[HTML][HTML] Allelic exclusion and peripheral reconstitution by TCR transgenic T cells arising from transduced human hematopoietic stem/progenitor cells

F Giannoni, CL Hardee, J Wherley, E Gschweng… - Molecular Therapy, 2013 - cell.com
F Giannoni, CL Hardee, J Wherley, E Gschweng, S Senadheera, ML Kaufman, R Chan…
Molecular Therapy, 2013cell.com
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 …
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.
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