Chemo-immunotherapy of murine cancer using alpha-tocopheryl succinate and non-matured dendritic cells

The search for anticancer drugs that are tumor specific and cause minimal side effects and the development of effective cancer vaccines are focal points of cancer therapy today. Dendritic cells (DC) are considered potential candidates for cancer immunotherapy due to their ability to process and present antigens to T cells and stimulate immune responses. However, DC-based vaccines have exhibited minimal effectiveness in abrogating established tumors in mice and human cancer patients. The use of appropriate adjuvants can enhance the efficacy of DC-based cancer vaccines in treating established tumors.; The studies in this dissertation describe a chemo-immunotherapeutic strategy, which combines a Vitamin E analog, alpha-tocopheryl succinate (alpha-TOS) that is selectively toxic to tumor cells with non-antigen pulsed, non-matured dendritic cells (nmDC) to treat established murine lung and breast tumors. The results demonstrate that alpha-TOS synergizes with nmDC to inhibit the growth of established tumors and significantly reduce residual lung metastasis when therapy is initiated after surgical removal of primary tumors. This outcome was correlated with increased IFN-gamma and IL-4 production by splenic and draining lymph node lymphocytes. In trying to understand the mechanism of action of the combination treatment we observed that alpha-TOS treated tumor cells factors cause DC maturation in vitro. This effect is mediated in part by heat shock proteins 60, 70 and 90 induced during alpha-TOS-mediated killing of tumor cells. This study demonstrates the potential usefulness of alpha-tocopheryl succinate, an agent nontoxic to normal cell types, as an adjuvant to augment the effectiveness of DC-based vaccines in treating cancer.