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Prepublished online as a Blood First Edition Paper on May 22, 2003; DOI 10.1182/blood-2003-01-0095.
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Blood, 15 September 2003, Vol. 102, No. 6, pp. 2004-2013
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Adoptive transfer of costimulated T cells induces lymphocytosis in patients with relapsed/refractory non-Hodgkin lymphoma following CD34+-selected hematopoietic cell transplantation
Ginna G. Laport,
Bruce L. Levine,
Edward A. Stadtmauer,
Stephen J. Schuster,
Selina M. Luger,
Stephan Grupp,
Nancy Bunin,
Frank J. Strobl,
Julio Cotte,
Zhaohui Zheng,
Brian Gregson,
Patricia Rivers,
Robert H. Vonderheide,
David N. Liebowitz,
David L. Porter, and
Carl H. June
From the Translational Research Program, Abramson Family Cancer Research Institute at The University of Pennsylvania Cancer Center; and the Bone Marrow and Stem Cell Transplant Program, University of Pennsylvania Medical Center, Philadelphia.
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.
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