Immunotherapy with agonistic antibodies to the glucocorticoid-induced tumour necrosis factor receptor-related protein (GITR) has shown promise in preclinical cancer models. Now, the results of a first-in-human study of one such agent, TRX518, have been reported.

In this phase I trial, 43 patients with advanced-stage solid tumours were treated with TRX518 at various doses. Pharmacodynamic studies revealed that TRX518 monotherapy effectively depleted regulatory T (Treg) cells from peripheral blood, interestingly, in apparent direct correlation with Treg cell depletion in tumour specimens. This finding raises the possibility of a minimally invasive biomarker assay of the effect of GITR agonists in tumours. However, blood CD8+ or CD4+ effector T (Teff) cell and natural killer cell populations were not notably modulated and, disappointingly, no objective clinical responses were observed: the best response was stable disease (n = 4).

In keeping with these clinical findings, mice with established tumours were found to be resistant to GITR agonism despite robust depletion of intratumoural Treg cells and corresponding increases in the ratio of Teff cells to Treg cells. By comparison, early tumours treated with a GITR agonist were more rapidly depleted of — and thus failed to accumulate — Treg cells and were responsive to treatment. Treg cell accumulation in established tumours before treatment was associated with imprinting of Teff cells with an exhausted phenotype, which could not subsequently be reversed by Treg cell depletion alone. Accordingly, exhausted, PD-1+ T cells persisted in patient tumour specimens with the highest levels of Treg cell depletion. Importantly, however, reinvigoration of T cells via PD-1 inhibition rescued the responsiveness of established mouse tumours to GITR agonism.

“Studies of the pharmacodynamic effects of GITR agonism with TRX518 enabled us to design the appropriate treatment regimen for rational, science-based combination therapy,” summarizes study co-lead Taha Merghoub. “We plan to further study the effects of GITR agonism in combination with PD-1 antagonism or chemotherapy and define biomarkers of clinical responses,” he adds. Indeed, the authors have initiated a trial using TRX518 in combination with PD-1 inhibitors (NCT02628574), with promising clinical responses already observed, including after disease progression on prior anti-PD-1 therapy.

conclusions on the importance of a pathway or drug should not be based solely on therapeutic outcomes

“Our study shows that conclusions on the importance of a pathway or drug should not be based solely on therapeutic outcomes: in depth study of the biological effects of a drug is key to designing efficacious treatment regimens,” Merghoub concludes.