Using lung epithelial and colorectal cancer mouse models, Riva et al. showed dual contrasting effects of combining anti-NKG2A ICB with therapeutic heterologous prime-boosts of KISIMATM protein vaccines and VSV-GP-TAg oncolytic viruses. NKG2A blockade reversed the exhaustion status, but not the magnitude of vaccine-induced intratumoral antigen-specific CD8+ T cells, and improved antitumor efficacy and mouse survival. In contrast, NKG2A blockade impeded vaccine stimulation of peripheral antigen-specific CD8+ T cell responses, promoted vaccine-induced generation of blood and splenic CD8+ TCM rather than TEM cells, and impaired the response to tumor rechallenge.
Contributed by Paula Hochman
ABSTRACT: Immune check-point blockade (ICB) has revitalized cancer immunotherapy, showing unprecedented efficacy despite only a narrow number of indications and with limited long-term protection. Cancer vaccines are promising combination partners for ICB to widen the patient population profiting from these treatments. Therapeutic heterologous prime-boost vaccination with KISIMA(TM) protein vaccine and VSV-GP-TAg oncolytic virus was shown to inflame the tumor microenvironment, promoting significant infiltration of antigen-specific CD8 T cells resulting in robust antitumoral efficacy in mouse tumor models, and clinical trials are currently ongoing. Here, we report the impact of NKG2A blockade on antitumoral CD8 T cell immune response elicited by KISIMA-VSV-GP-TAg vaccination in tumor mouse models. Combination therapy significantly reduced the amount of vaccine-induced exhausted CD8 T cells infiltrating the tumor, resulting in short-term improved tumor growth control and prolonged mouse survival, while it also influenced the establishment of systemic effector memory CD8 T cell response. Taken together, these data show a compartment-dependent effect of NKG2A blockade on cancer vaccine-induced T cell immunity, increasing intratumoral T cell efficacy and attenuating the development of peripheral effector memory CD8 T cell response.
Author Info: (1) Amal Therapeutics, Fondation Pour Recherches Médicales, Avenue de la Roseraie 64, 1205 Geneva, Switzerland. Boehringer Ingelheim International GmbH, 55216 Ingelheim, Germany. (
Author Info: (1) Amal Therapeutics, Fondation Pour Recherches Médicales, Avenue de la Roseraie 64, 1205 Geneva, Switzerland. Boehringer Ingelheim International GmbH, 55216 Ingelheim, Germany. (2) Amal Therapeutics, Fondation Pour Recherches Médicales, Avenue de la Roseraie 64, 1205 Geneva, Switzerland. Boehringer Ingelheim International GmbH, 55216 Ingelheim, Germany. (3) Amal Therapeutics, Fondation Pour Recherches Médicales, Avenue de la Roseraie 64, 1205 Geneva, Switzerland. Boehringer Ingelheim International GmbH, 55216 Ingelheim, Germany. (4) Amal Therapeutics, Fondation Pour Recherches Médicales, Avenue de la Roseraie 64, 1205 Geneva, Switzerland. Boehringer Ingelheim International GmbH, 55216 Ingelheim, Germany. (5) Amal Therapeutics, Fondation Pour Recherches Médicales, Avenue de la Roseraie 64, 1205 Geneva, Switzerland. Boehringer Ingelheim International GmbH, 55216 Ingelheim, Germany. (6) Amal Therapeutics, Fondation Pour Recherches Médicales, Avenue de la Roseraie 64, 1205 Geneva, Switzerland. Boehringer Ingelheim International GmbH, 55216 Ingelheim, Germany. (7) Amal Therapeutics, Fondation Pour Recherches Médicales, Avenue de la Roseraie 64, 1205 Geneva, Switzerland. Boehringer Ingelheim International GmbH, 55216 Ingelheim, Germany.
