Although durable responses to single agent immune checkpoint inhibitors have been reported, additional approaches are needed to extend this therapeutic benefit to a greater proportion of patients. Combination of immunotherapy agents with tumor microenvironment modulators has the potential to overcome barriers that tumor cells develop to evade the immune system, and provide benefit to a greater proportion of patients. Focal Adhesion Kinase (FAK) and the family member PYK2 are potentially valuable targets due to their roles in regulating key cellular populations in the tumor microenvironment. The FAK/PYK2 dual inhibitors, VS-6063 and VS-4718, have previously been shown to inhibit monocyte-derived macrophages, reduce tumor-associated macrophages in xenograft models, and promote a CD8+ T cell-mediated anti-tumor response in squamous cell carcinoma models.
We now report the combination of VS-4718 with an anti-PD-1 mAb shows substantially improved efficacy over anti-PD-1 mAb alone in MC38 syngeneic tumor-bearing animals. Analysis of MC38 tumors at day 12 of treatment revealed a significant increase in the CD8+ T cell/Treg ratio in tumors in the VS-4718 + anti-PD-1 combination group, providing a mechanistic understanding for the enhanced efficacy of this combination.
To explore additional combination options, we tested the combination of VS-4718 with anti-4-1BB in the MC38 model. Consistent with what was observed with the anti-PD-1 combination, addition of VS-4718 also enhanced the efficacy of an anti-4-1BB mAb inducing full tumor regression.
To further delineate the effect of FAK inhibition, an in vitro T cell proliferation assay was conducted. VS-6063 and VS-4718 dose-dependently stimulated proliferation of CD8+ cytotoxic T cells isolated from healthy donors. This is in distinct contrast to other protein kinase inhibitors, such as the SRC inhibitor dasatinib which potently impaired the proliferation of CD8+ cytotoxic T cells. In addition, both VS-4718 and VS-6063 decreased CD8+ T cell exhaustion markers (LAG3 and PD-1), and increased T cell-mediated tumor cell killing in vitro.
These data provide additional rationale for ongoing clinical trials testing the FAK/PYK2 inhibitor VS-6063 in combination with pembrolizumab (anti-PD-1) plus gemcitabine in pancreatic cancer or in combination with avelumab (anti-PD-L1) in ovarian cancer.
Citation Format: Jonathan A. Pachter, David T. Weaver. FAK/PYK2 inhibition enhances antitumor efficacy of anti-PD-1 and anti-4-1BB antibodies [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B031.
- ©2016 American Association for Cancer Research.