Abstract LB-152: Local selivery of GITR agonistic antibody induces a stronger antitumor immunity than systemic administration

Abstract

Abstract The field of cancer immunotherapy is expanding rapidly with the success of an antagonistic antibody against CTLA-4 and PD-1/PD-L1. However, since approximately half of patients do not respond to the therapies even the combination regimen, the development of novel checkpoint inhibitors is desired for the recurrent or refractory patients. Recently, newer targets including select members of the tumor necrosis factor receptor (TNFR) family, including 4-1BB, OX40 and glucocorticoid-induced tumor necrosis factor receptor (GITR), are gathering attention. GITR is expressed at a low basal level on naïve murine T cells and at a very low level on human T cells, whereas a GITR ligand (GITRL) was abundantly expressed in murine dendritic cells and macrophages. Multiple studies have shown that GITR-GITRL interaction can provide a co-stimulatory signal to both CD4+ and CD8+ naïve T cells, enhancing proliferation and effector function, particularly in the setting of suboptimal T cell receptor stimulation. In contrast, murine and human Tregs constitutively express GITR, and it had been shown that activation of GITR signaling by GITR ligand or agonistic antibody inhibit the suppressive activity of Tregs. To enhance the antitumor effect of immune stimulatory reagents, we have been focusing on the intratumoral administration route. Since the GITR agonistic Ab directly activates effector T cells and suppresses Tregs, the increase of Ab concentration in tumors and surrounding tissues including lymph nodes by the intratumoral route may enhance only the tumor-infiltrating T cells and break the tumor-specific immune-tolerant microenvironment, sparing the unexpected effect on the systemic immune system. In this study, first, in a murine colon cancer model, we showed that the intratumoral delivery of Ab significantly increased the number of effector T cells infiltrated into tumors, and suppressed tumor growth more effectively than the intraperitoneal injection did. Then, we found that the injection of Ab into the peritumoral area induced a systemic antitumor immunity at a similar level to the intratumoral injection. Therefore, we hypothesized that the transfer of locally administrated Ab into tumor-draining lymph nodes (TDLNs) plays an important role in inducing an effective immunity. In fact, intratumorally or peritumorally injected Ab was detected in TDLNs, and resection of Ab-injected TDLNs significantly reduced GITR Ab-mediated systemic tumor immunity. Intratumoral injection showed less number of auto-reactive T cells in the spleen than the intraperitoneal injection did. Furthermore, the AH-1 tetramer assay and ELISpot assay showed that the combination of GITR Ab with anti-PD-1 Ab synergistically enhanced an induction of antitumor immunity, leading to eradication of the tumor. Intratumoral delivery of GITR Ab is a promising approach to induce an effective immunity than the systemic delivery. Citation Format: Kazunori Aoki, Kenta Narumi, Chihiro Shibasaki, Reina Miyakawa. Local selivery of GITR agonistic antibody induces a stronger antitumor immunity than systemic administration [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 LB-152.