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Biol Blood Marrow Transplant. 2010 Sep;16(9):1245-56. doi: 10.1016/j.bbmt.2010.03.014. Epub 2010 Mar 19.

Antitransgene rejection responses contribute to attenuated persistence of adoptively transferred CD20/CD19-specific chimeric antigen receptor redirected T cells in humans.

Author information

1
Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010-3000, USA. mjensen@coh.org

Abstract

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 CD19- 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 CAR(+) 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 CD19-specific CAR (along with HyTK, a fusion of hygromycin resistance and HSV-1 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.

PMID:
20304086
PMCID:
PMC3383803
DOI:
10.1016/j.bbmt.2010.03.014
[Indexed for MEDLINE]
Free PMC Article

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