Therapeutic effects of adoptive splenocyte transfer following in situ AdIL-12 gene therapy in a mouse prostate cancer model.
We developed a preclinical prostate cancer model to study the feasibility of adoptive immunotherapy for residual tumor following neo-adjuvant in situ adenoviral-vector-mediated interleukin 12 (AdIL-12) gene therapy. Splenocytes were obtained from mice with orthotopic 178-2 BMA metastatic mouse prostate cancers treated previously with AdIL-12, or a vector with the IL-12 genes plus the costimulatory gene B7-1 (AdIL-12/B7), or a control gene (Adbetagal). The splenocytes were subsequently injected intravenously into syngeneic mice bearing orthotopic 178-2 BMA tumors generated 3 days previously. Significant orthotopic tumor growth suppression was achieved with splenocytes derived from mice whose tumors had been injected with AdIL-12 compared to splenocytes from control Adbetagal mice (P = 0.0005) and splenocytes from AdIL-12/B7-treated mice significantly suppressed spontaneous lung metastases compared to splenocytes from control mice (P = 0.0356). Adoptive transfer of splenocytes from either AdIL-12 (P = 0.004) or AdIL-12/B7 (P = 0.009)-treated mice significantly prolonged survival relative to controls. Transfer of NK and tumor-specific CTL activities was detected and depletion of CD4+ and CD8+ T cells by in vitro antibody-mediated complement lysis of the splenocytes prior to injection abrogated the effects. Systemic IL-12 administration delivered by intramuscular AdIL-12 injection enhanced the antitumor effects of adoptive splenocyte transfer and boosted the CTL response. Our data provide evidence that this form of adoptive immunotherapy can enhance the effectiveness of neo-adjuvant in situ IL-12 gene therapy in cases of persistent malignancy.
Saika
T
T
Scott Department of Urology, Baylor College of Medicine, Houston, TX 77030, USA.
Kusaka
N
N
Mouraviev
V
V
Satoh
T
T
Kumon
H
H
Timme
T L
TL
Thompson
T C
TC
D019264:Adoptive Transfer / Q000379:methods*; D000818:Animals; D018122:B7-1 Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D015316:Genetic Therapy; D007167:Immunotherapy; D018664:Interleukin-12 / Q000378:metabolism*; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000628:therapy*; D013154:Spleen / Q000166:cytology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism; D013997:Time Factors
D018122:B7-1 Antigen; D018664:Interleukin-12