TY - JOUR
T1 - Anti-glucocorticoid-induced tumor necrosis factor-related protein (GITR) Therapy overcomes radiation-induced treg immunosuppression and drives abscopal effects
AU - Schoenhals, Jonathan E.
AU - Cushman, Taylor R.
AU - Barsoumian, Hampartsoum B.
AU - Li, Ailin
AU - Cadena, Alexandra P.
AU - Niknam, Sharareh
AU - Younes, Ahmed I.
AU - Da Silva Caetano, Mauricio
AU - Cortez, Maria Angelica
AU - Welsh, James W.
N1 - Funding Information:
This work was supported and funded by Bristol-Myers Squibb, and further supported by the family of M. Adnan Hamed, the Susan and Peter Goodwin Foundation, Mabuchi Research fund, and the Orr Family Foundation (to MD Anderson Cancer Center’s Thoracic Radiation Oncology program), and the Wiegand Foundation. We also have support the from the MD Anderson Knowledge Gap award, Doctors Cancer Foundation Grant, The Lung Cancer Research Foundation, Cancer Center Support (Core) GrantCA016672 from the NCI (to The University of Texas MD Anderson Cancer Center).
Funding Information:
Conflict of Interest Statement: JW reports support from University of Texas MD Anderson, Healios, MolecularMatch, OncoResponse; non-financial support from Reflexion Medical, Checkmate Pharmaceuticals, grants from BMS, Merck, Varian; lab research support from Incyte, Merck, Calithera, Checkmate Pharmaceuticals, Mavu, Nanobiotix and Aileron; and grants from OncoResponse.
Publisher Copyright:
© 2007-2018 Frontiers Media S.A. All Rights Reserved.
PY - 2018/9/20
Y1 - 2018/9/20
N2 - Despite the potential to cure metastatic disease, immunotherapy on its own often fails outright or early on due to tumor immune evasion. To address this obstacle, we investigated combinations of anti-GITR, anti-PD1 and radiation therapy (XRT) in our previously developed anti-PD1 resistant 344SQ non-small cell lung adenocarcinoma preclinical tumor model. We hypothesized that targeting multiple mechanisms of immune evasion with this triple therapy would lead to an enhanced tumor-specific immune response and improve survival more so than any mono-or dual therapy. In a two tumor 344SQR murine model, treatment with anti-GITR, anti-PD1, and XRT led to significantly improved survival and an abscopal response, with half of the mice becoming tumor free. These mice showed durable response and increased CD4+ and CD8+ effector memory on tumor rechallenge. Regulatory T cells (Tregs) expressed the highest level of GITR at the tumor site and anti-GITR therapy drastically diminished Tregs at the tumor site. Anti-tumor effects were largely dependent on CD4+ T cells and partially dependent on CD8+ T cells. Anti-GITR IgG2a demonstrated superior efficacy to anti-GITR IgG1 in driving antitumor effects. Collectively, these results suggest that combinatorial strategies targeting multiple points of tumor immune evasion may lead to a robust and lasting antitumor response.
AB - Despite the potential to cure metastatic disease, immunotherapy on its own often fails outright or early on due to tumor immune evasion. To address this obstacle, we investigated combinations of anti-GITR, anti-PD1 and radiation therapy (XRT) in our previously developed anti-PD1 resistant 344SQ non-small cell lung adenocarcinoma preclinical tumor model. We hypothesized that targeting multiple mechanisms of immune evasion with this triple therapy would lead to an enhanced tumor-specific immune response and improve survival more so than any mono-or dual therapy. In a two tumor 344SQR murine model, treatment with anti-GITR, anti-PD1, and XRT led to significantly improved survival and an abscopal response, with half of the mice becoming tumor free. These mice showed durable response and increased CD4+ and CD8+ effector memory on tumor rechallenge. Regulatory T cells (Tregs) expressed the highest level of GITR at the tumor site and anti-GITR therapy drastically diminished Tregs at the tumor site. Anti-tumor effects were largely dependent on CD4+ T cells and partially dependent on CD8+ T cells. Anti-GITR IgG2a demonstrated superior efficacy to anti-GITR IgG1 in driving antitumor effects. Collectively, these results suggest that combinatorial strategies targeting multiple points of tumor immune evasion may lead to a robust and lasting antitumor response.
KW - Cancer
KW - GITR
KW - Immunotherapy
KW - PD1 resistance
KW - Radiotherapy
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U2 - 10.3389/fimmu.2018.02170
DO - 10.3389/fimmu.2018.02170
M3 - Article
C2 - 30294332
AN - SCOPUS:85054458678
SN - 1664-3224
VL - 9
JO - Frontiers in immunology
JF - Frontiers in immunology
IS - SEP
M1 - 2170
ER -