Combination of monalizumab and durvalumab as a potent immunotherapy treatment for solid human cancers

Inhibitory CD94-NKG2A (Natural Killer Group 2A) receptors are expressed on subsets of natural killer (NK) cells, γδ and CD8 + T cells. HLA-E (Human Leukocytes Antigen-E), the ligand for CD94-NKG2A, is upregulated on cancer cells of several solid tumors, providing a negative regulatory signal to tumor-infiltrating lymphocytes (TILs). Blockade of this immune checkpoint pathway with anti-NKG2A monoclonal antibodies (Ab) enhances NK cell responses to tumor cells in vitro and in humanized mice. Here, we describe NK and CD8 + T cell infiltrates in several human solid tumors by immunohistochemistry (IHC) and multicolor flow cytometry. We then studied the effects of in vitro targeting both pathways on primary human NK and CD8 + T cells. By using IHC on formalin-fixed paraffin-embedded samples on cohorts of solid tumors i.e. non-small cell lung cancer (NSCLC, n=45), stomach tumor (n=76), colorectal cancer (CRC, n=103), head and neck tumor (HNSCC, n=68), pancreatic tumors (n=77) and renal cell carcinoma (RCC, n=75), we observed NKp46 + NK cells in the large majority of cancer types (especially in RCC, HNSCC and stomach cancers). CD8 + T cells were found at significantly higher densities in all tumor types. In another cohort of HNSCC samples (n=60), higher proportions of CD94 + lymphocytes were found within the tumor islets both in the primary tumors and in the metastatic lymph nodes. In addition, in CRC patients with liver metastasis (n=101), high CD94 + cell densities were associated with poor overall survival. These data suggest that NKG2A blockade might unleash NK and T cells that are present in close contact to tumor cells. As previously shown, we confirmed that CD94-NKG2A ligand, HLA-E, was expressed by tumor cells in the large majority of solid tumor. In addition, high PD-L1 expressions were observed in NSCLC, stomach tumors, CRC and HNSCC. Flow cytometry analyses revealed that NK and CD8 + T cells co-expressing NKG2A and PD-1 were more numerous in tumor compared to matched peripheral blood and adjacent tissues of NSCLC and HNSCC patients. To mimic the “NKG2A + PD-1 +” TILs phenotype, chronic stimulation of peripheral blood cells from healthy volunteers was performed using IL-15. The conditions led to the induction of NKG2A and PD-1 on NK and antigen-specific CD8 + T cell subsets. These effector cells were then co-cultured with tumor cell lines expressing HLA-E +/- PD-L1. We showed that monalizumab, a first-in class anti-NKG2A Ab, combined with durvalumab resulted in higher responses (CD107 mobilization and IFN-γ production) compared to each Ab alone. These data were confirmed in a syngeneic mouse model where both NK and CD8 + T cells were found to be involved in tumor rejection. Together, these data confirm that blocking NKG2A can potentiate the anti-tumor efficacy of PD-1 inhibitors and support the rationale for ongoing clinical trials investigating the monalizumab/durvalumab combination (NCT02671435 and NCT03088059). Citation Format: Caroline Soulas, Romain Remark, Vedran Brezar, Julie Lopez, Elodie Bonnet, Flavien Caraguel, Ana Lalanne, Caroline Hoffmann, Caroline Denis, Thomas Arnoux, Clarisse Caillet, Arnaud Dujardin, Guillaume Habif, Olivier Lantz, Cecile Bonnafous, Eric Vivier, Pascale Andre. Combination of monalizumab and durvalumab as a potent immunotherapy treatment for solid human cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2714.