Rational design of anti-GITR-based combination immunotherapy

Modulating T cell homeostatic mechanisms with checkpoint blockade can efficiently promote endogenous anti-tumor T cell responses 1 – 11 . However, many patients still do not benefit from checkpoint blockade 12 , highlighting the need for targeting of alternative immune pathways 13 . Glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) is an attractive target for immunotherapy, owing to its capacity to promote effector T cell (T eff ) functions 14 , 15 and hamper regulatory T cell (T reg ) suppression 16 – 20 . On the basis of the potent preclinical anti-tumor activity of agonist anti-GITR antibodies, reported by us and others 16 , 21 , 22 , we initiated the first in-human phase 1 trial of GITR agonism with the anti-GITR antibody TRX518 ( NCT01239134 ). Here, we report the safety profile and immune effects of TRX518 monotherapy in patients with advanced cancer and provide mechanistic preclinical evidence to rationally combine GITR agonism with checkpoint blockade in future clinical trials. We demonstrate that TRX518 reduces circulating and intratumoral T reg cells to similar extents, providing an easily assessable biomarker of anti-GITR activity. Despite T reg reductions and increased T eff :T reg ratios, substantial clinical responses were not seen. Similarly, in mice with advanced tumors, GITR agonism was not sufficient to activate cytolytic T cells due to persistent exhaustion. We demonstrate that T cell reinvigoration with PD-1 blockade can overcome resistance of advanced tumors to anti-GITR monotherapy. These findings led us to start investigating TRX518 with PD-1 pathway blockade in patients with advanced refractory tumors ( NCT02628574 ). GITR agonism can be exploited in combination with checkpoint blockade to overcome immune refractoriness in solid tumors.