Optimizing Timing of Immunotherapy Improves Control of Tumors by Hypofractionated Radiation Therapy.
The anecdotal reports of promising results seen with immunotherapy and radiation in advanced malignancies have prompted several trials combining immunotherapy and radiation. However, the ideal timing of immunotherapy with radiation has not been clarified. Tumor bearing mice were treated with 20Gy radiation delivered only to the tumor combined with either anti-CTLA4 antibody or anti-OX40 agonist antibody. Immunotherapy was delivered at a single timepoint around radiation. Surprisingly, the optimal timing of these therapies varied. Anti-CTLA4 was most effective when given prior to radiation therapy, in part due to regulatory T cell depletion. Administration of anti-OX40 agonist antibody was optimal when delivered one day following radiation during the post-radiation window of increased antigen presentation. Combination treatment of anti-CTLA4, radiation, and anti-OX40 using the ideal timing in a transplanted spontaneous mammary tumor model demonstrated tumor cures. These data demonstrate that the combination of immunotherapy and radiation results in improved therapeutic efficacy, and that the ideal timing of administration with radiation is dependent on the mechanism of action of the immunotherapy utilized.
Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, 4805 NE Glisan St, Portland, OR, 97213, United States of America.|The Oregon Clinic, Portland, OR, 97213, United States of America.
Kristina H
http://orcid.org/0000-0002-3363-0063
KH
Young
Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, 4805 NE Glisan St, Portland, OR, 97213, United States of America.
Jason R
JR
Baird
Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, 4805 NE Glisan St, Portland, OR, 97213, United States of America.
Talicia
T
Savage
Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, 4805 NE Glisan St, Portland, OR, 97213, United States of America.
Benjamin
B
Cottam
Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, 4805 NE Glisan St, Portland, OR, 97213, United States of America.
David
D
Friedman
Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, 4805 NE Glisan St, Portland, OR, 97213, United States of America.
Shelly
S
Bambina
Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, 4805 NE Glisan St, Portland, OR, 97213, United States of America.
David J
DJ
Messenheimer
Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, 4805 NE Glisan St, Portland, OR, 97213, United States of America.
Bernard
B
Fox
The Oregon Clinic, Portland, OR, 97213, United States of America.|Providence Hepatobiliary and Pancreatic Cancer Program, Providence Portland Medical Center, 4805, NE Glisan St, Portland, OR, 97213, United States of America.
Pippa
P
Newell
Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, 4805 NE Glisan St, Portland, OR, 97213, United States of America.
Keith S
KS
Bahjat
Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, 4805 NE Glisan St, Portland, OR, 97213, United States of America.
Michael J
MJ
Gough
Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, 4805 NE Glisan St, Portland, OR, 97213, United States of America.|The Oregon Clinic, Portland, OR, 97213, United States of America.
Marka R
MR
Crittenden
D000818:Animals; D017951:Antigen Presentation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000276:immunology* / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000276:immunology / Q000628:therapy*; D003131:Combined Modality Therapy; D019583:Dose Fractionation, Radiation; D005260:Female; D007167:Immunotherapy; D015674:Mammary Neoplasms, Animal / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D053262:Receptors, OX40 / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D053262:Receptors, OX40