Research in this laboratory combines knowledge of cell biology and immunology and use of experimental tumor models to develop and test new strategies to enhance the immune response, resulting in effective elimination and prevention of tumors. Our program has two overall goals: 1) to contribute to basic understanding of the nature of the anti-tumor immune response and 2) to understand why current immunotherapies often fail in patients with cancer and with this understanding, help develop improved biological therapies.

A long-standing program continues on the study of molecular and structural changes that occur in response to various physiological states, particularly thermal stress (fever). The reorganization of the plasma membrane cytoskeleton and important signaling molecules such as protein kinase C in response to various activation signals are being examined. In recent studies, we have extended this research to models of human tumor antigen-specific cytolytic T cells and autologous tumor cells.

We have observed that the thermal microenvironment can regulate T cells, NK and dendritic cells, and cause significant alterations in cellular polarity (involving cytoskeletal organization, PKC activation and uropod formation), as well as induce substantial levels of heat shock proteins. On-going studies are evaluating the adjuvant potential of thermal therapy with vaccines, cytokines and various chemotherapy and radiation approaches. These studies have led to the initiation of new Phase I/II clinical trials to evaluate the potential of fever-like hyperthermia as an immune adjuvant in patients with cancer.

Other interests involve studies on human tumor progression to obtain information regarding existent cellular and antibody-mediated immunity in patients with existent disease and those who have achieved long-term survivor status. This information is being used to help identify the most effective immunotherapies/vaccines. One related goal is to help identify human tumor antigens that may serve as the basis of new vaccine development. To help accomplish this goal, immunodeficient SCID mice are being used to expand patient tumors derived from surgical specimens. This resource is used for molecular studies of tumor progression and metastasis and as a source of human tumor antigen for detection of antitumor T cells and antibodies. It is also used to evaluate new treatment strategies, including the testing of novel biologics (e.g., CD40L, Apo2L/TRAIL), and new antibodies that target human tumor antigens.

Significant Findings

Elizabeth A. Repasky demonstrated that the thermal microenvironment can affect anti-tumor immune responses which led to new Phase I/II clinical trials to evaluate the potential of fever-like hyperthermia as an adjuvant for cancer immunotherapy and chemotherapy.

Developed several human-SCID xenograft models used for characterizing human tumor progression and metastasis and for evaluating novel biological anti-tumor therapies.