Adoptive therapy with T cells rendered tumor specific by genetic modifications is a conceptually attractive strategy to selectively augment graft-versus-leukemia reactivity following allogeneic bone marrow transplantation for acute lymphoblastic leukemia and to generate anti- tumor effector cells for targeting residual lymphoma cells following autologous stem cell transplantation. Our laboratory has engineered chimeric immuno receptor cDNA constructs consisting of CD20- and CD19-specific-chain antibody extracellular domains fused to the cytoplasmic tail of the T cell receptor CD3 complex zeta chain (scFv:Fc: zeta) and has developed methodologies to genetically modify T lymphocytes with naked plasmid vectors. Ex vivo expanded gene- modified scFvFc: zeta expressing CD8+ cytotoxic T lymphocyte (CTL) clones specifically recognize and lyse malignant B-cells. The studies proposed in Project VI will examine for the first time the clinical application for adoptive T cell therapy following autologous and allogeneic hematopoietic stem cell transplantation of CD20+ non- Hodgkin's lymphoma and pre-B acute lymphoblastic leukemia utilizing scFvFc: zeta-expressing CD8+ CTL clones specific for CD20 and CD19. Pilot phase I clinical trials will be initiated in years 1 and 2 of the grant to determine the safety and toxicity of this approach as well as to examine the in vivo persistence, trafficking, and potential immunogenicity of gene-modified CTL. In years 3-5, larger phase II clinical trials will be conducted to evaluate the impact of adoptive therapy on the incidence of post-transplant relapse and improvement in the overall outcome of bone marrow/stem cell transplantation.
The specific aims for Project VI are: 1.) To evaluate the safety and anti-lymphoma activity of adoptively transferred CD20-specific CD8+ CTL clones in patients with recurrent CD20+ diffuse large cell lymphoma undergoing autologous stem cell transplantation. 2.) To evaluate in patients with Philadelphia chromosome-positive pre-B ALL the safety and anti-leukemic effects of adoptive therapy with donor- derived CD19-specific CD8+ CTL clones at the time of molecular relapse following allogeneic BMT. 3.) To design and evaluate second generation CD20- and CD19-specific CD8+ CTL clones at the time of molecular relapse following allogeneic BMT.
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