Efficacy of herpes simplex virus thymidine kinase in combination with cytokine gene therapy in an experimental metastatic breast cancer model

Abstract

Immunotherapy in combination with suicide gene therapy for breast cancer was tested using a metastatic animal model. Subcutaneous injection of the nonimmunogenic breast cancer cell line 4T1 in BALB/C mice gave rise to tumors in 100% of mice with both micrometastases and macrometastases in the lung. We used the herpes simplex virus thymidine kinase (HSV-TK) gene along with the cytokine genes granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-2 (IL-2) to determine their effect on tumor regression and inhibition of lung metastasis. Adenoviral (AV) vectors carrying these transgenes, in separate constructs, were used in this study. Intratumoral administration of AV-TK followed by 10 days of ganciclovir treatment resulted in a delay in tumor growth and, in some cases, in a low to moderate reduction in tumor volume. Inclusion of either GM-CSF or IL-2 gene with HSV-TK resulted in a slightly greater reduction in tumor volume, although these data were not significantly different from those obtained for TK treatment alone. However, when both cytokine genes were combined with TK, a substantial reduction in tumor growth was observed compared with HSV-TK alone (P < .02). Tumor weight data also exhibited superior efficacy of TK/GM-CSF/IL-2 treatment when compared with animals treated with TK gene only (P < .01). More importantly, TK/GM-CSF/IL-2 combination gene therapy induced a significant reduction in lung metastasis compared with any other treatment groups in the 4T1 model (P < .001 between TK GM-CSF/IL-2 versus TK only). Surgical excision of primary tumors after TK/GM-CSF/IL-2 plus ganciclovir treatment resulted in anti-metastatic activity that was similar to that observed for animals in which no surgery was performed. Survival analysis showed a significant difference between animals treated with AV-TK/GM-CSF/IL-2 and animals treated with TK only at 35 days after virus injection (P < .01). Immunophenotypic data suggest infiltration of lymphocytes within the tumor microenvironment in TK- and cytokine gene-treated animals. Thus, the overall data presented here demonstrate that TK gene therapy in combination with GM-CSF and IL-2 gene-mediated immunotherapy strategies have important implications in the treatment of breast cancer.

The telomerase reverse transcriptase promoter drives efficacious tumor suicide gene therapy while preventing hepatotoxicity encountered with constitutive promoters

“…Tumor size was determined employing the formula used to calculate the volume of an ellipsoid body (L × W × H/2, where L = length, W = width, H = height, or L × (W) 2 /2, when W = H). 52 In vivo gene therapy using adenoviral vectors Ten-day-old subcutaneously grown 143B tumors were injected with 9.6 × 10 8 p.f.u. of hTERTp/TK or CMVp/TK adenoviruses.…”

Suicide gene and cytokines combined nonviral gene therapy for spontaneous canine melanoma

“…20 The effectiveness of this combination was also demonstrated for murine colon cancer, 21 melanoma, 22 gastric 23 and breast cancer. 24,25 Therefore, repeated injections of both SG system and cytokine-secreting xenogeneic cells into the tumor bed could be a powerful strategy to prevent relapse and thus support a longer immune response with a stronger antitumor memory.…”

Cytotoxicity of HSVtkand hrTNF-alpha fusion genes with IRES in treatment of gastric cancer

“…Besides, the "bystander effect" induced by tk gene can also enhance the tumor-killing capacity of the HSVtk/GCV system. [25][26][27] However, it was found in some investigations that the anti-tumor efficiency of this system was limited by the lower rate of gene transfection and their insufficient induction of host immunity.…”

“…Chen et al 26 reported that cytokine gene IL-2 could act synergistically with the suicide gene to induce a systemic anti-tumor immunity. In another study, Majumdar and his associates 27 have compared the therapeutic effect of IL-2 expression alone with that by the coexpression of IL-2 and tk genes on squamous cell carcinoma in nude mice, and found that the combined gene expression was most efficient for the gene therapy. Unfortunately, there have been few In the present study, we tried to observe the anti-tumor effects by the coexpression of suicide gene HSVtk and cytokine gene TNF-α on gastric carcinoma cell lines SGC7901.…”