American Association for Cancer Research
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Figure S3 from Anti-OX40 Antibody Directly Enhances The Function of Tumor-Reactive CD8+ T Cells and Synergizes with PI3Kβ Inhibition in PTEN Loss Melanoma

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journal contribution
posted on 2023-03-31, 21:10 authored by Weiyi Peng, Leila J. Williams, Chunyu Xu, Brenda Melendez, Jodi A. McKenzie, Yuan Chen, Heather L. Jackson, Kui S. Voo, Rina M. Mbofung, Sara Elizabeth Leahey, Jian Wang, Gregory Lizee, Hussein A. Tawbi, Michael A. Davies, Axel Hoos, James Smothers, Roopa Srinivasan, Elaine M. Paul, Niranjan Yanamandra, Patrick Hwu

In vivo effect of PI3K inhibition in combination with anti-OX40 treatment on T cell proliferation



Melanoma Research Alliance

Cancer Prevention and Research Institute of Texas



OX40 agonist–based combinations are emerging as a novel avenue to improve the effectiveness of cancer immunotherapy. To better guide its clinical development, we characterized the role of the OX40 pathway in tumor-reactive immune cells. We also evaluated combining OX40 agonists with targeted therapy to combat resistance to cancer immunotherapy.Experimental Design: We utilized patient-derived tumor-infiltrating lymphocytes (TILs) and multiple preclinical models to determine the direct effect of anti-OX40 agonistic antibodies on tumor-reactive CD8+ T cells. We also evaluated the antitumor activity of an anti-OX40 antibody plus PI3Kβ inhibition in a transgenic murine melanoma model (Braf mutant, PTEN null), which spontaneously develops immunotherapy-resistant melanomas. We observed elevated expression of OX40 in tumor-reactive CD8+ TILs upon encountering tumors; activation of OX40 signaling enhanced their cytotoxic function. OX40 agonist antibody improved the antitumor activity of CD8+ T cells and the generation of tumor-specific T-cell memory in vivo. Furthermore, combining anti-OX40 with GSK2636771, a PI3Kβ-selective inhibitor, delayed tumor growth and extended the survival of mice with PTEN-null melanomas. This combination treatment did not increase the number of TILs, but it instead significantly enhanced proliferation of CD8+ TILs and elevated the serum levels of CCL4, CXCL10, and IFNγ, which are mainly produced by memory and/or effector T cells. These results highlight a critical role of OX40 activation in potentiating the effector function of tumor-reactive CD8+ T cells and suggest further evaluation of OX40 agonist–based combinations in patients with immune-resistant tumors.

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