Research interest

Our laboratory studies strategies to optimize the immune response to tumors for therapeutic purposes. We have found that we can sensitize T cells to weak tumor antigens in vaccine-draining lymph nodes and then purify recently stimulated T cells. These T cells can be activated in vitro to proliferate and acquire effector function and treat established tumor following adoptive transfer. We are currently working with a transgenic mouse model of HER2/neu breast cancer to define tumor-rejection antigens on cancer stem cells.

Current program

• T cell immunotherapy of spontaneous breast cancer in HER2/neu transgenic mice to study reversal of tolerance.
• Understanding the influence of the tumor microenvironment on T cell immunotherapy of primary breast tumors.
• Identifying target antigens expressed by cancer stem cells.
• Identification of tumor antigens on brain tumor stem cells.

Description

The overall goal of our translational research program is to develop methods to stimulate an anti-tumor immune response in cancer patients. Tumors contain multiple mutations and genomic changes that can lead to overexpression or aberrant expression of genes within the tumor. However, because tumors are self tissue and frequently suppress the immune response it has been very difficult to stimulate a therapeutic response in cancer patients. Our strategy, called T cell adoptive immunotherapy, is to provide a tumor vaccine then harvest the tumor-reactive T cells and stimulate them outside of the patient where conditions can be optimized and then re-infuse them. We previously performed phase I clinical trials of T cell adoptive immunotherapy in patients with brain tumors (GBM) or kidney cancer (RCC).

Our recent projects have defined several important immunologic features of the T cell immune response to tumor. These include defining the synergistic roles of CD4 and CD8 T cells and understanding the transition from effector to memory T cells. We have recently used a transgenic model of HER2/neu positive breast cancer to explore whether we could generate an anti-tumor response in animals who are tolerant to their tumors. We found that breast cancer stem cells express antigens that induce an effective T cell response and tumor regression lead to development of a humoral immune response also. We are using serum from treated animals to determine the molecular identity of the antigens on cancer stem cells.