Many patients still do not benefit from immune checkpoint blockade. Therefore, there is a need for targeting of alternative immune pathways. Glucocorticoid-induced tumour necrosis factor receptor-related protein (GITR) is an attractive target for immunotherapy, owing to its capacity to promote effector T cell functions and hamper regulatory T cell suppression. Two recent reports from the studies published in the Nature Medicine and reported at ASCO 2019 Annual Meeting draw attention to GITR targeting opportunities.
On the basis of the potent preclinical anti-tumour activity of agonist anti-GITR antibodies, a group of researchers led by Jedd D. Wolchok and Taha Merghoub of the Memorial Sloan Kettering Cancer Center, New York, USA initiated the first in-human phase I trial of GITR agonism with the anti-GITR antibody TRX518.
In the letter published on 29 April 2019 in the Nature Medicine, the study team reported 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.
The researchers demonstrated that TRX518 reduces circulating and intratumoural regulatory T cells to similar extents, providing an easily assessable biomarker of anti-GITR activity. Despite regulatory T cell reductions and increased effector T cell: regulatory T cell ratios, substantial clinical responses were not seen. Similarly, in mice with advanced tumours, GITR agonism was not sufficient to activate cytolytic T cells due to persistent exhaustion. The study team demonstrated that T cell reinvigoration with PD-1 blockade can overcome resistance of advanced tumours to anti-GITR monotherapy.
These findings led the study team to start investigating TRX518 with PD-1 pathway blockade in patients with advanced refractory tumours.
The TCR sequencing data that support the findings are available on the immuneACCESS Analyzer portal.
This research was funded in part through the US NIH/NCI grants, the Swim Across America, Ludwig Institute for Cancer Research, Ludwig Center for Cancer Immunotherapy at Memorial Sloan Kettering, Cancer Research Institute, Parker Institute for Cancer Immunotherapy and Breast Cancer Research Foundation.
The second study was presented at Clinical Science Symposium entitled ‘Next-Generation Therapeutics and Biomarkers in Melanoma’ during ASCO 2019 Annual Meeting (31 May – 4 June, Chicago, US). Data from the first-in-human phase I study of MK-4166 as monotherapy or in combination with pembrolizumab were presented. MK-4166 is a humanized IgG1 agonist monoclonal antibody targeting GITR.
Study included a dose escalation/confirmation cohort in metastatic solid tumours and an expansion cohort of treatment-naive and pretreated melanoma. A T cell inflamed gene expression profile was assessed using RNA from baseline tumour samples. Of 113 patients, 48 received monotherapy and 65 combination therapy; 20 were in the melanoma expansion.
Common adverse events (>20%) were fatigue, infusion-related reaction, nausea, abdominal pain, and pruritus; 7.7% of patients experienced grade 3-4 treatment-related adverse events with the combination of MK-4166 plus pembrolizumab. One dose-limiting toxicity (bladder perforation in a urothelial patient with a neobladder) possibly related to study drug was observed with monotherapy. No treatment-related deaths were observed.
MK-4166 at a dose up to 900 mg as monotherapy and in combination with pembrolizumab was well tolerated, with dose-related evidence of target engagement. Responses were observed with MK-4166 900 mg plus pembrolizumab, particularly in patients with melanoma naive to immune checkpoint inhibitors.
For immune checkpoint inhibitors naive melanoma patients, the objective response rate (ORR) was 69% (9 of 13 patients), including four complete responses and 5 partial responses. No response was observed in 7 patients previously treated with immune checkpoint inhibitors. High ORRs were observed in non-inflamed and inflamed immune checkpoint inhibitors-naive melanoma patients.
Janice M. Mehnert of the Rutgers Cancer Institute of New Jersey who discussed the study data said that ORR rate seen in this study is intriguing, although the study sample size is small.
The study was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Zappasodi R, Sirard C, Li Y, et al. Rational design of anti-GITR-based combination immunotherapy. Nature Medicine 2019; 25(5):759–766.
Papadopoulos KP, Autio KA, Golan T, et al. Phase 1 study of MK-4166, an anti-human glucocorticoid-induced tumor necrosis factor receptor (GITR) antibody, as monotherapy or with pembrolizumab (pembro) in patients (pts) with advanced solid tumors. J Clin Oncol 37, 2019 (suppl; abstr 9509).