Infusion of donor-derived CD8+ memory T cells for relapse following allogeneic hematopoietic cell transplantation

• Published in: Blood advances 2018-03, Vol.2 (6), p.681-690
• Main Authors: Muffly, Lori, Sheehan, Kevin, Armstrong, Randall, Jensen, Kent, Tate, Keri, Rezvani, Andrew R., Miklos, David, Arai, Sally, Shizuru, Judith, Johnston, Laura, Meyer, Everett, Weng, Wen-Kai, Laport, Ginna G., Negrin, Robert S., Strober, Sam, Lowsky, Robert
• Format: Article
• Language: English
• Subjects: Animals; Biomarkers; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Clinical Trials and Observations; Cytokines - genetics; Cytokines - metabolism; Flow Cytometry; Gene Expression; Graft vs Host Disease - etiology; Hematopoietic Stem Cell Transplantation - adverse effects; Hematopoietic Stem Cell Transplantation - methods; Humans; Immunohistochemistry; Immunologic Memory; Kaplan-Meier Estimate; Lymphocyte Transfusion; Mice; Phenotype; Recurrence; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Tissue Donors; Transplantation, Homologous; Treatment Outcome
• ISSN: 2473-9529; 2473-9537
• DOI: 10.1182/bloodadvances.2017012104

Murine models showed that CD8+CD44hi memory T (TM) cells could eradicate malignant cells without inducing graft-versus-host disease (GVHD). We evaluated the feasibility and safety of infusing freshly isolated and purified donor-derived phenotypic CD8+ TM cells into adults with disease relapse after allogeneic hematopoietic cell transplantation (HCT). Phenotypic CD8 TM cells were isolated after unmobilized donor apheresis using a tandem immunomagnetic selection strategy of CD45RA depletion followed by CD8+ enrichment. Fifteen patients received CD8+ TM cells at escalating doses (1 × 106, 5 × 106, or 10 × 106 cells per kg). Thirteen received cytoreduction before CD8+ TM cell infusion, and 9 had active disease at the time of infusion. Mean yield and purity of the CD8+ TM infusion were 38.1% and 92.8%, respectively; >90% had CD8+ T effector memory phenotype, cytokine expression, and secretion profile. No adverse infusional events or dose-limiting toxicities occurred; GVHD developed in 1 patient (grade 2 liver). Ten patients (67%) maintained or achieved response (7 complete response, 1 partial response, 2 stable disease) for at least 3 months after infusion; 4 of the responders had active disease at the time of infusion. With a median follow-up from infusion of 328 days (range, 118-1328 days), median event-free survival and overall survival were 4.9 months (95% confidence interval [CI], 1-19.3 months) and 19.6 months (95% CI, 5.6 months to not reached), respectively. Collection and enrichment of phenotypic CD8+ TM cells is feasible, well tolerated, and associated with a low incidence of GVHD when administered as a manipulated infusion of donor lymphocytes in patients who have relapsed after HCT. This trial was registered at www.clinicaltrials.gov as #NCT01523223. •Phenotypic TM isolation from unmanipulated donor apheresis via CD45RA depletion followed by CD8+ enrichment is feasible.•TM infusion for patients with relapse after allogeneic HCT was safe and resulted in minimal GVHD. [Display omitted]