We previously reported that DRP-104, a novel broad acting glutamine antagonist, has significant therapeutic potential in cancer by directly targeting tumor metabolism and simultaneously inducing a potent antitumor immune response. We also reported the immunomodulatory effect of DRP-104 on tumor growth inhibition (TGI) as a single agent and in combination with PD-1/PD-L1 checkpoint inhibitors in the MC38 and CT26 colon cancer syngeneic models(1). DRP-104 mediated TGI is associated with increased tumor-infiltrating leukocytes (TIL) including T, NKT, and NK cells; M1-polarized tumor associated macrophages; and decreased immune-suppressive cells such as MDSCs.Here we further elucidate the immunomodulatory effect of DRP-104 on tumor growth inhibition. In the MC38 mouse model, CD8+, CD4+, or NK cells were depleted by anti-CD8+Ab, anti-CD4+Ab, or anti-asialoGM1 Ab respectively to assess the contribution of these immune cells towards DRP-104 efficacy. CD8+T cell depletion significantly reduced anti-tumor efficacy for DRP-104 (73.9% TGI in CD8+T depletion setting vs 120% TGI with 57.8% regression in undepleted animals). NK cell depletion delayed early anti-tumor response to DRP-104 treatment, while in undepleted mice DRP-104 treatment showed TGI as early as 2 days after dose initiation. Interestingly, CD4+depleted mice showed enhanced efficacy to DRP-104 with TGI of 213% (regressions) and 6/8 tumor free mice 29 days after the end of treatment vs 1/8 mice tumor free in the CD4+ undepleted group with DRP-104 treatment. As such, we tested the combination of DRP-104 with anti-TIGIT antibody which has been reported to deplete Treg cells in the TME(2). In MC38 (anti-TIGIT insensitive) and CT26 (anti-TIGIT sensitive), DRP-104 showed significant single agent TGI. Furthermore, combination of DRP-104 with anti-TIGIT Ab demonstrated enhanced tumor growth inhibition and resulted in improvement in survival.

In summary, immune cell depletion experiments confirmed DRP-104's immuno-oncology mechanism of action. CD8+ or NK cell depletion reduced DRP-104 efficacy while CD4+ cell depletion enhanced efficacy. Furthermore, combination therapy of DRP-104 with anti-PD-1 or anti-TIGIT Ab achieved significantly enhanced anti-tumor efficacy even in checkpoint inhibitor resistant models. This unique and non-overlapping mechanism of action supports clinical development of DRP-104 alone and in combination with immune checkpoint inhibitors. The first in human clinical study of DRP-104 is ongoing.

References:

1.Yokoyama Y, Wild R. Abstract 5607: Cancer Research 2020;80:56072.Kurtulus S, Sakuishi K, Ngiow SF, Joller N, Tan DJ, Teng MW, et al. J Clin Invest 2015;125:4053-62

Citation Format: Yumi Yokoyama, Robert Wild. DRP-104, a broad acting glutamine antagonist, synergizes with immune checkpoint blockade in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1563.