Abstract 253: Synergistic antitumor activity of PD-1 signaling blockade and CD27 costimulation correlates with enhanced ratio of effector to regulatory T cells at the tumor site

Abstract

Abstract Varlilumab (CDX-1127) is a fully human agonist antibody to CD27, a TNF receptor superfamily member expressed on the majority of T cells and subsets of NK cells and B cells. As such, varlilumab is an immunotherapy designed to harness the body's natural immune response by enhancing the activation of T cells that can specifically recognize and kill cancer cells. In an ongoing Phase 1 clinical trial, varlilumab has been very well tolerated and has demonstrated clear biologic activity and promising signs of clinical activity in advanced, treatment-refractory patient populations. This clinical data provides the rationale for combination studies with other immunomodulatory therapies, including inhibitors of PD-1 signaling. In this study we investigated the activity of varlilumab in combination with anti-PD-L1 using a disseminated murine B cell tumor, BCL1 in human CD27 transgenic mice. In this model of i.v. inoculated BCL1 cells, we have previously shown that varlilumab can delay tumor growth, but rarely results in cures. Despite expression of PD-L1, the BCL1 tumors were completely resistant to anti-PD-L1 monotherapy. However, the combination of varlilumab and anti-PD-L1 resulted in a significant improvement in survival and approximately 50% long-term survivors. To investigate the mechanism resulting in the synergistic activity, we collected spleens (the major site of tumor growth) from tumor bearing animals treated with individual or combined regimens and processed them for flow cytometry analysis. We found that animals treated with the combination of varlilumab and anti-PD-L1 had a higher ratio of infiltrating immune cells to tumor cells relative to monotherapy or saline controls. In particular, the ratio of effector (CD8+) T cells to Treg and the number of IFNγ+ CD4 and CD8 T cells were highly increased with the combination treatment. These data demonstrate that CD27 costimulation combined with checkpoint inhibition with anti-PD-L1 can result in improved immune profile in the tumor and synergistic survival benefit. This study, along with the good safety profile of varlilumab reported in the Phase 1 study, support the design of future combination studies in patients with cancer. Citation Format: Lawrence J. Thomas, Li-Zhen He, Anna Wasiuk, Lauren E. Gergel, James M. Boyer, Sarah M. Round, Henry C. Marsh, Tibor Keler. Synergistic antitumor activity of PD-1 signaling blockade and CD27 costimulation correlates with enhanced ratio of effector to regulatory T cells at the tumor site. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 253. doi:10.1158/1538-7445.AM2015-253