Clinical Activity of an hTERT-Specific Cancer Vaccine (Vx-001) in “Immune Desert” NSCLC

SIMPLE SUMMARY: We investigated whether there is any correlation between Vx-001 clinical activity and the tumor immune microenvironment (TIME). Our hypothesis was that Vx-001 should be clinically effective in patients with tumor-infiltrating lymphocyte (TIL) negative/low infiltrated (non-immunogenic/cold) tumors which are lacking immunosuppressive TIME but not in highly TIL infiltrated (immunogenic/hot) tumors associated with immunosuppressive TIME. In this study, we show that the tumor vaccine Vx-001 offers a clinical benefit in patients with tumors lacking or weakly infiltrated with TILs. In contrast, Vx-001 is completely inactive in the context of tumors highly infiltrated with TILs, thus confirming our hypothesis. TIL negative/low tumor signature is an independent predictive factor of Vx-001 efficacy. To our knowledge, this is the first study showing an inverse correlation between tumor vaccine efficacy and the presence of TILs. These data support the selection of patients with TIL negative or low infiltrated tumors (i.e., patients known to be resistant to immune checkpoint inhibitors (ICIs) and with poor prognosis) as the best candidates to receive tumor vaccines and to get a clinical benefit from vaccination. ABSTRACT: Background: Tumors can be separated into immunogenic/hot and non-immunogenic/cold on the basis of the presence of tumor-infiltrating lymphocytes (TILs), the expression of PD-L1 and the tumor mutation burden (TMB). In immunogenic tumors, TILs become unable to control tumor growth because their activity is suppressed by different inhibitory pathways, including PD-1/PD-L1. We hypothesized that tumor vaccines may not be active in the immunosuppressive microenvironment of immunogenic/hot tumors while they could be efficient in the immune naïve microenvironment of non-immunogenic/cold tumors. Methods: The randomized phase II Vx-001-201 study investigated the effect of the Vx-001 vaccine as maintenance treatment in metastatic non-small cell lung cancer (NSCLC) patients. Biopsies from 131 (68 placebo and 63 Vx-001) patients were retrospectively analyzed for PD-L1 expression and TIL infiltration. TILs were measured as tumor-associated immune cells (TAICs), CD3-TILs, CD8-TILs and granzyme B-producing TILs (GZMB-TILs). Patients were distinguished into PD-L1(+) and PD-L1(-) and into TIL high and TIL low. Findings: There was no correlation between PD-L1 expression and Vx-001 clinical activity. In contrast, Vx-001 showed a significant improvement of overall survival (OS) vs. placebo in TAIC low (21 vs. 8.1 months, p = 0.003, HR = 0.404, 95% CI 0.219–0.745), CD3-TIL low (21.6 vs. 6.6 months, p < 0.001, HR = 0.279, 95% CI 0.131–0.595), CD8-TIL low (21 vs. 6.6 months, p < 0.001; HR = 0.240, 95% CI 0.11–0.522) and GZMB-TIL low (20.7 vs. 11.1 months, p = 0.011, HR = 0.490, 95% CI 0.278–0.863). Vx-001 did not offer any clinical benefit in patients with TAIC high, CD3-TIL high, CD8-TIL high or GZMB-TIL high tumors. CD3-TIL, CD8-TIL and GZMB-TIL were independent predictive factors of Vx-001 efficacy. Conclusions: These results support the hypothesis that Vx-001 may be efficient in patients with non-immunogenic/cold but not with immunogenic/hot tumors.