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.
Infection and relapse of leukemia are unfortunately common complications of umbilical cord blood transplantation (UCBT). This grant application will test whether immune cells (T cells) can be generated that are specific for virus and leukemia and infused to prevent infection and relapse. This is part of a group-wide effort by investigators in the Texas Medical Center to both develop and implement new therapies for UCBT.
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