Abstract 2711: Rational combination of GITR agonism with PD-1 blockade
Authors: Zappasodi Roberta , Sirard Cynthia , Li Yanyun , Budhu Sadna , Abu-Akeel Moshen , Liu Cailian , Yang Xia , Zhong Hong , Newman Walter , Qi Jingjing , Wong Philip , Schaer David , Koon Henry , Velcheti Vamsidhar , Callahan Margaret K. , Wolchok Jedd , Merghoub Taha 
Published: August 2019

Abstract
The clinical successes of checkpoint blockade have demonstrated that proper modulation of T cell co-inhibitory/co-stimulatory pathways can achieve substantial anti-tumor activity. However, many patients are or become refractory to checkpoint blockade. Additional forms of immunotherapy targeting alternative immune pathways are thus needed. Antibodies (Abs) engaging the TNF receptor GITR can enhance T cell functions and counteract regulatory T cell (Treg) suppression and have shown potent anti-tumor activity in animal models. Based on this evidence, we initiated the first in-human phase-I trial with the humanized aglycosylated anti-GITR Ab TRX518 (NCT01239134). Here, we report the immune effects of a single ascending dose of TRX518 monotherapy in 37 advanced cancer patients in this phase-I trial and provide mechanistic preclinical evidence to rationally combine GITR agonism with checkpoint blockade. We found that TRX518 frequently reduces circulating Tregs. In 8 patients for whom pre- and post-treatment tumor biopsies were available, reductions in intra-tumor and circulating Tregs after TRX518 were positively correlated. Yet, these patients did not experience substantial clinical responses. To explain this outcome, we modeled sensitivity and refractoriness to anti-GITR by treating B16F10-melanoma-bearing mice with the Ab DTA-1 on day 4 (curative regimen) or day 7 (refractory regimen) after tumor implantation respectively. We found that Tregs were significantly reduced and CD8+:Treg and Teff:Treg ratios increased in both responding and refractory tumors. Interestingly, CD8+ T cells from refractory tumors overexpressed T cell exhaustion markers and did not up-regulate memory and functional markers. We thus tested whether counteracting exhaustion could overcome resistance of advanced tumors to anti-GITR. PD-1 blockade in combination with anti-GITR starting on day 7 after tumor implantation controlled tumor growth similar to the curative anti-GITR monotherapy regimen (day 4 treatment) and achieved 50% complete response rate associated with long-lasting anti-tumor immunological memory. This was associated with more activated and less exhausted profiles of intra-tumor CD8+ T cells, which displayed enhanced tumor-lytic capacity compared to CD8+ T cells from non-responding tumors treated with each agent alone. These results indicate that Treg reduction can serve as a pharmacodynamic biomarker of anti-GITR in patients. However, Treg elimination from advanced tumors may not be sufficient to activate cytotoxic CD8+ T cell responses unless the T cell exhaustion process is concurrently blocked. This provides the rationale to combine immunotherapies targeting Tregs with strategies able to counteract exhaustion, such as anti-PD-1, to regress advanced tumors. Based on these observations, we have started to investigate TRX518 in combination with PD-1 pathway blockade in patients with advanced solid tumors (NCT02628574).
Citation Format: Roberta Zappasodi, Cynthia Sirard, Yanyun Li, Sadna Budhu, Moshen Abu-Akeel, Cailian Liu, Xia Yang, Hong Zhong, Walter Newman, Jingjing Qi, Philip Wong, David Schaer, Henry Koon, Vamsidhar Velcheti, Margaret K. Callahan, Jedd Wolchok, Taha Merghoub. Rational combination of GITR agonism with PD-1 blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2711.