Abstract
The development of successful cancer vaccines is contingent on the ability to induce effective anti-tumor immunity against self-antigens that do not typically elicit immunity. We are working on strategies to overcome immunologic tolerance/ignorance to cancer through the use of gene products closely related to self-antigens, including xenogeneic DNA and mutated DNA, and have initiated clinical trials of DNA vaccines in patients with advanced melanoma or prostate cancer. Recent studies have demonstrated that homeostasis-driven T-cell proliferation in the reconstituted lymphodepleted host could enhance the efficacy of whole-cell tumor vaccines. We hypothesized that immunization of sub-lethally irradiated and immune reconstituted mice against specific tumor antigens could increase anti-tumor immunity. B6 mice were irradiated with 600 cGy and immediately reconstituted with 30 x 106 syngeneic splenocytes. Weekly DNA immunization using either human tyrosinase-related protein (TRP)-2 DNA (xenogeneic melanoma differentiation antigen (MDA) or Opt-Tyrp1 DNA (a mutated MDA, which has been optimized for CD8 epitopes), was begun on day 1. We have found that: (1) by day 14 after irradiation and reconstitution, recipients have considerable numbers of splenic T cells, including de novo generated donor T cells, which suggests that vaccination aimed at T cells might be feasible; (2) DNA immunization against a single tumor antigen can provide protection from a tumor challenge that is significantly greater than that observed in immunized non-irradiated hosts (Figure); (3) DNA immunization induces higher levels of tumor-specific CD8+ T cells in the irradiated and reconstituted recipients (detected by intracellular cytokine flow cytometry assay); and (4) the effects of DNA immunization after lymphodepletion with immune reconstitution on both tumor-free survival and CD8+ T cell responses have been validated for two different DNA vaccine strategies (TRP-2 DNA and Opt-Tyrp1 DNA). These results demonstrate that DNA immunization following sub-lethal irradiation and immune reconstitution can induce potent anti-tumor effects. Furthermore, they provide a strong rationale for the development of novel therapeutic strategies that combine lymphodepletion with immune reconstitution and DNA immunization in human clinical trials.
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