Interleukin-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.
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. Ex vivo expansion of cord blood T cells can be achieved with interleukin (IL)-2 and CD3/CD28 costimulatory 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 show that interleukin (IL)-7 not only reduces apoptosis of activated T lymphocytes and enhances their proliferation but also promotes functional maturation, leading to secretion of IFN-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 children and adults.
Department of Pediatrics, Pediatric Blood and Marrow Transplant Program, Duke University Medical Center, Durham, North Carolina 27705, USA.
Craig C
CC
Davis
Luciana C
LC
Marti
Gregory D
GD
Sempowski
Durairaj A
DA
Jeyaraj
Paul
P
Szabolcs
D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D023201:CD40 Ligand / Q000096:biosynthesis / Q000276:immunology; D005312:Fetal Blood / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000637:transplantation*; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D015851:Interleukin-7 / Q000494:pharmacology*; D007945:Leukemia, Lymphoid / Q000276:immunology / Q000628:therapy; D007951:Leukemia, Myeloid / Q000276:immunology / Q000628:therapy; D008213:Lymphocyte Activation / Q000187:drug effects; D054353:Perforin / Q000096:biosynthesis / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000637:transplantation; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000096:biosynthesis / Q000276:immunology
D018106:CD28 Antigens; D017252:CD3 Complex; D015851:Interleukin-7; D016693:Receptors, Antigen, T-Cell, alpha-beta; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D054353:Perforin; D023201:CD40 Ligand