In a phase I clinical trial, 43 patients with advanced cancers were treated with a single dose of TRX518, an agonistic monoclonal antibody that triggers GITR signaling, inducing hyperactivation and destabilization of activated Tregs. Treatment was well-tolerated and reduced peripheral and intratumoral Tregs, however, it did not induce clinical responses. Mouse models suggested that extended exposure to Tregs induces PD-1+ exhaustion in effector T cells, limiting their antitumor efficacy. Combining anti-GITR with anti-PD-1 to reverse cell exhaustion overcame resistance in mice. Early clinical results of the combination are promising.
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 (Teff) functions(14,15) and hamper regulatory T cell (Treg) 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 Treg cells to similar extents, providing an easily assessable biomarker of anti-GITR activity. Despite Treg reductions and increased Teff:Treg 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 ).