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A non-human primate model for analysis of safety, persistence, and function of adoptively transferred T cells.

ABSTRACT: Adoptive immunotherapy with antigen-specific effector T-cell (T(E) ) clones is often limited by poor survival of the transferred cells. We describe here a Macaca nemestrina model for studying transfer of T-cell immunity.We derived, expanded, and genetically marked CMV-specific CD8(+) T(E) clones with surface markers expressed on B cells. T(E) cells were adoptively transferred, and toxicity, persistence, retention of introduced cell-surface markers, and phenotype of the persisting T cells were evaluated.CD8(+) T(E) clones were efficiently isolated from distinct memory precursors and gene-marking with CD19 or CD20 permitted in vivo tracking by quantitative PCR. CD19 was a more stable surface marker for tracking cells in vivo and was used to re-isolate cells for functional analysis. Clonally derived CD8(+) T(E) cells differentiated in vivo to phenotypically and functionally heterogeneous memory T-cell subsets.These studies demonstrate the utility of Macaca nemestrina for establishing principles for T-cell therapeutics applicable to humans.

SUBMITTER: Berger C

PROVIDER: S-EPMC3048898 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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A non-human primate model for analysis of safety, persistence, and function of adoptively transferred T cells.

Berger C C Berger M M Anderson D D Riddell S R SR

Journal of medical primatology 20101102 2

<h4>Background</h4>Adoptive immunotherapy with antigen-specific effector T-cell (T(E) ) clones is often limited by poor survival of the transferred cells. We describe here a Macaca nemestrina model for studying transfer of T-cell immunity.<h4>Methods</h4>We derived, expanded, and genetically marked CMV-specific CD8(+) T(E) clones with surface markers expressed on B cells. T(E) cells were adoptively transferred, and toxicity, persistence, retention of introduced cell-surface markers, and phenotyp ...[more]

PMID: 21044089

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Project description: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.

Dataset Information

A non-human primate model for analysis of safety, persistence, and function of adoptively transferred T cells.

Publications

A non-human primate model for analysis of safety, persistence, and function of adoptively transferred T cells.

Similar Datasets

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