PMID- 31371342
OWN - NLM
STAT- Publisher
LR  - 20190912
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
DP  - 2019 Aug 1
TI  - Anti-OX40 Antibody Directly Enhances The Function of Tumor-Reactive CD8(+) T
      Cells and Synergizes with PI3Kbeta Inhibition in PTEN Loss Melanoma.
LID - 10.1158/1078-0432.CCR-19-1259 [doi]
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 CD8(+) T cells. We also evaluated the antitumor activity of an
      anti-OX40 antibody plus PI3Kbeta 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
      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 PI3Kbeta-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 IFNgamma, 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 CD8(+) T cells
      and suggest further evaluation of OX40 agonist-based combinations in patients
      with immune-resistant tumors.
CI  - (c)2019 American Association for Cancer Research.
FAU - Peng, Weiyi
AU  - Peng W
AD  - Department of Melanoma Medical Oncology, The University of Texas MD Anderson
      Cancer Center, Houston, Texas. phwu@mdanderson.org Niranjan.x.yanamandra@gsk.com 
      Wpeng2@central.uh.edu.
FAU - Williams, Leila J
AU  - Williams LJ
AD  - Department of Melanoma Medical Oncology, The University of Texas MD Anderson
      Cancer Center, Houston, Texas.
FAU - Xu, Chunyu
AU  - Xu C
AD  - Department of Melanoma Medical Oncology, The University of Texas MD Anderson
      Cancer Center, Houston, Texas.
FAU - Melendez, Brenda
AU  - Melendez B
AD  - Department of Melanoma Medical Oncology, The University of Texas MD Anderson
      Cancer Center, Houston, Texas.
FAU - McKenzie, Jodi A
AU  - McKenzie JA
AD  - Department of Melanoma Medical Oncology, The University of Texas MD Anderson
      Cancer Center, Houston, Texas.
FAU - Chen, Yuan
AU  - Chen Y
AD  - Department of Melanoma Medical Oncology, The University of Texas MD Anderson
      Cancer Center, Houston, Texas.
FAU - Jackson, Heather L
AU  - Jackson HL
AD  - Oncology R&D, Immuno-Oncology and Combinations RU, GlaxoSmithKline, Collegeville,
      Pennsylvania.
FAU - Voo, Kui S
AU  - Voo KS
AD  - Department of Oncology Research for Biologics and Immunotherapy Translation
      Platform, The University of Texas MD Anderson Cancer Center, Houston, Texas.
FAU - Mbofung, Rina M
AU  - Mbofung RM
AD  - Department of Melanoma Medical Oncology, The University of Texas MD Anderson
      Cancer Center, Houston, Texas.
FAU - Leahey, Sara Elizabeth
AU  - Leahey SE
AD  - Department of Melanoma Medical Oncology, The University of Texas MD Anderson
      Cancer Center, Houston, Texas.
FAU - Wang, Jian
AU  - Wang J
AD  - Department of Biostatistics, The University of Texas MD Anderson Cancer Center,
      Houston, Texas.
FAU - Lizee, Gregory
AU  - Lizee G
AD  - Department of Melanoma Medical Oncology, The University of Texas MD Anderson
      Cancer Center, Houston, Texas.
FAU - Tawbi, Hussein A
AU  - Tawbi HA
AD  - Department of Melanoma Medical Oncology, The University of Texas MD Anderson
      Cancer Center, Houston, Texas.
FAU - Davies, Michael A
AU  - Davies MA
AD  - Department of Melanoma Medical Oncology, The University of Texas MD Anderson
      Cancer Center, Houston, Texas.
FAU - Hoos, Axel
AU  - Hoos A
AD  - Oncology R&D, Immuno-Oncology and Combinations RU, GlaxoSmithKline, Collegeville,
      Pennsylvania.
FAU - Smothers, James
AU  - Smothers J
AD  - Oncology R&D, Immuno-Oncology and Combinations RU, GlaxoSmithKline, Collegeville,
      Pennsylvania.
FAU - Srinivasan, Roopa
AU  - Srinivasan R
AD  - Oncology R&D, Immuno-Oncology and Combinations RU, GlaxoSmithKline, Collegeville,
      Pennsylvania.
FAU - Paul, Elaine M
AU  - Paul EM
AD  - Oncology R&D, Immuno-Oncology and Combinations RU, GlaxoSmithKline, Collegeville,
      Pennsylvania.
FAU - Yanamandra, Niranjan
AU  - Yanamandra N
AD  - Oncology R&D, Immuno-Oncology and Combinations RU, GlaxoSmithKline, Collegeville,
      Pennsylvania. phwu@mdanderson.org Niranjan.x.yanamandra@gsk.com
      Wpeng2@central.uh.edu.
FAU - Hwu, Patrick
AU  - Hwu P
AD  - Department of Melanoma Medical Oncology, The University of Texas MD Anderson
      Cancer Center, Houston, Texas. phwu@mdanderson.org Niranjan.x.yanamandra@gsk.com 
      Wpeng2@central.uh.edu.
LA  - eng
PT  - Journal Article
DEP - 20190801
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for
      Cancer Research
JID - 9502500
SB  - IM
EDAT- 2019/08/03 06:00
MHDA- 2019/08/03 06:00
CRDT- 2019/08/03 06:00
PHST- 2019/04/21 00:00 [received]
PHST- 2019/06/10 00:00 [revised]
PHST- 2019/07/26 00:00 [accepted]
PHST- 2019/08/03 06:00 [pubmed]
PHST- 2019/08/03 06:00 [medline]
PHST- 2019/08/03 06:00 [entrez]
AID - 1078-0432.CCR-19-1259 [pii]
AID - 10.1158/1078-0432.CCR-19-1259 [doi]
PST - aheadofprint
SO  - Clin Cancer Res. 2019 Aug 1. pii: 1078-0432.CCR-19-1259. doi:
      10.1158/1078-0432.CCR-19-1259.