Extensive preclinical studies, as well as early indications from clinical trials, suggest that vaccination with tumor-derived mRNA transfected autologous dendritic cells (DC) represents a potentially effective and broadly applicable treatment modality for disseminated metastatic cancer. The underlying hypothesis of this application is that the RNA transfected DC vaccination approach, promising as it may be in its current form, will require significant improvements to realize it's full potential. The purpose of the proposed studies is to explore strategies that will augment, in a significant manner, the therapeutic impact of this intervention modality. Animal models will be used to (a) develop improved DC antigen presenting platforms and (b) design adjunct treatments to enhance, qualitatively as well as quantitatively, the immune response generated by the RNA transfected DC.
In Specific Aim 1 the applicant will explore the importance of DC maturation. Since the maturation process of DC is more complex than initially thought and the influence of various maturation agents has not been clearly defined, he will first determine the biological impact of various agents on DC maturation and then correlate with their potency to stimulate T cell responses and protective immunity. He will also follow up on preliminary observations suggesting that calreticulin (CRT) functions as a potent maturation agent.
In Specific Aim 2, the applicant will test whether Flt-3L mobilized DC are effective APC in a vaccination setting. The significance from a clinical standpoint is that generation of Flt-3L mobilized DC is much simpler compared to the generation of monocyte derived DC, which is currently used by the applicant and others in clinical trials.
In Specific Aim 3 the applicant will explore adjunct treatments designed to expand in vivo the tumor-specific T cell response generated by vaccination with RNA transfected DC. The applicant hypothesizes that the inherent deficiency of vaccination with RNA transfected DC to stimulate an effective CD4+ T cell response (T-help) will limit the therapeutic benefit of this intervention modality. Methods to boost tumor-specific CD4+, as well as CD8+ T cell responses will be explored by co-administration of agents such as IL-2, IL-12, CpG ODNs, Poly I:C or anti-CTLA4 ab. Promising strategies indicated by the murine studies will be channeled into the applicant's ongoing clinical program. The studies proposed in this application will set the stage for the development of improved generation of RNA transfected DC vaccines.
| Hess, Paul R; Boczkowski, David; Nair, Smita K et al. (2006) Vaccination with mRNAs encoding tumor-associated antigens and granulocyte-macrophage colony-stimulating factor efficiently primes CTL responses, but is insufficient to overcome tolerance to a model tumor/self antigen. Cancer Immunol Immunother 55:672-83 |
| Zhao, Yangbing; Boczkowski, David; Nair, Smita K et al. (2003) Inhibition of invariant chain expression in dendritic cells presenting endogenous antigens stimulates CD4+ T-cell responses and tumor immunity. Blood 102:4137-42 |
| Nair, Smita; McLaughlin, Catherine; Weizer, Alon et al. (2003) Injection of immature dendritic cells into adjuvant-treated skin obviates the need for ex vivo maturation. J Immunol 171:6275-82 |
| Nair, Smita; Boczkowski, David; Moeller, Benjamin et al. (2003) Synergy between tumor immunotherapy and antiangiogenic therapy. Blood 102:964-71 |
