Prostate cancer is the most common visceral cancer and the second leading cause of death from cancer in men in the United States. Metastatic prostate cancer is treated in a palliative manner by androgen ablation. The appearance of hormone-independent cancer denotes cancer progression for which no curative treatment is available. Immunotherapy offers an approach for the development of treatments of an otherwise untreatable cancer. However, even though new technology has provided superior activation of antitumor immune responses, the therapeutic benefit of treating previously diagnosed cancer has not proven efficacious. Recent studies demonstrate that many tumor recognition antigens are normal, non-mutated antigens common to normal cells of similar histological type. Furthermore, in recent immunotherapy trials activation of immunity to antigens on malignant melanoma cells induced an autoimmune response to normal melanocytes. These data show that tumor cells and normal parenchymal cells share common self-determinants that are recognized by the immune system. Such responses are tightly regulated to prevent the development of autoimmune disease. The applicant has performed immunotherapy studies in a prostate cancer model using the non-replicative canarypox virus, ALVAC, as an immune-activating gene delivery system. Treatment of prostate tumors with ALVAC cytokine recombinant induced antitumor activity but also activated immunoregulatory mechanisms that inhibited the immune effector events necessary for the elimination of cancers. The studies outlined in this application will characterize the immmunoregulation induced by immunotherapy of prostate cancer and will determine the relationship between the identified tumor escape mechanisms and the regulation of immunity to self antigens expressed on normal prostate cells. To this end the following specific aims are proposed: (1) Characterization of the CD8+ T cell regulation observed after ALVAC cytokine treatment. This will include: a) Determination of functional characteristics of the regulatory phenomenon induced by cytokine-secreting RM-1 tumor cell vaccines, b) Determination of phenotypic characteristics of the CD4+ regulatory T cell, and c) Characterization of the inhibition of CD8+ T cell function after the in vivo administration of ALVAC cytokine recombinants; (2) Determination of the effects of ALVAC cytokine treatment on CD8+ T cell activation in vivo. This will include: a) Characterization of the effects of ALVAC cytokine treatment on CD8+ T cell activation and b) Characterization of the regulation of CD8+ T cell activation in a transgenic tumor system. The studies proposed in this application address a PRIORITY ONE research objective described in the """"""""Report of the Prostate Cancer Progress Review Group"""""""". These studies address the specific recommended action that requested support for """"""""...research that emphasizes specific cell-cell interactions between and among developing epithelial cells...and inflammatory cells"""""""".
| Vickman, Renee E; Crist, Scott A; Kerian, Kevin et al. (2016) Cholesterol Sulfonation Enzyme, SULT2B1b, Modulates AR and Cell Growth Properties in Prostate Cancer. Mol Cancer Res 14:776-86 |
| Grant, Julieann F; Iwasawa, Toshihisa; Sinn, Haley W et al. (2006) Induction of protective immunity to RM-1 prostate cancer cells with ALVAC-IL-2/IL-12/TNF-alpha combination therapy. Int J Cancer 119:2632-41 |
| Elzey, B D; Siemens, D R; Ratliff, T L et al. (2001) Immunization with type 5 adenovirus recombinant for a tumor antigen in combination with recombinant canarypox virus (ALVAC) cytokine gene delivery induces destruction of established prostate tumors. Int J Cancer 94:842-9 |
| Griffith, T S; Kawakita, M; Tian, J et al. (2001) Inhibition of murine prostate tumor growth and activation of immunoregulatory cells with recombinant canarypox viruses. J Natl Cancer Inst 93:998-1007 |
