Although early diagnosis and standard-of-care treatment cure the majority of clinically localized prostate cancers (CaP), approximately 20%-30% of treated men will relapse. Androgen depletion therapy (ADT) is generally accepted as the best method for treating metastatic CaP; however, eventually overall responses diminish, and virtually all patients progress to hormone-refractory disease. The absence of curative therapies for advanced or recurrent forms of CaP emphasizes the crucial need to develop innovative treatment strategies that are efficacious, with minimal toxicity, against systemic disease.

Melanoma differentiation associated gene-7/Interleukin-24 (MDA-7/IL-24), a unique therapeutic cytokine discovered in our laboratory, holds significant promise for cancer therapy due to its antitumor properties demonstrated in nearly all cancers, including CaP, as well as its ability to work synergistically with other conventional treatment modalities such as radiation therapy and chemotherapy. The safety and clinical efficacy of MDA-7/IL-24, when administered by an adenovirus, has been observed in patients with advanced carcinomas and melanomas. In this application, we will develop and evaluate an innovative combinatorial approach that integrates the targeted delivery of the MDA-7/IL-24 therapeutic with adoptive immunotherapy employing tumor-reactive T lymphocytes for optimal control of advanced CaP.

T cells protect us from disease throughout our lives by targeting and eliminating diseased cells. Tumor-specific T cells can be isolated, followed by activation and expansion in vitro, and then re-infused back into the patient to mediate cancer regression, a process termed adoptive cell transfer (ACT). The properties of this adoptive immunotherapy provide attractive options for CaP, given its accessible primary location, the presence of a wealth of unique tissue and tumor antigens, and the ability to induce collateral destruction of noncancerous prostate tissue. Strategic use of tumor-reactive or antigen-specific T cells to direct MDA-7/IL-24 to the tumor site will not only circumvent the potential issues associated with viral delivery that were evident in earlier studies, but also lead to enhanced tumor destruction due to the mobilization of multiple antitumor mechanisms or pathways, including T cell-mediated killing, cancer-specific toxicity and anti-angiogenesis promoted by MDA-7/IL-24. Using multiple clinically relevant CaP models, we will assess the therapeutic efficacy of Cytokine Adoptive Immune Therapy (CAIT), which in principle will prove therapeutically synergistic in both local and systemic control of primary CaP and metastases, therefore offering an attractive alternative to conventional treatment modalities because of low toxicity and a high degree of specificity. Besides providing therapeutic benefits to CaP patients with established metastatic disease, this approach may also be used in an adjuvant setting in combination with other standard-of-care treatments (radiation therapy, hormonal therapy) to provide long-lasting immune protection against relapse or metastases in patients at high risk. The insights gained from the mechanistic studies we propose will also facilitate rational design of improved treatment modalities for CaP. Successful completion of this multidisciplinary, synergistic research may lead to rapid translation of this unique approach into the clinic to potentially "cure" patients with advanced CaP.