Περίληψη:
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. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
Συγγραφείς:
Pateras, I.S.
Kotsakis, A.
Avgeris, M.
Baliou, E.
Kouroupakis, P.
Patsea, E.
Georgoulias, V.
Menez-Jamet, J.
Kinet, J.-P.
Kosmatopoulos, K.
Λέξεις-κλειδιά:
cancer vaccine; CD3 antigen; granzyme B; immune checkpoint inhibitor; placebo; programmed death 1 ligand 1; telomerase reverse transcriptase; unclassified drug; vx 001, aged; Article; cancer prevention; cancer prognosis; cancer resistance; cancer survival; comparative effectiveness; controlled study; drug efficacy; female; human; human tissue; immunocompetent cell; lymphocytic infiltration; major clinical study; male; multicenter study; non small cell lung cancer; overall survival; prediction; protein expression; randomized controlled trial; tumor associated immune cell; tumor associated leukocyte; tumor biopsy; tumor microenvironment
