Transduction and transplantation of human hematopoietic stem/progenitor cells (HSPC) with the genes for a T-cell receptor (TCR) that recognizes a tumor-associated antigen may lead to sustained long-term production of T cells expressing the TCR and confer specific antitumor activity. We evaluated this using a lentiviral vector (CCLc-MND-F5) carrying cDNA for a human TCR specific for an HLA-A*0201-restricted peptide of Melanoma Antigen Recognized by T cells (MART-1). CD34(+) HSPC were transduced with the F5 TCR lentiviral vector or mock transduced and transplanted into neonatal NSG mice or NSG mice transgenic for human HLA-A*0201 (NSG-A2). Human CD8(+) and CD4(+) T cells expressing the human F5 TCR were present in the thymus, spleen, and peripheral blood after 4-5 months. Expression of human HLA-A*0201 in NSG-A2 recipient mice led to significantly increased numbers of human CD8(+) and CD4(+) T cells expressing the F5 TCR, compared with control NSG recipients. Transduction of the human CD34(+) HSPC by the F5 TCR transgene caused a high degree of allelic exclusion, potently suppressing rearrangement of endogenous human TCR-β genes during thymopoiesis. In summary, we demonstrated the feasibility of engineering human HSPC to express a tumor-specific TCR to serve as a long-term source of tumor-targeted mature T cells for immunotherapy of melanoma.Molecular Therapy (2013); doi:10.1038/mt.2013.8.
"Furthermore, the introduction of CAR-modified HSPCs in the HSCT context would favor effective immune response against minimal residual malignancy, favor the engraftment of modified cells, and decrease the probability of immunogenicity of the CAR constructs on the surface of effector cells. Transduced HSPCs will yield granulocytes and monocytes within 1-2 weeks, followed by production of NK cells in a few months and T-lymphocytes potentially over a longer time-course (Rappeport et al., 2011; Giannoni et al., 2013; Kitchen et al., 2012; Vatakis et al., 2011). CAR expression by these cells may confer enduring anti-leukemic immunity with a continuously generated mix of effector cell types, as opposed to current cancer immunotherapy approach using modified mature "
[Show abstract][Hide abstract] ABSTRACT: Chimeric Antigen Receptors (CARs) against CD19 have been shown to direct T-cells to specifically target B-lineage malignant cells in animal models and clinical trials, with efficient tumor cell lysis. But, in some cases, there has been insufficient persistence of effector cells, limiting clinical efficacy. We propose gene transfer to hematopoietic stem/progenitor cells (HSPC) as a novel approach to deliver the CD19-specific CAR, with potential for ensuring persistent production of effector cells of multiple lineages targeting B-lineage malignant cells. Assessments were performed using in vitro myeloid or NK differentiation of human HSPCs transduced with lentiviral vectors carrying first and second generations of CD19-specific CAR. Gene transfer did not impair hematopoietic differentiation and cell proliferation when transduced at 1-2 copies/cell. CAR-bearing myeloid and NK cells specifically lysed CD19-positive cells, with second generation CAR including CD28 domains being more efficient in NK cells. Our results provide evidence for the feasibility and efficacy of the modification of HSPC with CAR as a strategy for generating multiple lineages of effector cells for immunotherapy against B-lineage malignancies to augment graft-versus-leukemia activity.
[Show abstract][Hide abstract] ABSTRACT: Advances in high-throughput sequencing have enabled the development of a powerful new technology for probing the adaptive immune system. Millions of B or T cell receptor sequences can be read in parallel from a single sample. The dynamics of an adaptive immune response, which is based on clonal expansion and contraction, can be monitored in real time at high sensitivity and the global properties of the adaptive immune repertoires can be studied. A large set of clinical applications for this technology are presently under study, with a few diagnostic applications for hematological malignancies already available. A review of this new field termed immunosequencing is presented.
Current opinion in immunology 10/2013; 25(5). DOI:10.1016/j.coi.2013.09.017 · 7.48 Impact Factor
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