Abstract 911: Anti-PD-L1 and anti-CD73 combination therapy promotes T cell response to EGFR mutant NSCLC
Authors: Eric Tu, Kelly McGlinchey, Yelena Lazdun, James Kurasawa, Susan Wilson, Leslie Wetzel, Karen Coffman, Zachary Cooper, Katie Streicher
Journal: Cancer Research (2020)

Abstract It has been reported that NSCLC patients with EGFR mutation do not respond to anti-PD-1(L1) therapies as well as patients without the mutation. We have previously shown that EGFR mutant tumors express more CD73 compared to EGFR wildtype tumors and we hypothesized that this may contribute to the resistance to anti-tumor immunity and anti-PD-1(L1) therapies. To understand how CD73 expression in EGFR mutant tumors may confer immunosuppression, we compared EGFR mutant cell lines (PC9, HCC2935) and wildtype cell lines (H1666, H1355) in in vitro T cell killing assays. Furthermore, we investigated the effect of anti-CD73 antibody, either as a monotherapy or in combination with anti-PD-L1 antibody, in promoting tumor growth inhibition (TGI) using a xenograft mouse model. In this model, NSG mice were implanted with MART1-expressing PC9 cells and treated with MART1-specific CD8+ T cells together with anti-PD-L1, anti-CD73 or combination. We showed that CD73 expression is regulated by EGFR signaling in NSCLC, possibly through activation of Protein Kinase C (PKC). EGFR mutant cell lines were significantly more resistant to T cells killing compared to wildtype cell lines in vitro, by suppressing T cell proliferation and function as indicated by Ki-67 and granzyme B expression. In the xenograft mouse model using MART1-expressing PC9 cells, anti-PD-L1 did not promote TGI compared to isotype control, which closely mimicked the limited therapeutic effect of anti-PD-1(L1) antibodies on EGFR mutant NSCLC. Although anti-CD73 alone did not reduce tumor size, mice treated with anti-CD73 and anti-PD-L1 combination therapy had significantly smaller tumors compared to mice treated with isotype control (~38%, p&amp;lt;0.0001), anti-PD-L1 alone (~32%, p&amp;lt;0.0001) or anti-CD73 alone (~32%, p&amp;lt;0.01). The combination therapy increased the number of MART1-specific CD8+ T cells in the tumor compared to isotype control (~280%, p&amp;lt;0.01), anti-PD-L1 alone (~556%, p&amp;lt;0.001) and anti-CD73 alone (~270%, p&amp;lt;0.01). The combination therapy also increased the frequency of CD62L+CD45RO+CCR7+ phenotype in CD8+ T cells in the spleen compared to isotype control (~120%, p&amp;lt;0.001), but not in the tumor, as well as enhancing IFNγ production by tumor antigen-specific CD8+ T cells compared to isotype control (~224%, p&amp;lt;0.001). Together, these results further support the ongoing clinical trials evaluating combination of anti-CD73 and anti-PD-L1 in treating EGFR mutant NSCLC while suggesting the increased central memory T cells may play a role in response to therapy. Citation Format: Eric Tu, Kelly McGlinchey, Yelena Lazdun, James Kurasawa, Susan Wilson, Leslie Wetzel, Karen Coffman, Zachary Cooper, Katie Streicher. Anti-PD-L1 and anti-CD73 combination therapy promotes T cell response to EGFR mutant NSCLC [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 911.