Immunotherapy of murine prostate cancer using whole tumor cells killed ex vivo by herpes simplex viral thymidine kinase/ganciclovir suicide gene therapy

Abstract

Whole cell cancer vaccines are currently under clinical evaluation. Their immunogenicity may depend on the mode of death of the vaccine cells prior to uptake by professional antigen-presenting cells and crosspriming of T cells. Destruction of tumor in vivo by genetic prodrug activation therapy leads to a marked local and systemic immune response, local T-cell infiltration and the establishment of T-cell memory. We postulated that this immunostimulation may be due to induction of danger signals and the inherent immunogenicity of products of HSVtk/ganciclovir kill. Using established models of murine prostate cancer, we have evaluated the efficacy of anti-tumor vaccines comprising irradiated allogeneic or autologous whole cells expressing HSVtK, which are first killed in vitro by prodrug activation using ganciclovir. HSVtk/ganciclovir-induced cell kill was through the induction of apoptosis. The vaccine was found to be effective in both models and superior to traditional irradiated whole tumor cells even after single doses. Protection against tumor challenge was associated with marked proliferative and Th1 cytokine responses. This approach would be applicable clinically in terms of ease of vaccine production, safety, storage and avoidance of potential toxicities of in vivo gene transfer.

Overview of Tumor Cell–Based Vaccines

“…Pandha et al induced cell death by using a retroviral vector to introduce herpes simplex virus thymidine kinase (HSVtk) into rat prostate cancer cell lines [99]. Thymidine kinase converts the prodrug gancyclovir to its active form, which was shown to induce apoptotic cell death [100].…”

“…In this model, gancyclovir-treated HSVtk cells gave protection against subsequent tumor challenge when used in prophylactic vaccination and induced a T H 1 type response as assessed by IFN-c production by splenocytes in the presence of parental tumor cells [99]. The mechanism by which these modified tumor cells elicit antitumor responses is not clear, but it has been postulated that the presence of heat shock proteins or viral DNA, both of which can act as danger signals, may participate in the immunogenicity of the vaccine [99]. Virally infected tumor cells have been used in cancer vaccines.…”

Prophylactic vaccines for prevention of prostate cancer

“…The efficacy of anti-tumor vaccines comprising irradiated allogeneic or autologous whole cells expressing HSV/tk, which are first killed in vitro by prodrug activation using ganciclovir, were evaluated (28). The vaccination was found to be effective in both models and superior to traditional irradiated whole tumor cells even after single doses.…”

Beyond Cancer Vaccines

“…Since tumor cells are often not inherently immunogenic, tumor cell vaccine approaches require genetic modification or modification of tumor cells with costimulatory molecules, of which granulocyte-macrophage colony-stimulating factor (GM-CSF) has been shown to be particularly effective. 23,24 Canvaxin ™ , a tumor cell vaccine, initially displayed clinical promise based on perceived favorable results for patients with Stage IV melanoma after complete surgical resection. 25 Unfortunately, the phase III trial was stopped prematurely due to a survival disadvantage compared to observation alone.…”