Combination nonviral interleukin 2 gene therapy and external-beam radiation therapy for head and neck cancer.
OBJECTIVE
To demonstrate that the combination of nonviral murine interleukin 2 (mIL-2) gene therapy and external-beam radiation therapy (XRT) have an enhanced therapeutic effect for the treatment of head and neck squamous cell carcinoma (HNSCC) in an orthotopic murine model and to elucidate the mechanism of action.


METHODS
Randomized, controlled studies in the murine orthotopic model of HNSCC. Squamous cell carcinoma VII cells were injected into the floor of the mouth to establish tumors in immunocompetent mice. The intervention groups were treated with mIL-2, radiation therapy, empty plasmid, no treatment, combination mIL-2/XRT, and combination empty plasmid/XRT. Nonviral mIL-2 gene transfer was performed on days 5 and 9. The XRT was administered to the assigned groups 24 hours after first mIL-2 delivery. The mice were killed on day 13. Tumors and local lymph nodes were harvested and evaluated. Primary and secondary cytokine expression, cytotoxic T-lymphocyte activity, and apoptosis were assayed.


RESULTS
The combination mIL-2/XRT demonstrated a significant increase in antitumor effects compared with single therapy or controls. Increased expression levels of primary and secondary cytokines were found in the group treated with mIL-2, and this effect was preserved when mIL-2 treatment was combined with XRT. Combination therapy significantly increased apoptosis compared with monotherapy.


CONCLUSIONS
The present study demonstrates that combination mIL-2/XRT generates potent antitumor immune responses and significantly increases apoptosis in an orthotopic murine model of HNSCC. Further optimization of this strategy is warranted as well as consideration for human clinical trials.
Bray
David
D
Department of Otolaryngology--Head and Neck Surgery, The Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, USA.
Yu
Shu-Zhen
SZ
Koprowski
Hilary
H
Rhee
Juong
J
Kumar
Sanjeev
S
Pericle
Federica
F
Suntharalingam
Mohan
M
Van Echo
David A
DA
Li
Daqing
D
O'Malley
Bert W
BW
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000502:physiology; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000503:physiopathology / Q000628:therapy*; D003131:Combined Modality Therapy; D016207:Cytokines / Q000096:biosynthesis; D015316:Genetic Therapy / Q000379:methods*; D006258:Head and Neck Neoplasms / Q000276:immunology / Q000503:physiopathology / Q000628:therapy*; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000235:genetics* / Q000627:therapeutic use*; D051379:Mice; D023421:Models, Animal; D011878:Radiotherapy / Q000379:methods*; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D016207:Cytokines; D007376:Interleukin-2; D007371:Interferon-gamma