GITR agonism and anti–PD-1 therapy reduces Tregs and reinvigorates exhausted CD8+ T-cell activity.
Major finding: GITR agonism and anti–PD-1 therapy reduces Tregs and reinvigorates exhausted CD8+ T-cell activity.
Concept: GITR activation concomitantly reduces Tregs and enhances anti–PD-1–mediated T-cell reactivation.
Impact: Combined anti-GITR and anti–PD-1 therapy is a potential strategy in patients with advanced solid tumors.
Despite the recent success of immunotherapy against several cancer types, many patients are resistant or acquire resistance to this treatment, highlighting a need for alternative approaches to modulate immune function. Zappasodi and colleagues report the results of a phase I clinical trial on 43 patients with refractory solid tumors to assess the safety, pharmacodynamics, pharmacokinetics, and immune effects of TRX518, an agonist for glucocorticoid-induced tumor necrosis factor receptor–related protein (GITR), whose activation can promote effector T-cell function and inhibit regulatory T-cell (Treg) function. Treatment with TRX518 resulted in reduced levels of GITR-expressing, suppressive Tregs in peripheral blood, at tumor sites, and within the tumors. Despite this, monotherapy with TRX518 was insufficient to mediate substantial clinical responses. To investigate mechanisms of resistance to this monotherapy, the agonist anti-GITR antibody DTA-1 was administered 4 days (early) or 7 days (advanced) post-implantation in a murine model of advanced melanoma. Inhibition of GITR at either time point reduced Treg populations, but only early treatment delayed tumor growth compared with untreated tumors. Moreover, late treatment resulted in significant increases in dysfunctional CD8+ T-cell populations that expressed an exhausted profile and failed to upregulate markers of activation and cytotoxicity. Supplementation of DTA-1 with PD-1 blockade in advanced tumors reduced tumor growth to levels comparable to early DTA-1 monotherapy and reinvigorated CD8+ T cells, which displayed enhanced tumor lytic capacity. This combinatorial treatment induced regression and protected against tumor rechallenge, indicating the development of long-term antitumor immunologic memory. Anti-GITR and anti–PD-1 also increased survival in a murine model of poorly immunogenic, highly metastatic breast carcinoma. Taken together, these results show that combined activation of GITR and inhibition of PD-1 can be an effective strategy in patients with advanced solid tumors and have resulted in the establishment of a clinical trial exploring this combinatorial therapy.
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