title: A phase 1 trial of donor lymphocyte infusions expanded and activated ex vivo via CD3/CD28 costimulation.
abstract: Donor lymphocyte infusions (DLIs) induce potent graft versus tumor (GVT) effects for relapsed chronic myelogenous leukemia (CML) after allogeneic stem cell transplantation (SCT) but are disappointing for other diseases. Disease resistance can occur if donor T cells are not appropriately activated in vivo. Ex vivo T-cell activation might overcome disease-induced anergy and augment GVT activity. We performed a phase 1 trial of ex vivo-activated DLI (aDLI) for 18 patients with relapse after SCT. Activated donor T cells are produced through costimulation with anti-CD3- and anti-CD28-coated beads. Patients with aggressive malignancies received induction chemotherapy, and all patients received conventional DLI (median, 1.5 x 10(8) mononuclear cells/kg) followed 12 days later by aDLI. Activated DLI was dose escalated from 1 x 10(6) to 1 x 10(8) CD3+ cells per kilogram in 5 levels. Seven patients developed acute graft versus host disease (GVHD) (5 grade I-II, 2 grade III), and 4 developed chronic GVHD. Eight patients achieved complete remission, including 4 of 7 with acute lymphocytic leukemia (ALL), 2 of 4 with acute myelogenous leukemia (AML), 1 with chronic lymphocytic leukemia (CLL), and 1 of 2 with non-Hodgkin lymphoma (NHL). Four complete responders relapsed while 4 remain alive in remission a median 23 months after aDLI. Overall, 10 of 18 remain alive 11 to 53 months after aDLI. Adoptive transfer of costimulated activated allogeneic T cells is feasible, does not result in excessive GVHD, and may contribute to durable remissions in diseases where conventional DLI has been disappointing.
authors.affiliation: Stem Cell Transplant Program, Division of Hematology-Oncology, 16 Penn Tower, 3400 Spruce St, Philadelphia, PA 19104, USA. david.porter@uphs.upenn.edu
authors.forename: David L
authors.initials: DL
authors.lastname: Porter
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Levine
authors.forename: Nancy
authors.initials: N
authors.lastname: Bunin
authors.forename: Edward A
authors.initials: EA
authors.lastname: Stadtmauer
authors.forename: Selina M
authors.initials: SM
authors.lastname: Luger
authors.forename: Steven
authors.initials: S
authors.lastname: Goldstein
authors.forename: Alison
authors.initials: A
authors.lastname: Loren
authors.forename: Julie
authors.initials: J
authors.lastname: Phillips
authors.forename: Sunita
authors.initials: S
authors.lastname: Nasta
authors.forename: Alexander
authors.initials: A
authors.lastname: Perl
authors.forename: Steven
authors.initials: S
authors.lastname: Schuster
authors.forename: Donald
authors.initials: D
authors.lastname: Tsai
authors.forename: Ambika
authors.initials: A
authors.lastname: Sohal
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Veloso
authors.forename: Stephen
authors.initials: S
authors.lastname: Emerson
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
mesh_terms: D000293:Adolescent; D000328:Adult; D015703:Antigens, CD / Q000097:blood; D018106:CD28 Antigens / Q000097:blood*; D016827:CD8 Antigens / Q000097:blood*; D002648:Child; D005260:Female; D006801:Humans; D007938:Leukemia / Q000628:therapy*; D008213:Lymphocyte Activation; D017710:Lymphocyte Transfusion / Q000009:adverse effects*; D008223:Lymphoma / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D033581:Stem Cell Transplantation / Q000009:adverse effects*; D014184:Transplantation, Homologous
chemical_list: D015703:Antigens, CD; D018106:CD28 Antigens; D016827:CD8 Antigens