The current emphasis of my research program is the development of a multipronged approach for cancer therapy. Our long-term goals are to: (1) evaluate the combined effects of individual strategies; (2) extend the clinical exploration to multiple cancers; and (3) combine immunotherapy and immune modulation with targeted cytotoxic therapy (specifically, oncolytic poliovirus).
Dendritic cells transfected with RNA as cancer vaccines: Research Question: Can we develop a novel vaccine strategy that is translatable and broadly applicable to all cancer patients, including patients with low tumor burden? Summary: We tested the hypotheses that: 1] Immunization with a broad repertoire of tumor antigens isolated form cancer cells is superior to using defined tumor antigens. 2] Loading antigen on DCs in the form of tumor mRNA is highly effective and provides unique advantages over other forms of tumor antigen, specifically, the ability to amplify the antigenic content of a small number of tumor cells. In a pioneering study, our group demonstrated that dendritic cells loaded with unfractionated total RNA isolated from tumor cells stimulates tumor immunity both in murine tumor models and in in vitro human assays. To render this innovative approach applicable to all cancer patients, protocols were developed for the generation of unlimited supply of tumor antigens for therapy using only a few tumor cells. I am a key inventor of the landmark invention: the use of RNA transfected dendritic cells as vaccines (patent awarded in 1998). In 1999, a company, Argos Therapeutics (formerly Merix Biosciences) was established in Durham, NC to commercialize this approach. Argos Therapeutics started a Phase 3 trial in patients with renal cancer in 2013 and went public in February 2014.
Modulation of immune responses to enhance tumor-specific immunity: Research Question: How can the therapeutic benefit for patients treated with RNA-transfected dendritic cells be improved? Summary: Modulating immune responses by blocking inhibitory immune receptors and activating stimulatory immune receptors on T cells enhances tumor-specific immunity. Systemic administration of antibodies (Abs) targeting inhibitory immune receptors enhanced the stimulation of immune responses in mice. However, clinical use of such Abs is limited by toxicity. We have developed an approach for local modulation of immune responses by delivering RNA encoding immune modulating proteins (Abs or receptor-binding ligands) regionally at the site of T cell activation. In preclinical studies, anti-tumor immunity was enhanced with no evidence of autoimmunity, when mice were immunized with dendritic cells transfected with RNA encoding Abs targeting the two immune receptors: GITR (glucocorticoid-induced TNFR-related gene) or CTLA-4. The approach for local modulation of human CTLA-4 and GITR is ready for clinical implementation in patients with prostate cancer and breast cancer.
Novel vaccine strat