Infusion of CD3/CD28 costimulated umbilical cord blood T cells at the time of single umbilical cord blood transplantation may enhance engraftment

Abstract

Limited cell numbers in umbilical cord blood (UCB) grafts present a major impediment to favorable outcomes in adult transplantation, largely related to delayed or failed engraftment. The advent of UCB transplantation (UCBT) using two grafts successfully circumvents this obstacle, despite the engraftment of only one unit. Preclinical models suggested that the addition of UCB T cells at the time of transplant can enhance engraftment. We tested whether ex vivo activation by CD3/CD28 costimulation and expansion of T cells from a single UCB graft would be safe and feasible in adults with advanced hematologic malignancies, with an overall objective of optimizing engraftment in single unit UCBT. In this phase 1 study, recipients of single UCB units were eligible if the unit was stored in two adequate fractions. Dose limiting toxicity was defined as grade 3 or grade 4 GVHD within 90 days of UCBT. Four patients underwent UCBT; all were treated at the first dose level (105cells/kg). At the 105cells/kg dose level two subjects experienced grade 3 intestinal GVHD, thus meeting stopping criteria. For three subjects, neutrophil engraftment was early (12, 17, and 20 days), while one subject experienced primary graft failure. We observed early donor T cell trafficking and found that expanded T cells produced supraphysiologic levels of cytokines relevant to engraftment and to lymphoid differentiation and function. Taken together, these preliminary data suggest rapid engraftment in recipients of a single UCBT combined with relatively low doses of activated T cells, though potentially complicated by severe GVHD.

Cord blood–derived T cells allow the generation of a more naïve tumor‐reactive cytotoxic T‐cell phenotype

“…This supports the clinical observation that CB T cells have robust antitumor effects after adoptive T‐cell transfer . The enhanced cytotoxic activity of CB T cells and their differentiation into a more central‐effector memory phenotype might explain why CB‐activated donor lymphocyte infusion is more likely to mediate acute GVHD than PB‐activated donor lymphocyte infusion, despite improved survival …”

“…Interestingly, we found that addition of IL‐12 inhibits IL‐21–induced CD8+ T‐cell proliferation. This might be due to known interferences of the IL‐12 and IL‐21 signaling pathways . In contrast, treatment with IL‐12 alone led to the augmentation of T‐cell functionality and cytotoxicity and increased CD62L expression on MART1‐reactive CTLs generated from both graft sources.…”

“…36 The enhanced cytotoxic activity of CB T cells and their differentiation into a more central-effector memory phenotype might explain why CB-activated donor lymphocyte infusion is more likely to mediate acute GVHD than PBactivated donor lymphocyte infusion, despite improved survival. [38][39][40] NFAT promotes PD-1 expression in early activated CD81 T cells in adults; therefore, unbalanced NFAT signaling may contribute to T-cell anergy. 16,41 Interestingly, our activated CD81 CB T cells did not express PD-1, maybe due to impaired NFAT signaling, but this should be analyzed in the future.…”

Engineering cord blood to improve engraftment after cord blood transplant

“…There were no infusion-related toxicities and there was no clinically GVHD arising as consequence of the DLI. In another phase 1 trial by Hexner et al, patients with CB frozen in 2 fractions received ex vivo expanded CB T cells at 1×10 5 cells/kg (82). There was evidence of early T cell trafficking and supraphysiological levels of cytokines relevant to engraftment.…”

Considerations in T Cell Therapy Product Development for B Cell Leukemia and Lymphoma Immunotherapy

“…Cell therapies have been generated from tumor infiltrating lymphocytes obtained by surgical resection, from mobilized hematopoietic stem cell products, bone marrow, cord blood, and even whole blood (23, 24). Each of these sources offers a unique cost/benefit profile with respect to yield and purity.…”