CD19-Specific CB T-cell Therapy for Patients with B-cell Malignancies

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Project 3 addresses the problems of (i) opportunistic viral infection and (ii) relapse of B-lineage malignancies after umbilical cord blood transplantation (UCBT). We hypothesize that the incidence of viral infection and leukemia relapse following allogeneic UCBT can be reduced by adoptively transferred donor-derived multi virus-specific cytotoxic T lymphocytes (CTL), genetically modified (transduced) to be specific for the CD19 molecule expressed by leukemic cells. To consolidate UCBT we have designed a chimeric antigen receptor (CAR) to redirect antigen specificity of T cells to the B cell lineage-restricted cell-surface molecule CD19 The virus-specific CTLs from Project 2 will be transduced to express this CAR, resulting in MHC-independent and CAR-dependent activation through chimeric CD28 and CD3-zeta to lyse lymphoid cells, upregulate IL-2, and anti-apoptotic genes in response to CD19. The studies proposed in Specific Aim #1 will evaluate whether UCB-derived multivirus-specific CTLs can be rendered specific for GDI 9 and whether HSV-1 thymidine kinase transgene can be expressed for imaging by positron emission tomography (PET) in immunodeficient mice. Adoptive immunotherapy using non-invasive bioluminescent imaging (BLI) and micro PET will longitudinally asses the persistence of the infused cells, and the anti-tumor effect. Specific Aim #2 will evaluate the feasibility, safety, and persistence of infusing multivirus-specific CTLs modified to express CAR CD19-specific after UCBT. The correlative studies will delineate the (i) magnitude and duration of persistence, (ii) trafficking, and (iii) anti-viral and anti-leukemic effects of adoptively transferred CTLs. In preparation for human PET T-cell imaging, in Specific Aim #3, we will develop a nonhuman primate model Monkey-derived T cells will be genetically modified with CARs and TK, and infused. Longitudinal PET imaging using [18FJFEAU, metabolized by thymidine kinase (TK) will be used to evaluate the distribution of these adoptively transferred macaque T cells. In aggregate, the results of the studies will facilitate the evolution of targeting post-UCBT MRD with viral- and CD19-specific CTLs for enhanced disease-free survival of patients with B cell malignancies.