Association of reinvigoration of circulating anti-telomerase CD4 Th1 response in cancer patients with anti-PD-1 response.

Abstract

3044 Background: Increasing evidence highlights the crucial roles played by CD4+ Th1 cells in cancer immunity and immunotherapy (Spitzer et al., Cell 2017, Borst et al., Nat rev Immunol 2018). Here, we investigate the relevance of circulating CD4 Th1 response against shared tumor-associated antigens (TAA) in cancer patients treated by anti-PD-1 immunotherapy. Methods: A total of 46 advanced cancer patients (pts) including 32 pts with non-small cell lung cancer (NSCLC), 14 pts with melanoma, were enrolled (ITHER trial NCT02840058). Patients were treated with anti-PD-1 therapy as standard of care (26 pts with nivolumab and 20 pts with pembrolizumab). Peripheral blood mononuclear cells were collected before and after treatment at 1 and 3 months. The presence of circulating TAA-specific Th1 response was measured by IFNy ELISPOT assay using a mixture of 15mer peptides derived from telomerase (TERT) (Laheurte et al., Oncoimmunology 2016 and Br J C 2019). Results: At the baseline, the anti-TERT Th1 response was observed in 37% of pts. After anti-PD-1 therapy, de novo induction and/or amplification of pre-existing anti-TERT Th1 response was found in 26 % of pts (12/46). Whereas, a decrease of this response was documented in 15% of pts (7/46).The presence of anti-TERT Th1 response in peripheral blood during anti-PD-1 treatment was associated with a prolonged progression free-survival (PFS) as compared to the immune non responder pts (14.4 vs 2.6 months respectively, p = 0.006, HR 0.39 [0.2;0.76]). Similar observation was made for the overall survival (OS) (22.3 vs 12.3 months respectively, p = 0.04 HR 0.45 [0.21;0.96]). Notably, de novo reinvigoration of peripheral anti-TERT Th1 response after anti-PD-1 therapy was associated with a better clinical outcome as compared to the group of pts with decreased immune response after treatment (Median OS not reached vs 5.8 months). In contrast, no association with anti-PD-1 response was observed neither with circulating anti-NY-ESO-1 or with anti-viral Th1 response, concurrently measured in these patients. Conclusions: The reinvigoration of circulating CD4 Th1 against telomerase in patients treated by anti-PD-1 is associated with a better clinical outcome. These results underline the potential interest of monitoring circulating antitumor CD4 Th1 response for immune checkpoint inhibitors management.

Telomerase and CD4 T Cell Immunity in Cancer

“…This suggests that immune checkpoint inhibitors also act by recruiting peripheral T cells in addition to reinvigorating pre-existing tumor-infiltrating lymphocytes. Importantly, NSCLC patients with increased systemic anti-TERT CD4 T cell immunity after anti-PD-1 therapy were shown to have a better outcome [132]. Altogether, monitoring of anti-TERT CD4 T cell responses in vitro could greatly help refine the stratification of cancer patients and predict clinical outcome in response to immune checkpoint blockade (Figure 2).…”