Expanding the therapeutic index of radiation therapy by combining in situ gene therapy in the treatment of prostate cancer.
The advances in radiotherapy (3D-CRT, IMRT) have enabled high doses of radiation to be delivered with the least possible associated toxicity. However, the persistence of cancer (local recurrence after radiotherapy) despite these increased doses as well as distant failure suggesting the existence of micro-metastases, especially in the case of higher risk disease, have underscored the need for continued improvement in treatment strategies to manage local and micro-metastatic disease as definitively as possible. This has prompted the idea that an increase in the therapeutic index of radiotherapy might be achieved by combining it with in situ gene therapy. The goal of these combinatorial therapies is to maximize the selective pressure against cancer cell growth while minimizing treatment-associated toxicity. Major efforts utilizing different gene therapy strategies have been employed in conjunction with radiotherapy. We reviewed our and other published clinical trials utilizing this combined radio-genetherapy approach including their associated pre-clinical in vitro and in vivo models. The use of in situ gene therapy as an adjuvant to radiation therapy dramatically reduced cell viability in vitro and tumor growth in vivo. No significant worsening of the toxicities normally observed in single-modality approaches were identified in Phase I/II clinical studies. Enhancement of both local and systemic T-cell activation was noted with this combined approach suggesting anti-tumor immunity. Early clinical outcome including biochemical and biopsy data was very promising. These results demonstrate the increased therapeutic efficacy achieved by combining in situ gene therapy with radiotherapy in the management of local prostate cancer. The combined approach maximizes tumor control, both local-regional and systemic through radio-genetherapy induced cytotoxicity and anti-tumor immunity.
Tetzlaff
Michael T
MT
Scott Department of Urology, Baylor College of Medicine, 6560 Fannin, ST 2100, Houston, Texas 77030, USA.
Teh
Bin S
BS
Timme
Terry L
TL
Fujita
Tetsuo
T
Satoh
Takefumi
T
Tabata
Ken-Ichi
K
Mai
Wei-Yuan
WY
Vlachaki
Maria T
MT
Amato
Robert J
RJ
Kadmon
Dov
D
Miles
Brian J
BJ
Ayala
Gustavo
G
Wheeler
Thomas M
TM
Aguilar-Cordova
Estuardo
E
Thompson
Timothy C
TC
Butler
E Brian
EB
D000818:Animals; D002986:Clinical Trials as Topic; D003131:Combined Modality Therapy; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000532:radiotherapy / Q000628:therapy*