Acute GVHD in patients receiving IL-15/4-1BBL activated NK cells following T-cell–depleted stem cell transplantation

• Published in: Blood Vol. 125; no. 5; pp. 784 - 792
• Main Authors: Shah, Nirali N., Baird, Kristin, Delbrook, Cynthia P., Fleisher, Thomas A., Kohler, Mark E., Rampertaap, Shakuntala, Lemberg, Kimberly, Hurley, Carolyn K., Kleiner, David E., Merchant, Melinda S., Pittaluga, Stefania, Sabatino, Marianna, Stroncek, David F., Wayne, Alan S., Zhang, Hua, Fry, Terry J., Mackall, Crystal L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29.01.2015; American Society of Hematology
• Subjects: 4-1BB Ligand - pharmacology; Acute Disease; Adolescent; Adoptive Transfer; Adult; Cells, Cultured; Clinical Trials and Observations; Female; Gastrointestinal Neoplasms - immunology; Gastrointestinal Neoplasms - pathology; Gastrointestinal Neoplasms - therapy; Graft vs Host Disease - immunology; Graft vs Host Disease - pathology; Graft vs Leukemia Effect; Histocompatibility Testing; Humans; Interleukin-15 - pharmacology; Killer Cells, Natural - cytology; Killer Cells, Natural - immunology; Killer Cells, Natural - transplantation; Lymphocyte Activation - drug effects; Lymphocyte Depletion; Male; Peripheral Blood Stem Cell Transplantation - methods; Siblings; Skin Neoplasms - immunology; Skin Neoplasms - pathology; Skin Neoplasms - therapy; T-Lymphocytes - cytology; T-Lymphocytes - immunology; Transplantation Chimera; Transplantation, Homologous; Treatment Failure; Unrelated Donors
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2014-07-592881

Natural killer (NK) cells can enhance engraftment and mediate graft-versus-leukemia following allogeneic hematopoietic stem cell transplantation (HSCT), but the potency of graft-versus-leukemia mediated by naturally reconstituting NK cells following HSCT is limited. Preclinical studies demonstrate that activation of NK cells using interleukin-15 (IL-15) plus 4-1BBL upregulates activating receptor expression and augments killing capacity. In an effort to amplify the beneficial effects of NK cells post-HSCT, we conducted a first-in-human trial of adoptive transfer of donor-derived IL-15/4-1BBL–activated NK cells (aNK-DLI) following HLA-matched, T-cell–depleted (1-2 × 104 T cells/kg) nonmyeloablative peripheral blood stem cell transplantation in children and young adults with ultra-high-risk solid tumors. aNK-DLI were CD3+-depleted, CD56+-selected lymphocytes, cultured for 9 to 11 days with recombinant human IL-15 plus 4-1BBL+IL-15Rα+ artificial antigen-presenting cells. aNK-DLI demonstrated potent killing capacity and displayed high levels of activating receptor expression. Five of 9 transplant recipients experienced acute graft-versus-host disease (GVHD) following aNK-DLI, with grade 4 GVHD observed in 3 subjects. GVHD was more common in matched unrelated donor vs matched sibling donor recipients and was associated with higher donor CD3 chimerism. Given that the T-cell dose was below the threshold required for GVHD in this setting, we conclude that aNK-DLI contributed to the acute GVHD observed, likely by augmenting underlying T-cell alloreactivity. This trial was registered at www.clinicaltrials.gov as #NCT01287104. •Acute GVHD occurred in 5 of 9 patients after major histocompatibility–matched, T-cell–depleted peripheral blood stem cell transplantation plus IL-15/4-1BBL aNK-DLI.•GVHD was more common in matched unrelated donor transplants and associated with higher CD3 chimerism, suggesting that aNK-DLI may augment T-cell alloreactivity.