title: Adoptive transfer of costimulated T cells induces lymphocytosis in patients with relapsed/refractory non-Hodgkin lymphoma following CD34+-selected hematopoietic cell transplantation.
abstract: We explored the feasibility and toxicity of administering escalating doses of anti-CD3/CD28 ex vivo costimulated T cells as a therapeutic adjunct for patients with relapsed, refractory, or chemotherapy-resistant, aggressive non-Hodgkin lymphoma (NHL) following high-dose chemotherapy and CD34+-selected hematopoietic cell transplantation (HCT). Sixteen patients had infusions on day 14 after HCT of autologous T cells that had been stimulated using beads coated with anti-CD3 and anti-CD28 monoclonal antibodies. At baseline, the subjects had severe quantitative and functional T-cell impairments. The culture procedure partially reversed impaired cytokine responsiveness in T cells in vitro and in vivo. Transient dose-dependent infusion toxicities were observed. There was a rapid reconstitution of lymphocytes; however, there were persistent defects in CD4 T cells. Most interestingly, 5 patients had a delayed lymphocytosis between day 30 and day 120 after HCT. Maximal clinical responses included 5 patients with a complete response (CR), 7 patients with a partial response (PR), and 4 patients with stable disease. At a median follow-up of 33 months (range, 26-60 months), 5 patients are alive with stable or relapsed disease and 3 patients remain in CR. In conclusion, this phase 1 trial demonstrates that adoptive transfer of autologous costimulated T cells (1) is feasible in heavily pretreated patients with advanced NHL, (2) is associated with a rapid recovery of lymphocyte counts, (3) reverses cytokine activation deficits in vitro, and (4) is associated with delayed lymphocytosis in a subset of patients.
authors.affiliation: Translational Research Program, Abramsonm Family Cancer Research Institute, University of Pennsylvania School of Medicine, 421 Curie Blvd, Philadelphia, PA 19104-6160, USA.
authors.forename: Ginna G
authors.initials: GG
authors.lastname: Laport
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Levine
authors.forename: Edward A
authors.initials: EA
authors.lastname: Stadtmauer
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Schuster
authors.forename: Selina M
authors.initials: SM
authors.lastname: Luger
authors.forename: Stephan
authors.initials: S
authors.lastname: Grupp
authors.forename: Nancy
authors.initials: N
authors.lastname: Bunin
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Strobl
authors.forename: Julio
authors.initials: J
authors.lastname: Cotte
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Zheng
authors.forename: Brian
authors.initials: B
authors.lastname: Gregson
authors.forename: Patricia
authors.initials: P
authors.lastname: Rivers
authors.forename: Robert H
authors.initials: RH
authors.lastname: Vonderheide
authors.forename: David N
authors.initials: DN
authors.lastname: Liebowitz
authors.forename: David L
authors.initials: DL
authors.lastname: Porter
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
mesh_terms: D000293:Adolescent; D019264:Adoptive Transfer / Q000009:adverse effects; D000328:Adult; D000368:Aged; D018952:Antigens, CD34 / Q000032:analysis; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002330:Carmustine / Q000627:therapeutic use; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000627:therapeutic use; D003561:Cytarabine / Q000627:therapeutic use; D005047:Etoposide / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000737:chemistry; D006801:Humans; D008218:Lymphocytosis / Q000276:immunology*; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D012074:Remission Induction; D013601:T-Lymphocytes / Q000637:transplantation*
chemical_list: D018952:Antigens, CD34; D003561:Cytarabine; D005047:Etoposide; D003520:Cyclophosphamide; D002330:Carmustine