PT  - JOURNAL ARTICLE
AU  - Palakurthi, Sangeetha
AU  - Kuraguchi, Mari
AU  - Zacharek, Sima J.
AU  - Zudaire, Enrique
AU  - Huang, Wei
AU  - Bonal, Dennis M.
AU  - Liu, Jeffrey
AU  - Dhaneshwar, Abha
AU  - DePeaux, Kristin
AU  - Gowaski, Martha R.
AU  - Bailey, Dyane
AU  - Regan, Samuel N.
AU  - Ivanova, Elena
AU  - Ferrante, Catherine
AU  - English, Jessie M.
AU  - Khosla, Aditya
AU  - Beck, Andrew H.
AU  - Rytlewski, Julie A.
AU  - Sanders, Catherine
AU  - Laquerre, Sylvie
AU  - Bittinger, Mark A.
AU  - Kirschmeier, Paul T.
AU  - Packman, Kathryn
AU  - Janne, Pasi A.
AU  - Moy, Christopher
AU  - Wong, Kwok-Kin
AU  - Verona, Raluca I.
AU  - Lorenzi, Matthew V.
TI  - The Combined Effect of FGFR Inhibition and PD-1 Blockade Promotes Tumor-Intrinsic Induction of Antitumor Immunity
AID  - 10.1158/2326-6066.CIR-18-0595
DP  - 2019 Sep 01
TA  - Cancer Immunology Research
PG  - 1457--1471
VI  - 7
IP  - 9
4099  - http://cancerimmunolres.aacrjournals.org/content/7/9/1457.short
4100  - http://cancerimmunolres.aacrjournals.org/content/7/9/1457.full
SO  - Cancer Immunol Res2019 Sep 01; 7
AB  - 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.