The immune system exists in a dynamic tension between tolerance and activation. Knowledge of the mechanisms responsible for achieving these states has great relevance for vaccine development, transplantation, and autoimmune diseases. With a focus on the T cell arm of this system, our laboratory is exploring the influence of factors that enhance T cell activation on the efficacy of vaccines engineered to generate immune responses tumors and infectious pathogens. Strategies being explored include; 1) in vivo targeting of recombinant viral vaccines to potent antigen presenting cells, 2) altering intracellular antigen trafficking to increase antigen density on the MHC of antigen presenting cells, 3) co-expression of antigen with molecules critical to T cell activation such as co-stimulatory molecules and cytokines, and 4) interference with homeostatic mechanisms that may limit the extent of antigen specific T cell amplification following immunization. Analysis of the mechanism of the antigen specific responses so generated is a central focus of our group. One such study has characterized a previously unappreciated pathway of antigen trafficking that enables exogenous antigens access to binding with MHC class I molecules for priming critical cytolytic T cell responses to tumor vaccines. A more detailed study of this pathway is ongoing.

In addition to the basic questions being investigated in the systems outlined above, our lab is involved in an ongoing intergroup program to test promising vaccines strategies in a clinical setting. The current trial of genetically modified autologous tumor vaccines will hopefully be the first of many to spring forth from laboratory-based studies, and will provide the opportunity to ask additional questions using the clinical materials such studies provide.

Sotomayor, E.M., Borrello,I., Rattis, F., Abrams, J., Staveley-O'Carroll, K., and Levitsky, H.I. (2001) Cross-Presentation of Tumor Antigens by Bone Marrow Derived Antigen Presenting Cells is the Dominant Mechanism in the Induction of T cell Tolerance During B-Cell Lymphoma Progression. Blood 267:93-96 [PubMed]

Nelson, W., Simons, J., Mikhak, B., Ju-Fay, C., DeMarzo, A., Carducci, M., Kim, M., Weber, C., Baccala, A., Goeman, M., Clift, S.,Ando, D., Levitsky, H, Cohen, L, Sanda, M, Mulligan, R., Partin, A., Carter, H., Piantadosi, S., Marshall, F. (2001) Cancer Cells Engineered to Secrete Granylocyte-macrophage Colony-stimulating Factor Using Ex Vivo Gene Transfer as Vaccines for the Treatment of Genitourinary Malignancies. Cancer Chemother Pharmacol 270:4387-4394 [PubMed]

Wu, B., Wu, J., Miagkov, A., Adams, R., Levitsky, H., and Drachman, D. (2001) Specific Immunotherapy by genetically engineered antigen presenting cells: the "Guided Missile"strategy. J. Immunol. 33:10851-10858 [PubMed]

Lu, Z., Yuan, L., Zhou, X., Sotomayor, E., Levitsky, H.I., Pardoll, D.M. (2000) CD40 Independent Pathways of T cell Help for Priming CD8+ Cytotoxic T Lymphocyte Precursors. J. Exp. Med. 37:965-970 [PubMed]

Borrello, I., Sotomayor, E.M., Rattis, F.M., Cooke,S., Gu, L., and Levitsky, H.I. (2000) Sustaining the Graft versus Tumor Effect Through Post-transplant Immunization with Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF) Producing Tumor Vaccines. Blood 92:9752-9756 [PubMed]

Sotomayor, E.M., Borrello, I.M., Tubb, E., Rattis, F.R., Bien, H., Lu, Z., Schoenberger, S.P., and Levitsky, H.I. (1999) Conversion of Tumor Specific CD4+ T-Cell Tolerance to T-Cell Priming Through In Vivo Ligation of CD40. Nature Medicine 41:7604-7609 [PubMed]

Sotomayor, E.M., Borrello, I.M., Tubb, E., Allison, J.P., and Levitsky, H.I. (1999) In Vivo Blockade of CTLA-4 Enhances the Priming of Responsive T-cells, but Fails to Prevent the Induction of Tumor Antigen-Specific Tolerance. Proc. Natl. Acad. Sci. USA 406:26-29 [PubMed]

Borrello, I., Sotomayor E., Cooke, S. and Levitsky, H.I. (1999) Universal GM-CSF Producing Bystander Cell Line for use in the Formulation of Autologous Tumor Cell-based Vaccines. Human Gene Therapy 18:6694-6704 [PubMed]