TY - JOUR
T1 - Anti-OX40 antibody directly enhances the function of tumor-reactive CD8þ T cells and synergizes with PI3Kb inhibition in PTEN loss melanoma
AU - Peng, Weiyi
AU - Williams, Leila J.
AU - Xu, Chunyu
AU - Melendez, Brenda
AU - McKenzie, Jodi A.
AU - Chen, Yuan
AU - Jackson, Heather L.
AU - Voo, Kui S.
AU - Mbofung, Rina M.
AU - Leahey, Sara Elizabeth
AU - Wang, Jian
AU - Lizee, Gregory
AU - Tawbi, Hussein A.
AU - Davies, Michael A.
AU - Hoos, Axel
AU - Smothers, James
AU - Srinivasan, Roopa
AU - Paul, Elaine M.
AU - Yanamandra, Niranjan
AU - Hwu, Patrick
N1 - Funding Information:
This work was supported in part by the following NCI grants: R01CA187076 (to P. Hwu and M.A. Davies), P50CA093459 (to UT M.D. Anderson Cancer Center SPORE in Melanoma), T32CA009666-21(to M.A. Davies), and P30CA016672 (to UT MDACC CCSG for the Flow Cytometry & Cellular Imaging facility), by philanthropic contributions to MDACC Melanoma Moon Shots Program; Melanoma Research Alliance Young Investigator Award (to W. Peng, 558998); Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; Aim at Melanoma Foundation, Miriam and Jim Mulva Research Fund; and by Cancer Prevention and Research Institute of Texas (to P. Hwu RP170401 and to J.A. McKenzie RP140106 and RP170067).
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/11/1
Y1 - 2019/11/1
N2 - Purpose: 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 CD8þ T cells. We also evaluated the antitumor activity of an anti-OX40 antibody plus PI3Kb inhibition in a transgenic murine melanoma model (Braf mutant, PTEN null), which spontaneously develops immunotherapy-resistant melanomas. Results: We observed elevated expression of OX40 in tumor-reactive CD8þ TILs upon encountering tumors; activation of OX40 signaling enhanced their cytotoxic function. OX40 agonist antibody improved the antitumor activity of CD8þ T cells and the generation of tumor-specific T-cell memory in vivo. Furthermore, combining anti-OX40 with GSK2636771, a PI3Kb-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 CD8þ TILs and elevated the serum levels of CCL4, CXCL10, and IFNg, which are mainly produced by memory and/or effector T cells. Conclusions: These results highlight a critical role of OX40 activation in potentiating the effector function of tumor-reactive CD8þ T cells and suggest further evaluation of OX40 agonist–based combinations in patients with immune-resistant tumors.
AB - Purpose: 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 CD8þ T cells. We also evaluated the antitumor activity of an anti-OX40 antibody plus PI3Kb inhibition in a transgenic murine melanoma model (Braf mutant, PTEN null), which spontaneously develops immunotherapy-resistant melanomas. Results: We observed elevated expression of OX40 in tumor-reactive CD8þ TILs upon encountering tumors; activation of OX40 signaling enhanced their cytotoxic function. OX40 agonist antibody improved the antitumor activity of CD8þ T cells and the generation of tumor-specific T-cell memory in vivo. Furthermore, combining anti-OX40 with GSK2636771, a PI3Kb-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 CD8þ TILs and elevated the serum levels of CCL4, CXCL10, and IFNg, which are mainly produced by memory and/or effector T cells. Conclusions: These results highlight a critical role of OX40 activation in potentiating the effector function of tumor-reactive CD8þ T cells and suggest further evaluation of OX40 agonist–based combinations in patients with immune-resistant tumors.
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U2 - 10.1158/1078-0432.CCR-19-1259
DO - 10.1158/1078-0432.CCR-19-1259
M3 - Article
C2 - 31371342
AN - SCOPUS:85074444731
SN - 1078-0432
VL - 25
SP - 6406
EP - 6416
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 21
ER -