BackgroundCheckpoint inhibitor (CPI) monotherapy has revolutionized the treatment of melanoma, yet most patients are primary nonresponders or develop secondary resistance. Lack of antigen-specific T cell priming and/or immunosuppressive mechanisms leading to T cell exhaustion are critical cancer-extrinsic factors contributing to CPI resistance mechanisms. Immunotherapeutic agents capable of sparking de novo anti-tumor T cell responses or reinvigorating pre-existing exhausted T cell immunity could help reinstate the activity of CPI.MethodsOur Phase 2, multi-center, open label study, NCT02981303 in collaboration with Merck & Co., Inc., is evaluating Imprime PGG (Imprime), a novel yeast derived, Dectin-1 agonist, β-glucan PAMP in combination with pembrolizumab (KEYTRUDA®, pembro) in heavily CPI pre-treated melanoma patients (20 patients; 65% had >2 prior CPI regimens with 17/20 having previously progressed on pembro). Patients received Imprime (4 mg/kg) + pembro (200 mg) intravenously in a 3-week cycle. Here, we present the immunopharmacodynamic (IPD) responses elicited by Imprime and pembro in the peripheral blood of 19 patients.ResultsIn the intent-to-treat population (ITT; N=20), the disease control rate was 45% (1 CR and 8 SD), 6-month and 12-month OS rates were 65% and 45% respectively, and median OS (mOS) was 8.8 months. In the patients showing disease control, a significant increase in CH50, the classical pathway complement function (~0.7-2.6-fold), HLA-DR expression on classical monocytes (~0.61-1.94-fold) and reduction of frequency of PD-1+Tbet-EOMES+ exhausted CD8 T cells (~0.9-4-fold) was observed. Stimulation of peripheral blood mononuclear cells from a subset of patients by CD3/CD28 beads showed enhanced production of IL-2 and IFN-gamma in the CD8 T cells. Some of these IPD responses were also associated with 6-month landmark OS analyses. Additionally, whole blood gene expression analyses showed >2-fold upregulation of several myeloid and T cell activation genes including IFNg, CD83, IP-10, and IL-2RA. Enhanced OS was observed in patients with >1.3 fold increase in CH50 (8/19; HR 0.385; p=0.1) or >1.5-fold reduction in the frequency of exhausted CD8 T cells (8/19; HR 0.102; p=0.001). The IPD responses observed in the ITT population included formation of circulating immune complexes (peak levels ranging from ~4.5-16.1-fold) and production of complement activation protein SC5b9 (~3.4-25.6-fold), and increase in the frequency of HLA-DR+ myeloid cells (~0.43-3.71-fold).ConclusionsOverall, these data, albeit in a small population, demonstrate that Imprime/pembro combination can drive the innate/adaptive IPD responses that are critical for providing clinical benefit to the patients who have progressed through prior CPI treatments.Ethics ApprovalThe study was approved by central and local ethics committees depending on site requirements. The central IRB for the study is Western Institutional Review Board (WIRB), approval number 20162506; all sites received IRB approval before opening the study at the respective sites.
Chromatin accessibility of circulating CD8+ T cells predicts treatment response to PD-1 blockade in patients with gastric cancer
