IL-7 Permits Th1/Tc1 Maturation And Promotes Ex-Vivo Expansion of Cord Blood T Cells: A Critical Step Toward Adoptive Immunotherapy After Cord Blood Transplantation

摘要

Donor leukocyte infusions (DLI) in the allogeneic hematopoietic transplant setting can provide a clinically relevant boost of immunity to reduce opportunistic infections and to increase graft-versus-leukemia activity. Despite significant advances in applicability, DLI has not been available for single unit recipients of unrelated cord blood transplant (UCBT). Ex-vivo expansion of cord blood T cells can be achieved with IL-2 and CD3/CD28 co-stimulatory beads. However, significant apoptosis occurs in proliferating T cells, diminishing the yield and skewing the CD4/CD8 ratio in the T cell population, jeopardizing the potential efficacy of DLI. In this study, we demonstrate that IL-7 not only reduces apoptosis of activated T lymphocytes and enhances their proliferation, but also promotes functional maturation leading to secretion of interferon-gamma and other key cytokines. Recognizing that infused T lymphocytes will need to meet microbial antigens in secondary lymphoid organs to generate effectors, we also show that expansion with IL-7 promotes the preservation of a polyclonal broad T cell receptor repertoire and a surface phenotype that favors lymph node homing. Expanded lymphocytes lack alloreactivity against recipient and other allogeneic cells indicating a favorable safety profile from graft-versus-host disease. Nevertheless, expanded T cells can be primed subsequently against lymphoid and myeloid leukemia cells to generate tumor-specific cytotoxic T cells. Taken together, our findings offer a major step in fulfilling critical numerical and biological requirements to quickly generate a DLI product ex vivo, using a negligible fraction of a cord blood graft that provides a flexible adoptive immunotherapy platform for both for children and adults.