Abstract
Cellular immunotherapy is revolutionizing cancer treatment. However, autologous transplants are complex, costly, and limited by the number and quality of T cells that can be isolated from and expanded for re-infusion into each patient. This paper demonstrates a stromal support cell-free in vitro method for the differentiation of T cells from umbilical cord blood hematopoietic stem cells (HSCs). For each single HSC cell input, approximately 5 × 104 T cells were created with an initial five days of HSC expansion and subsequent T cell differentiation over 49 days. When the induced in vitro differentiated T cells were activated by cytokines and anti-CD3/CD28 beads, CD8+ T cell receptor (TCR) γδ+ T cells were preferentially generated and elicited cytotoxic function against ovarian cancer cells in vitro. This process of inducing de novo functional T cells offers a possible strategy to increase T cell yields, simplify manufacturing, and reduce costs with application potential for conversion into chimeric antigen receptor (CAR)-T cells for cancer immunotherapy and for allogeneic transplantation to restore immune competence.
Highlights
Immunotherapy is a recognized pillar of cancer treatment alongside chemotherapy, radiation, surgery, and therapeutic small molecules
umbilical cord blood (UCB) is an enriched source of hematopoietic stem cells (HSCs), that can be differentiated to human lymphoid cells, including T cells
Freshly isolated HSCs from UCB samples were expanded for five days prior to T cell differentiation (Day −5–Day 0)
Summary
Immunotherapy is a recognized pillar of cancer treatment alongside chemotherapy, radiation, surgery, and therapeutic small molecules. This success is mainly attributed to checkpoint inhibitors and cell therapies such as chimeric antigen receptor (CAR)-T cells [1]. There is a clear correlation between immunodeficiency, thymic atrophy in adults and reduced numbers of naive T cells [7,8,9] This leads to poor immunity in the aged, and has direct consequences on the ability of cancer patients to recover immune competency following myeloablative chemotherapy and rescue hematopoietic stem cell (HSC) transplantation. The utilization of γδ T and natural killer (NK) cells in an allogeneic setting is rapidly growing due to their innate functional characteristics and better safety profiles [12,13]
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