Abstract 2342: NKG2A immune checkpoint blockade enhances the anti-tumor efficacy of PD1/PD-L1 inhibitors in a preclinical model
Authors: Sola Caroline , Arnoux Thomas , Chanuc Fabien , Fuseri Nicolas , Rossi Benjamin , Gauthier Laurent , Leget Corinne , Bonnafous Cécile , Wagtmann Nicolai , Morel Yannis , André. Pascale 
Published: July 2016

Monalizumab (IPH2201) is a novel, first-in-class humanized IgG4 targeting the immune checkpoint receptor NKG2A (Natural Killer Group 2A). NKG2A is expressed as a heterodimer with CD94 on the surface of subsets of cytotoxic lymphocytes: NK (Natural Killer) cells, γδ T cells and tumor infiltrating CD8 T lymphocytes. CD94/NKG2A is an inhibitory receptor that binds to HLA-E (Human Leukocyte Antigen-E) in humans and orthologous Qa-1b in mice. Upon ligand binding, CD94/NKG2A triggers inhibitory signaling that reduces NK and CD8 T cell responses. HLA-E is frequently up-regulated on cancer cells of many solid tumors or hematological malignancies, protecting from killing by NKG2A+ immune cells. By blocking the binding of CD94/NKG2A to HLA-E, monalizumab leads to enhancement of NK and cytotoxic T cell responses.

The immune checkpoint receptor programmed cell death 1 (PD-1) is another inhibitory receptor widely upregulated by tumor-infiltrating T lymphocytes (TILs). In many tumor types immune surveillance is hampered by the expression of PD-L1, one of the ligands of PD-1. Blocking the PD-1 pathway has proven efficient as anti-tumor therapy. Nevertheless many patients remain refractory to these therapeutics. Combination treatment with PD-1 blockers and mAb to a second checkpoint receptor, CTLA-4, have proven effective only for some patients, suggesting a need for combining with other checkpoint blockers.

The A20 cell line is a mouse B cell lymphoma line that expresses PD-L1, but not Qa-1b. Upon subcutaneous injection into Balb/c mice, A20 formed solid tumors in which PD-L1 expression was retained and where Qa-1b expression was induced. A20 tumor growth was controlled by NK and CD8 T cells. In spite of high expression of PD-1 on many immune infiltrating cells, and high expression of PD-L1 on tumor cells, monotherapy with anti-PD-1 or -PD-L1 mAb resulted in only moderate reduction in tumor growth.

Interestingly, more than 50% of A20 tumor infiltrating NK cells and about 10% of CD8 T cells expressed CD94/NKG2A. The NKG2A+ CD8 T cell population also co-expressed PD-1. Qa-1b expression was induced not only on the surface of tumor cells but also on infiltrating immune cells in vivo. Consistent with the hypothesis that Qa-1b protects tumor cells from killing by NKG2A+ effector NK and T cells, treatment with an antibody that blocks NKG2A significantly delayed A20 tumor growth. Mice were then treated with both anti-NKG2A and anti-PD-1 or -PD-L1 in combination. These combinations resulted in significantly higher anti-tumor responses compared to monotherapies, characterized by an increased frequency of complete tumor cell regression.

Together, these data indicate that blocking NKG2A in conjunction with PD-1/PD-L1 checkpoint inhibitors could provide synergistic anti-tumor efficacy and support the rationale for investigating this combination in clinical trials.

Citation Format: Caroline Sola, Thomas Arnoux, Fabien Chanuc, Nicolas Fuseri, Benjamin Rossi, Laurent Gauthier, Corinne Leget, Cécile Bonnafous, Nicolai Wagtmann, Yannis Morel, Pascale André. NKG2A immune checkpoint blockade enhances the anti-tumor efficacy of PD1/PD-L1 inhibitors in a preclinical model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2342.