Abstract 3628: PD-1 checkpoint blockade therapy enhances adoptive immunotherapy by human Vγ2Vδ2 T cells against prostate tumors in a preclinical model

Abstract

Abstract Cancer immunotherapy is an effective treatment against a variety of malignancies. Checkpoint blockade with anti-PD-1 or anti-CTLA-4 antibodies has resulted in durable clinical responses. However, targeting PD-1 or PD-L1 provides clinical benefits for only a minority of patients. Moreover, the effectiveness of checkpoint blockade correlates with the numbers of nonsynonymous mutations present in the tumor explaining the poor responsiveness of certain tumors such as prostate cancers. Therefore, additional therapies are needed for patients not currently responding. Unlike αβT cells, the anti-tumor activity of Vγ2Vδ2 T cells does not require MHC and is independent of the number of tumor mutations. Instead, Vγ2Vδ2 T cells use their TCRs to surveil tumor cells for alterations in isoprenoids metabolism induced by bisphosphonate treatment in a process requiring butyrophilin 3A1. This allows Vγ2Vδ2 T cells to recognize and kill all types of tumors. In clinical trials involving more than 200 patients, adoptive immunotherapy with Vγ2Vδ2 T cells has been proven to be safe. However, there have been few partial or complete responses with the most common beneficial response being stable disease. To find ways to increase its effectiveness, we have now assessed the benefits of combining PD-1 checkpoint blockade with the adoptive transfer of human Vγ2Vδ2 T cells. Vγ2Vδ2 T cells were found to express the major inhibitory receptors, PD-1, CTLA-4, LAG3, and TIM3 at varying times during the fourteen day ex vivo expansion period. To assess the effect of checkpoint blockade in vivo, immunodeficient NSG mice were inoculated with human PC-3 prostate cancer cells that naturally express the PD-L1 ligand. After 2 weeks, weekly treatments were started with intravenous pamidronate followed a day later by purified Vγ2Vδ2 T cells combined with either anti-PD-1 (clone J116) or control IgG1 mAbs. The addition of anti-PD-1 mAb treatment, markedly enhanced Vγ2Vδ2 T cell immunity to PC-3 tumors. Combination treatment was able to reduce tumor volume almost to zero after 5 weeks. These results demonstrate that PD-1 checkpoint blockade can greatly enhance adoptive immunotherapy with γδ T cells in a preclinical tumor model and suggests that combination therapy with anti-PD1 and Vγ2Vδ2T cells could be an effective strategy to treat patients with a variety of cancers. Citation Format: Mohanad H. Nada, Hong Wang, Craig Morita. PD-1 checkpoint blockade therapy enhances adoptive immunotherapy by human Vγ2Vδ2 T cells against prostate tumors in a preclinical model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3628.