Radiotherapy augments the immune response to prostate cancer in a time-dependent manner.
BACKGROUND
Cancer immunotherapy refers to an array of strategies intended to treat progressive tumors by augmenting a patient's anti-tumor immune response. As immunotherapy is eventually incorporated into oncology treatment paradigms, it is important to understand how these therapies interact with established cancer treatments such as chemotherapy or Radiotherapy (RT). To address this, we utilized a well-established, autochthonous murine model of prostate cancer to test whether RT could augment (or diminish) the CD4 T cell response to a tumor vaccine.


METHODS
Transgenic mice that develop spontaneous prostate cancer (TRAMP) which also express a unique tumor associated antigen (Influenza hemagglutinin) under the control of a prostate-specific promoter were given local RT in combination with immunotherapy. The immunological outcome of this combinatorial strategy was assayed by monitoring the effector response of adoptively transferred, prostate-specific CD4 T cells.


RESULTS
Neither RT nor immunotherapy alone was capable of priming an anti-tumor immune response in animals with evolving tumors. The combination of immunotherapy with RT resulted in anti-tumor T cell activation--this effect was profoundly dependent on the relative timing of RT and immunotherapy. Anti-tumor immune responses occurred when immunotherapy was administered 3-5 weeks post-RT, but such responses were undetectable when immunotherapy was administered either earlier (peri-radiotherapy) or later.


CONCLUSIONS
The therapeutic temporal window of immunotherapy post-RT suggests that highly aggressive, immuno-suppressive tumors might be most sensitive to immunotherapy in a fairly narrow time window; these results should help to guide future development of clinical combinatorial strategies.
Harris
Timothy J
TJ
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Hipkiss
Edward L
EL
Borzillary
Scott
S
Wada
Satoshi
S
Grosso
Joseph F
JF
Yen
Hung-Rong
HR
Getnet
Derese
D
Bruno
Tullia C
TC
Goldberg
Monica V
MV
Pardoll
Drew M
DM
DeWeese
Theodore L
TL
Drake
Charles G
CG
D000818:Animals; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D019496:Cancer Vaccines / Q000494:pharmacology*; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D006389:Hemagglutinins, Viral / Q000378:metabolism; D007167:Immunotherapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009975:Orthomyxoviridae / Q000276:immunology; D011471:Prostatic Neoplasms / Q000276:immunology / Q000473:pathology / Q000532:radiotherapy* / Q000628:therapy*; D013997:Time Factors
D015295:Antigens, Tumor-Associated, Carbohydrate; D019496:Cancer Vaccines; D006389:Hemagglutinins, Viral