Intratumoral co‐injection of NK cells and NKG2A ‐neutralizing monoclonal antibodies

Abstract

NK‐cell reactivity against cancer is conceivably suppressed in the tumor microenvironment by the interaction of the inhibitory receptor NKG2A with the non‐classical MHC‐I molecules HLA‐E in humans or Qa‐1 b in mice. We found that intratumoral delivery of NK cells attains significant therapeutic effects only if co‐injected with anti‐NKG2A and anti‐Qa‐1 b blocking monoclonal antibodies against solid mouse tumor models. Such therapeutic activity was contingent on endogenous CD8 T cells and type‐1 conventional dendritic cells (cDC1). Moreover, the anti‐tumor effects were enhanced upon combination with systemic anti‐PD‐1 mAb treatment and achieved partial abscopal efficacy against distant non‐injected tumors. In xenografted mice bearing HLA‐E‐expressing human cancer cells, intratumoral co‐injection of activated allogeneic human NK cells and clinical‐grade anti‐NKG2A mAb (monalizumab) synergistically achieved therapeutic effects. In conclusion, these studies provide evidence for the clinical potential of intratumoral NK cell‐based immunotherapies that exert their anti‐tumor efficacy as a result of eliciting endogenous T‐cell responses. image An approach that involves intratumoral injections of NK cells together with neutralizing antibodies against the NKG2A inhibitory receptor was developed, aiming at extending the efficacy of NK cell‐based immunotherapies to solid malignances. Intratumoral co‐injection of pre‐activated NK cells and NKG2A neutralizing antibodies achieves synergistic anti‐tumor activity against solid mouse tumor models. CD8 T cell‐ and cDC1 responses mediate the anti‐tumor efficacy of intratumoral NK cells and anti‐NKG2A/Qa‐1b mAb administrations. Systemic anti‐PD‐1 mAb injections synergistically enhance the efficacy of intratumoral NK cells + anti‐NKG2A/Qa‐1 b mAbs. Intratumoral delivery of human NK cells and monalizumab (anti‐NKG2A) to xenografted mouse tumors exerts synergistic effects.