Year: 2008
Type: article
Abstract: Genetic modification of clinical-grade T cells is undertaken to augment function, including redirecting specificity for desired antigen. We and others have introduced a chimeric antigen receptor (CAR) to enable T cells to recognize lineage-specific tumor antigen, such as CD19, and early-phase human trials are currently assessing safety and feasibility. However, a significant barrier to next-generation clinical studies is developing a suitable CAR expression vector capable of genetically modifying a broad population of T cells. Transduction of T cells is relatively efficient but it requires specialized manufacture of expensive clinical grade recombinant virus. Electrotransfer of naked DNA plasmid offers a cost-effective alternative approach, but the inefficiency of transgene integration mandates ex vivo selection under cytocidal concentrations of drug to enforce expression of selection genes to achieve clinically meaningful numbers of CAR(+) T cells. We report a new approach to efficiently generating T cells with redirected specificity, introducing DNA plasmids from the Sleeping Beauty transposon/transposase system to directly express a CD19-specific CAR in memory and effector T cells without drug selection. When coupled with numerical expansion on CD19(+) artificial antigen-presenting cells, this gene transfer method results in rapid outgrowth of CD4(+) and CD8(+) T cells expressing CAR to redirect specificity for CD19(+) tumor cells.
Source: Cancer Research
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: U.S. Department of Defense, Pediatric Cancer Research Foundation, Alliance for Cancer Gene Therapy, Lymphoma Research Foundation, Alex's Lemonade Stand Foundation for Childhood Cancer, National Foundation for Cancer Research, Leukemia and Lymphoma Society, Gillson Longenbaugh Foundation, National Institutes of Health, National Cancer Institute, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G1619438925, G1727840030, T-cell Therapy for B-lineage Acute Lymphoblastic Leukemia, G348510721, Gene Therapy for Metabolic Disorders, UCB-DERIVED CD19-SPECIFIC T CELLS FOR UNIVERSAL TREATMENT OF B-CELL MALIGNANCY, G6456933293, Enhancing the efficacy of CD19-specific cord blood-derived T Cells, Adoptive immunotherapy after umbilical cord blood transplant, UCB-DERIVED CD19-SPECIFIC T CELLS FOR UNIVERSAL TREATMENT OF B-CELL MALIGNANCY, Cancer Center Support Grant, Imaging Infused CD19 Specific T Cells in the Tumor
OpenAlex ID: W2111740872