Abstract 2220: Non-clinical tumor models reveal broad combination potential of ICOS agonist antibodies

Unprecedented rates of durable clinical responses have been observed for antibody-based therapeutics targeting immune checkpoint proteins such as cytotoxic T lymphocyte antigen-4 (CTLA-4) or programmed death receptor-1 (PD-1). Nonetheless, a significant number of patients fail to respond, highlighting the need for alternative and complementary immunotherapeutic interventions for cancer. Inducible T-cell costimulator (ICOS/CD278) is a CD28 superfamily receptor that is predominantly expressed on effector and cytotoxic T cells shortly after T cell receptor (TCR) activation. In addition to promotion of T cell and B cell collaboration, ICOS signaling (via ICOS ligand [ICOSL] or antibody-based crosslinking) has been shown to improve T cell antitumor activity, survival, durable tumor rejection. To support the clinical development of GSK3359609 (a hIgG4 ICOS agonist antibody) several in vivo combination studies were conducted using a tool anti-mouse ICOS agonist antibody (clone 7E.17G9). Analogous with the Fc-based characteristics of a human IgG4 antibody, the anti-mouse ICOS tool antibody exhibited significant antitumor activity when grafted on a murine IgG1 (or Fc-reduced) backbone. Using an in vivo models of breast cancer (EMT6, BALB/c), the murinized ICOS tool antibody demonstrated potent antitumor activity alone (tumor growth inhibition [TGI] of 40-60%) in combination with immune checkpoint inhibitors (ICI) targeting PD-1 and CTLA-4 (TGI of 100% and 90%, respectively). Antitumor activity was associated with increased total T cell infiltration into the tumor, a higher tumor CD8/Treg cell ratio, and broad increases in T cell activation markers (e.g. CD25, CD69, Granzyme B, perforin, and PD-1). The cancer immunity cycle posits that multiple points of intervention exist for cancer immunotherapy, many of which should be considered in order to identify complementary therapeutic strategies. With this in mind, and consistent with ICI, antitumor activity was observed in combination with innate immune modulators (e.g. TLR4 agonist) and chemo/cytotoxic (e.g. carboplatin and paclitaxel) therapies in different syngeneic tumor models. Altogether these data underscore the broad utility of ICOS agonist antibodies as a reliable combination partner for cancer immunotherapy. Citation Format: Jeremy D. Waight, Meixia Bi, David Kilian, Christopher Hopson, Shu-Yun Zhang, Sara Brett, Sapna Yadavilli, Tianqian Zhang, Hong Shi, Kenneth W. Hance, Marc Ballas, Axel Hoos. Non-clinical tumor models reveal broad combination potential of ICOS agonist antibodies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2220.