Combined treatment effects of radiation and immunotherapy: studies in an autochthonous prostate cancer model.
OBJECTIVE
To optimize the combination of ionizing radiation and cellular immunotherapy using a preclinical autochthonous model of prostate cancer.


METHODS
Transgenic mice expressing a model antigen under a prostate-specific promoter were treated using a platform that integrates cone-beam CT imaging with 3-dimensional conformal therapy. Using this technology we investigated the immunologic and therapeutic effects of combining ionizing radiation with granulocyte/macrophage colony-stimulating factor-secreting cellular immunotherapy for prostate cancer in mice bearing autochthonous prostate tumors.


RESULTS
The combination of ionizing radiation and immunotherapy resulted in a significant decrease in pathologic tumor grade and gross tumor bulk that was not evident with either single-modality therapy. Furthermore, combinatorial therapy resulted in improved overall survival in a preventive metastasis model and in the setting of established micrometastases. Mechanistically, combined therapy resulted in an increase of the ratio of effector-to-regulatory T cells for both CD4 and CD8 tumor-infiltrating lymphocytes.


CONCLUSIONS
Our preclinical model establishes a potential role for the use of combined radiation-immunotherapy in locally advanced prostate cancer, which warrants further exploration in a clinical setting.
Department of Oncology, James Buchanan Brady Urological Institute, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Satoshi
S
Wada
Timothy J
TJ
Harris
Erik
E
Tryggestad
Kiyoshi
K
Yoshimura
Jing
J
Zeng
Hung-Rong
HR
Yen
Derese
D
Getnet
Joseph F
JF
Grosso
Tullia C
TC
Bruno
Angelo M
AM
De Marzo
George J
GJ
Netto
Drew M
DM
Pardoll
Theodore L
TL
DeWeese
John
J
Wong
Charles G
CG
Drake
D000230:Adenocarcinoma / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy / Q000379:methods / Q000401:mortality; D054893:Cone-Beam Computed Tomography / Q000379:methods*; D006388:Hemagglutinins / Q000276:immunology / Q000378:metabolism; D016219:Immunotherapy, Adoptive / Q000379:methods* / Q000401:mortality; D016246:Lymphocytes, Tumor-Infiltrating / Q000166:cytology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D060787:Neoplasm Grading; D061206:Neoplasm Micrometastasis / Q000517:prevention & control; D058958:Organs at Risk / Q000000981:diagnostic imaging; D011471:Prostatic Neoplasms / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy; D011877:Radionuclide Imaging; D011879:Radiotherapy Dosage; D020266:Radiotherapy, Conformal / Q000379:methods* / Q000401:mortality; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology; D047368:Tumor Burden; D001743:Urinary Bladder / Q000000981:diagnostic imaging
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D006388:Hemagglutinins