The Combined Effect of FGFR Inhibition and PD-1 Blockade Promotes Tumor-Intrinsic Induction of Antitumor Immunity

[D.ap]

The Combined Effect of FGFR Inhibition and PD-1 Blockade Promotes Tumor-Intrinsic Induction of Antitumor Immunity




Abstract

The success of targeted or immune therapies is often hampered by the emergence of resistance and/or clinical benefit in only a subset of patients. We hypothesized that combining targeted therapy with immune modulation would show enhanced antitumor responses. Here, we explored the combination potential of erdafitinib, a fibroblast growth factor receptor (FGFR) inhibitor under clinical development, with PD-1 blockade in an autochthonous FGFR2K660N/p53mut lung cancer mouse model. Erdafitinib monotherapy treatment resulted in substantial tumor control but no significant survival benefit. Although anti–PD-1 alone was ineffective, the erdafitinib and anti–PD-1 combination induced significant tumor regression and improved survival. For both erdafitinib monotherapy and combination treatments, tumor control was accompanied by tumor-intrinsic, FGFR pathway inhibition, increased T-cell infiltration, decreased regulatory T cells, and downregulation of PD-L1 expression on tumor cells. These effects were not observed in a KRASG12C-mutant genetically engineered mouse model, which is insensitive to FGFR inhibition, indicating that the immune changes mediated by erdafitinib may be initiated as a consequence of tumor cell killing. A decreased fraction of tumor-associated macrophages also occurred but only in combination-treated tumors. Treatment with erdafitinib decreased T-cell receptor (TCR) clonality, reflecting a broadening of the TCR repertoire induced by tumor cell death, whereas combination with anti–PD-1 led to increased TCR clonality, suggesting a more focused antitumor T-cell response. Our results showed that the combination of erdafitinib and anti–PD-1 drives expansion of T-cell clones and immunologic changes in the tumor microenvironment to support enhanced antitumor immunity and survival.

https://cancerimmunolres.aacrjournals.o ... t/7/9/1457

[D.ap]

Cancer immunotherapies, such as those targeting the immune checkpoint PD-1, have revolutionized cancer treatment across a variety of tumor types, including NSCLC. However, only a subset of patients benefits from PD-1/PD-L1 checkpoint blockade. Lack of response to immunotherapy is characterized by several factors, such as a noninflamed tumor microenvironment (TME) with limited infiltrating T cells and/or the presence of immunosuppressive cell types. Tumor genetics can also influence response to checkpoint inhibitors, as evidenced by reports showing that activation of the β-catenin/Wnt pathway renders a non-T cell–inflamed TME (12). Patients with tumors carrying low mutational burden or certain driver pathway mutations such as ALK or EGFR benefit much less from anti–PD-1 or anti–PD-L1 therapy due to a lack of an inflammatory microenvironment and CD8+ T cells that recognize tumor neoantigens (13–15). Overall, these data suggest that defects in antitumor immunity need to be addressed to extend immunotherapy benefit in patients with these driver pathway mutations (16). Here, we specifically explored the contribution of tumor-intrinsic targeting of FGFR driver pathway mutations and its impact on remodeling the TME in an autochthonous lung cancer FGFR2-driven mouse model with low mutational burden (17). Our data showed the key role of FGFR inhibition on remodeling the immune microenvironment of tumors, especially inducing new T-cell responses, which in turn acts in concert with anti–PD-1 to promote antitumor immunity. These results provide a rationale for the combined clinical testing of erdafitinib and PD-1 blockade in patients with FGFR-altered tumors.