Recent advances in T cell phenotyping and high speed sorting have coalesced to allow the direct testing of an important basic tenet in immunotherapy-specifically that adoptive immunotherapy with antigen specific T cells will eradicate antigen expressing cells in vivo. Although immunotherapy with T cells activated and expanded in vitro have shown promise, an alternative broadly applicable strategy may allow therapy with antigen specific T cells prior to significant activation. Specifically, peptide major histocompatibility complex (MHC)-tetramers allow the identification of T cells that specifically bind to unique nanopeptides in the context of a specific human leukocyte antigen (HLA) allele. This technology allows for the sorting and isolation of highly purified populations of antigens specific T cells from peripheral blood mononuclear cells (PBMC). We have hypothesized that the adoptive immunotherapy with purified populations of antigen specific T cells will have clinical benefits in patients immunosuppressed following bone marrow/peripheral blood stem cell transplant. A relevant model system to test this hypothesis exists in immuno-compromised patients with cytomegalovirus (CMV) infection or Epstein Barr virus (EBV) associated LPD (LPD). Clinical benefit has been achieved with administration CMV specific clones expanded in vitro and as few as 10(7) cells/M2PBMC activated in vitro with autologous EBV transformed B cells. While these strategies are clinically effective, they cannot be widely applied because they are complex and time-consuming, taking as long as to 3 to 4 months to generate the appropriate cells for administration. An exciting alternative to this laborious process would be to directly isolate CMV or EBV specific T cells from peripheral blood samples by high speed sorting with CMV or EBV peptide MHC tetramers. This strategy would allow for the rapid isolation of up to 10-40 x 10(6) antigen specific T cells. These cells could then be directly administered, or administered after a brief period of ex vivo activation and expansion. This application proposes pre-clinical studies and pilot clinical trials of adoptive immunotherapy with peptide MHC tetramer sorted T cells. It is anticipated that these studies would provide an important proof of principle for this general concept which would have wide application for antigen specific adoptive immunotherapy of vial disorders and cancer.
| Hobeika, Ac; Osada, T; Serra, D et al. (2008) Detailed analysis of cytomegalovirus (CMV)-specific T cells expanded for adoptive immunotherapy of CMV infection following allogeneic stem cell transplantation for malignant disease. Cytotherapy 10:289-302 |
| Mosca, Paul J; Lyerly, H Kim; Clay, Timothy M et al. (2007) Dendritic cell vaccines. Front Biosci 12:4050-60 |
