David W. Mullins
Primary AppointmentAssistant Professor,
- PhD, Immunology and Molecular Cell Biology, Virginia Polytechnic Institute and State University, Blacksburg, VA
- BS, Virginia Tech
- BS, Biology, Virginia Polytechnic Institute and State University, Blacksburg, VA
- BS, Biochemistry, Virginia Polytechnic Institute and State University, Blacksburg, VA
- Postdoc, Tumor Immunology, University of Virginia
Immunotherapy; Tumor Immunology
The basic premise of tumor immunotherapy is that the immune system can be stimulated to affect an immune response to specific antigens on autologous tumor cells. Like the immune reactions to intracellular pathogens, effective anti-tumor responses are often mediated by CD8+ cytotoxic T-lymphocytes (CTL). Unlike standard vaccinations against infections pathogens, tumor vaccines are not routinely provided as prophylaxis, but rather, as a means of therapeutic intervention. It is therefore likely that endogenous immune responses directed against tumor-associated antigen will have already occurred prior to vaccination, leading to the formation of tumor-specific memory T cell populations. Therefore, successful anti-tumor vaccination will likely require the reactivation of memory T cells, induced in the context of chronic antigen stimulation, rather than the induction of "new" memory T cells as would occur in a prophylactic setting. To date, the seminal research on memory T cell induction, activation, and function relies on infectious models of acute infection. Therefore, an opportunity exists to make significant advances in the understanding of immune function in the context of cancer, and to develop therapeutic strategies to appropriately and efficiently stimulate a patient's memory T cells to infiltrate and kill tumor.
Current Research Efforts
The goals of my research program are to generate new knowledge pertaining to the CD8+ memory T cell response to cancer, and to translate these discoveries onto clinically-applicable therapies. Therefore, the research enterprise consists of interrelated areas of study involving the memory T cells, including:
- Evaluation of the CD8 memory T cell response, with emphasis on molecular mediators of cell migration (chemokine receptor and integrin expression) in the context of cancer and anti-cancer immune therapy. We are focusing on two aspects of T cell migration: expression of homing receptors by the T cells (Mullins Lab), and expression of the chemo-attractant molecules (chemokines) in tumor (in collaboration with the labs of Drs. Craig L. Slingluff, Jr., and Robert M. Strieter). We previously identified an association between clinical outcomes of patients with advanced metastatic melanoma and CD8 T cell expression of the chemokine CXCR3, suggesting that vaccines which specifically induce CXCR3 (or potentially other similar molecules) on T cells may provide a significant therapeutic advantage. Currently, using murine models and human isolates, we are evaluating therapeutic strategies to modulate CXCR3 on tumor-specific T cells. Simultaneously, we are working with Drs. Slingluff and Strieter to evaluate the expression of chemokines in the tumor microenvironment and test the efficacy of various biological agents for the site-specific induction of chemokine production. Collectively, these data will form the foundation for a clinical vaccine trial in 2009-2010.
- Identification of genes and pathways that differentiate productive and non-productive immune responses to cancer. In an ongoing project led by the lab (in collaboration with Bill Knaus and Irene Mullins from Public Health Sciences, Victor Engelhard from Microbiology, and Craig Slingluff from Surgery), we are evaluating immune isolates from patients with divergent clinical outcomes with advanced metastatic melanoma. To date, we have identified gene expression profiles in CD4 and CD8 T cells that correlate with enhanced immune response and survival. These data provide the underpinnings for a prognostic instrument (patent pending) and novel targets for immune intervention in the treatment of melanoma.
- Identification and characterization of immune escape mechanisms that facilitate cancer progression in the presence of tumor antigen-specific CD8+ memory T cells. While studies of immune cells are critical for their understanding of tumor immunity, studies of the tumor cells themselves are providing new clues as to how cancer evades immune responses and spreads throughout the body. For example, our lab has demonstrated that melanomas secrete proteins from the tumor necrosis factor superfamily. These molecules are normally produced only in growing bone, where they prevent immune rejection of the newly-formed osteoblasts. Production of these proteins by melanoma may afford the tumor significant protection against immune defenses and simultaneously promote metastatic dissemination. These studies may provide new insights into the early detection of metastatic melanoma as well as new targets for therapeutic treatment of melanoma.