title: Nonengraftment haploidentical cellular immunotherapy for refractory malignancies: tumor responses without chimerism.
abstract: Allogeneic bone marrow transplantation relies on immunosuppression, which controls graft-versus-host disease (GVHD) and allows engraftment at the expense of diminished graft versus-tumor (GVT) activity. Advances in hematologic transplantation have prompted the development of effective, less-toxic regimens that attempt to balance GVH and GVT immunoreactions. We analyzed the safety and efficacy of haploidentical transplantation in a Phase I/II nonimmunosuppressive, nonmyeloablative setting. A total of 41 patients with relapsed refractory cancer received 100 cGy of total body irradiation (TBI), along with an infusion of 1 x 10(6) to 2 x 10(8) CD3+ cells/kg; 29 patients received the highest dose. A postinfusional cellular graft rejection syndrome resembling engraftment syndrome was noted at the 2 highest CD3+ infusion cohorts. There were 26 patients with hematologic malignancies with 14 responses, 9 of which were major. Two of 6 patients with lymphoma remained free of disease at 76 months and 82 months, respectively; there were 5 durable complete responses and 4 partial responses in 13 patients with acute myelogenous leukemia (AML). All responses occurred outside of donor chimerism. TBI at 100 cGy followed by HLA-haploidentical immunotherapy is a biologically active therapy for patients with refractory AML and lymphoma. Possible mechanisms contributing to its effectiveness include initial GVT kill, breaking of host tolerance to tumor through cross-reactive alloreactive responses, persistent nondetectable microchimerism, or some combination of these.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Rhode Island Hospital, Providence, Rhode Island 02903, USA. gcolvin@lifespan.org
authors.forename: Gerald A
authors.initials: GA
authors.lastname: Colvin
authors.forename: David
authors.initials: D
authors.lastname: Berz
authors.forename: Muthalagu
authors.initials: M
authors.lastname: Ramanathan
authors.forename: Eric S
authors.initials: ES
authors.lastname: Winer
authors.forename: Loren
authors.initials: L
authors.lastname: Fast
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Elfenbein
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Quesenberry
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016026:Bone Marrow Transplantation; D017252:CD3 Complex; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000401:mortality / Q000628:therapy*; D006086:Graft vs Host Disease / Q000401:mortality / Q000628:therapy*; D006801:Humans; D007108:Immune Tolerance; D007167:Immunotherapy; D017710:Lymphocyte Transfusion; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000401:mortality / Q000628:therapy*; D012008:Recurrence; D015996:Survival Rate; D018183:Transplantation Chimera; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation
chemical_list: D017252:CD3 Complex