Journal
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION
Volume 16, Issue 9, Pages 1245-1256Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.bbmt.2010.03.014
Keywords
Cellular immunotherapy; Adoptive therapy; T lymphocyte; Clinical trial
Categories
Funding
- National Institutes of Health [P01 CA30206, P50 CA107399]
- General Clinical Research Center [M01 RR0004]
- Lymphoma Research Foundation
- Marcus Foundation
- Tim Nesvig Family Foundation
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Immunotherapeutic ablation of lymphoma is a conceptually attractive treatment strategy that is the subject of intense translational research. Cytotoxic T lymphocytes (CTLs) that are genetically modified to express CD 19- or CD20-specific, single-chain antibody derived chimeric antigen receptors (CARs) display HLA-independent antigen-specific recognition/killing of lymphoma targets. Here, we describe our initial experience in applying CAR-redirected autologous CTL adoptive therapy to patients with recurrent lymphoma. Using plasmid vector electrotransfer/drug selection systems, cloned and polyclonal CARP CTLs were generated from autologous peripheral blood mononuclear cells and expanded in vitro to cell numbers sufficient for clinical use. In 2 FDA-authorized trials, patients with recurrent diffuse large cell lymphoma were treated with cloned CD8(+) CTLs expressing a CD20-specific CAR (along with NeoR) after autologous hematopoietic stem cell transplantation, and patients with refractory follicular lymphoma were treated with polyclonal T cell preparations expressing a CDI9-specific CAR (along with HyTK, a fusion of hygromycin resistance and HSV-I thymidine kinase suicide genes) and low-dose s.c. recombinant human interleukin-2. A total of 15 infusions were administered (5 at 10(8)cells/m(2), 7 at 10(9)cells/m(2), and 3 at 2 x 10(9)cells/m(2)) to 4 patients. Overt toxicities attributable to CTL administration were not observed; however, detection of transferred CTLs in the circulation, as measured by quantitative polymerase chain reaction, was short (24 hours to 7 days), and cellular antitransgene immune rejection responses were noted in 2 patients. These studies reveal the primary barrier to therapeutic efficacy is limited persistence, and provide the rationale to prospectively define T cell populations intrinsically programmed for survival after adoptive transfer and to modulate the immune status of recipients to prevent/delay antitransgene rejection responses. Biol Blood Marrow Transplant 16: 1245-1256 (2010) (C) 2010 American Society fin. Blood and Marrow Transplantation
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