Abstract 5595: Antitumor immune responses to Nitroreductase/CB1954 and 4-1BBL gene therapy

Abstract

Abstract Gene-directed enzyme prodrug therapy using the non-mammalian nitroreductase enzyme (NTR) and CB1954 prodrug is a promising approach for local management of cancer through targeted chemotherapy. Whilst there is some evidence that tumor cell killing via NTR/CB1954 may also induce a systemic, immune bystander effect, this needs further investigation. To address this, a transgenic adenocarcinoma of the mouse prostate tumor cell line stably expressing cytoplasmic ovalbumin (TRAMPOva) was transduced with retroviruses encoding either the therapeutic NTR or 4-1BBL gene. The generated sub-clones were used to establish subcutaneous tumor in syngeneic mice. Adoptive transfer of Ova-specific transgenic (OT-1) T cells facilitates tracking of the specific anti-tumor immune response to the gene therapy in vivo. By examining the effect of NTR/CB1954 mediated cytotoxicity on the generation of effector memory T cells, we find that treatment of Ova+NTR+ tumor bearing mice with prodrug induced significant tumor regression. This was associated with enhanced CD8+ T cell maturation and cytolytic activity. However, adoptive transfer of 1×105 of these Ova-specific memory cells did not provide prophylactic protection to immunodeficient mice against TRAMPOva tumor challenge. Therefore, we attempted to enhance the immunogenicity of tumors by delivering the 4-1BBL costimulatory ligand gene to tumor cells. We demonstrate that immunocompetent mice receiving TRAMPOva+4-1BBL cells resisted tumor formation in a 120 day follow-up period, while those receiving TRAMPOva cells developed progressive tumors at earlier time points. Tumor rejection was accompanied by generation of higher frequencies of Ova-specific CD8+ memory T cells that showed effector cytolytic function following challenge with splenocytes loaded with Ova peptide in vivo. Overall, our results show that either NTR/CB1954-mediated cell death, or tumor expression of 4-1BBL can induce a tumor-specific CD8+ T cell response. Combining these approaches may offer a strategy to provide long-lasting anti-tumor immunity in vivo. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5595.