454. Recognition of Tumor Antigens by In Vitro Developed T Cells from Hematopoietic Stem Cells Retrovirally Transduced with TCR Genes
Year: 2006
Type: article
Abstract: Adoptive cell transfer is an effective method for the immunotherapy of patients with metastatic melanoma. Animal studies indicated that the anti-tumor efficacy of adoptively transferred T cells is dependent on their differentiation status. Despite enhanced in vitro anti-tumor properties, more_differentiated effector T cells were less effective for in vivo tumor treatment. Recent advances in T cell in vitro development technologies provide a new opportunity to generate naïve T cells in vitro for the purpose of adoptive immunotherapy. In this study, human CD133+ hematopoietic stem cells (HSC) isolated from cord blood mononuclear cells were transduced with retroviral vectors encoding anti_tumor antigen TCR alpha/beta cDNAs (directed against NY_ESO_1 or p53) and co_cultured with a murine stromal cell line engineered with Notch_1 ligand Delta_1 (OP9_DL1). The cells proliferated and the cell number increased rapidly for the first 6 weeks post co_cultivation (approximately 500_fold expansion) and decreased thereafter. Transduction efficiency was 30% to 90% for NY_ESO_1 TCR and p53 TCR (or GFP) vectors (respectively). The HSCs differentiated into committed T cells as evidenced by the expression of T cell markers, such as CD7, CD1a, CD4, CD8, CD27, CD25, CD62, CD69, CD45RA and CD56. Furthermore, T cell receptor excision circles (TRECs) could be detected by PCR only after the HSCs were co_cultured with OP9_DL1 cell line. CD3 and alpha/beta TCR expression were nearly undetectable for the non_TCR vector transduced groups, but was expressed in the TCR vector_transduced cell populations. These cells manifest both NK cell_like nonspecific killing of tumor cell lines and specific recognition and killing of tumor antigen peptide pulsed cells, as evidenced by cytokine secretion and 51Cr release assay. These results were reproducible using cord blood cells but as of now, we have not been able to successfully generate reactive T cells from CD34+ (or CD133+) bone marrow cells or G_CSF mobilized peripheral blood CD34+ (or CD133+) cells.
Source: Molecular Therapy
Institution: National Cancer Institute
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
OpenAlex ID: W2079007950