Dr. David W. Mullins

Background

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:

1. 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.

2. Determination of memory T cell phenotype and function in a model of spontaneous melanoma with a high degree of relatedness to clinical cancer.

3. Identification and characterization of immune escape mechanisms that facilitate cancer progression in the presence of tumor antigen-specific CD8+ memory T cells.

Graduate Training

I completed undergraduate degrees in Biology (1993) and Biochemistry (1994) and the Ph.D. in Microbiology and Immunology (1998) at Virginia Polytechnic Institute and State University (Virginia Tech). My graduate work was conducted in the laboratory of Dr. Klaus D. Elgert, an expert in tumor-induced immune suppression. In a series of papers, beginning with Dr. Elgert's earlier students, the lab demonstrated that cancers disrupt macrophage and CD4+ T cell function, thus down-regulating innate immunity and dampening subsequent adaptive anti-tumor immune responses. Dr. Elgert's previous students had studied only the mechanisms by which tumors dysregulate macrophage and T cell function, whereas my research was the first to evaluate clinically-relevant strategies to reverse immune suppression by cancers. Murine models were used to evaluate immune-mediated control of tumor following pharmacologic and biologic interventions designed to augment macrophage activation and lymphocyte function (my dissertation is available as a pdf document at http://www.people.virginia.edu/~dm7x/mullins%20dissertation.pdf). Interestingly, the plant-derived chemotherapeutic agent paclitaxel (TAXOL®) was found to restore macrophage function in the tumor-bearing host by rescuing activation and cytokine balance. However, paclitaxel negatively impacted T cell activation in response to antigen. Building upon these observations, I developed a regimen consisting of metronomic treatment with paclitaxel followed by immunotherapeutic treatment with recombinant IL-12 to maximally induce anti-tumor immune responses. In a murine tumor model system, this combination therapy significantly limited tumor progression and enhanced survival. Clinical application of this concept may significantly enhance anti-tumor effects by simultaneously assaulting tumors and restoring immune system activity. These results were published in several journals, including Cancer Immunology and Immunotherapy and the Journal of Immunology; further, these studies were recognized with the 1999 Horsely Award for Meritorious Original Research, the highest honor bestowed by the Virginia Academy of Science.

Postdoctoral Training

From 1999-2003, I was a Postdoctoral Fellow at the Carter Immunology Center, a part of the University of Virginia Health System. Under the mentorship of Dr. Victor H. Engelhard, I received a fellowship from the American Cancer Society to develop murine melanomas expressing chimeric HLA-A2 molecules. In combination with HLA-A2 transgenic mice, these tumors facilitated the evaluation of anti-tumor vaccine efficacy of human A2-restricted antigens. Using the HLA-A2 mice and tumors as a preclinical research platform, we demonstrated that the A2-restricted epitopes from melanocyte differentiation antigens gp100 and tyrosinase are tumor rejection antigens. These studies also demonstrated the efficacy of peptide-pulsed, in vitro-matured dendritic cells as adjuvants for the induction of tumor-specific immune responses, even in the situation of tolerance. Continuing to explore the biological mechanisms that govern immunization with exogenous dendritic cells, the preclinical model was used to demonstrate several novel concepts, including: regional immunity to tumor is associated with dendritic cell injection site and lymphoid homing; immunogenicity of exogenous dendritic cells is limited by the capacity of peripheral lymph nodes to retain DC and naïve T cells; and expression of the activation- and adhesion-marker CD48 is required for exogenous dendritic cell retention in peripheral lymph nodes. These studies established a broad research paradigm in Dr. Engelhard's laboratory, forming the basis of multiple ongoing projects. These studies have been published in the Journal of Experimental Medicine and the Journal of Immunology, and two manuscripts are currently in preparation. Collectively, these studies were recognized by the American Association of Immunologists with the AAI-Huang Foundation Trainee Achievement Award at the 2002 National Meeting.