Leukemia Relapse remains a significant obstacle to the success of allogeneic HSCT, particularly for patientswith acute leukemias and MDS transplanted in advanced stages of disease. Adoptive transfer of donor-derivedantigen-specific T cells has emerged as a promising approach for the tretment and prevention of life-threateningviral infections post transplant, and may also be used to provide expandable populations of tumoricidal effector Tcells to tumor-beariing hosts. In this project, we propose to explore and develop practicable broadly applicablestrategies for generating donor-derived T cells that selectively react againstdeterminants differentially expressedon leukemia cells for adoptive immunotherapy to treat or, ultimately, prevent leukemia relapse in the posttransplant peeriod.
In Aim 1, we propose to develop and evaluate new strategies for rapid generation of WT1peptide specific T cells from normal transplant donors expressing at least one of a series of common HLA class Ior II alleles by in vitro sensitization with a selectable panel of immediately accessible and replenishable artificialantigen presented cells engineered to express critical costimulatory molecules and single class I or class II allelesshared by the donor which have been either loaded with specific WT1 epitopes or a pool of synthetic overlappingpentadecapeptides spanning the WT1 sequence or transduced to express the WT1 protein. These T cells willthen be compared with T cells sensitized with autologous, WT1 peptide loaded dendritic cells as to yield,phenotype, peptide-speciflc reactivity and leukemocidal activity.
In Aim 2, we will develop and evaluate in vitrogenerated and selected EBV or CMV virus-specific T cells transduced to also express either a T cell receptorspecific for an immunogenic WT1 peptide presented by a prevalent class I HLA allele, or CD19-specific ScFv-based chimeric antigen receptor and evaluate them for their activity against WT1+ and/or CD19+ leukemias andlymphomas and their viral antigen targets. We hypothesize that introduction of a leukemia reactive WT1-specificTCR or CE19-specific CAR will abrogate the risk of transducing alloreactive T cells and may also enhancepersistence of dual receptor T cells through ongoing stimulation in vivo by cells expressing latent viral antigens.
In Aim 3, we propose to comparatively evaluate WT1 specific and CD19 specific T vcells generated in aims 1 and2 for their capacity to migrate to, accumulate and persist in and induce regressions of leukemia xenografts inNOD/SCID mice, and to also assess the effects of the WT1 peptide sensitized T cells and T cells expressingtransduced receptors on the engraftment and in vivo expansion of normal hematopoietic cells and leukemia blastsin the permissive NOD/SCIDyc''' mouse model. Relevance: These studies may yield rapid, practicable andbroadly applicable approaches and replenishable reagents for generating leukemia-reactive T cells for adoptivetherapy and should provide comparative estimates of the anti-leukemia effects of such T cells essential to planand prioritize clinical trials
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