential synergy, leading to Phase III studies in tumors such as endometrial and non–small-cell lung cancer. Analyst Andy Hsieh notes the initial results of PD-(L)1 combinations with TKIs is encouraging for Exelixis' Cabometyx, which is in several ongoing studies including the Phase III CheckMate-9ER study with Opdivo in newly-diagnosed renal cell carcinoma. Lastly, Dr. Schmidt drew attention to the use of mouse models as an imperfect but necessary means of screening potential clinical combinations. At Merck they use multiple syngeneic models for evaluating novel combinations, selecting one with high responses to PD1 monotherapy (such as MC38), a second with partial responses to PD1 monotherapy (such as CT-26), and a third with low responses to PD1 monotherapy (such as B16/F10). To date, this has still only resulted in a 55% positive predictive value for selecting combinations that result in positive initial human data.

Significant focus remains on stimulating the innate and adaptive immune systems and modulating the tumor microenvironment. Given the significant number of patients who lack an appropriate immune response in the tumor or whose immune cells are excluded from infiltrating into the tumor (considered an immune desert or immune excluded phenotype, respectively), many companies and academics remain focused on novel mechanisms to overcome these pathways. Several key modalities were discussed at the conference including targeting neoantigens, pathways to stimulate innate cells and antigen presentation (Neoantigen vaccines, TLR and STING agonists, and CD40 antibodies), oncolytic viruses, targeting MDSCs, and blocking the adenosine pathway. Xu highlights Lieping Chen's keynote presentation on the discovery of Siglec-15, a novel immune suppression pathway upregulated on human cancers and tumor infiltrating myeloid cells. Interestingly, Siglec15 expression is upregulated by macrophage colony stimulating factor (M-CSF) and downregulated by interferon-gamma (IFNγ), and therefore the expression profile is mutually exclusive to PD-L1 expression and could provide a resistance mechanism in PD-L1 negative tumors.

A treatment landscape with bispecifics, CAR-T, and transplants. With the potential for physicians to have bispecifics (T-cell engagers), adoptive cell therapies such as CAR-Ts, and hematopoetic stem cell transplants as available options for patients with leukemia, lymphoma, and myeloma, it is clear the treatment paradigm is in flux. A panel discussion on this topic concluded that while it is too early to declare true winners, an off-the-shelf therapy with reasonable costs would likely get preference if efficacy is not too far below more intensive modalities. However, all three modalities will likely be used across different treatment settings. Due to the rise of engineered cell therapies, transplant use in specific indications has been in decline. However, in many hematologic malignancies successful stem cell transplant continues to provide the greatest potential for durable cures, such as AML, and therefore bispecifics and cell therapies may be used as a bridge to transplant. Lastly, while T-cell engaging bispecifics have garnered significant attention recently, dual-checkpoint and tumor-antigen checkpoint bispecifics are generating increased enthusiasm in the industry. Biotech analyst Matt Phipps highlights the PD-(L)1 x 4-1BB bispecifics entering clinics as ones to watch, although initial dose escalation studies will take time as regulators continue to require caution when agonistic immune targets are included.

For a copy of the "Highlights From the Ninth Annual Cancer Immunotherapy Conference" report or for more information on the companies from Katherine Xu's, Matt Phipps', Andy Hsieh's, and/or Raj Prasad's coverage list, please contact your William Blair sales rep.

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