Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRζ/CD28 receptor Journal Article

Authors: Maher, J.; Brentjens, R. J.; Gunset, G.; Rivière, I.; Sadelain, M.
Article Title: Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRζ/CD28 receptor
Abstract: Artificial receptors provide a promising approach to target T lymphocytes to tumor antigens. However, the receptors described thus far produce either an activation or a co-stimulatory signal alone, thus limiting the spectrum of functions accomplished by the genetically modified cells. Here we show that human primary T lymphocytes expressing fusion receptors directed to prostate-specific membrane antigen (PSMA) and containing combined T-cell receptor-ζ (TCRζ), and CD28 signaling elements, effectively lyse tumor cells expressing PSMA. When stimulated by cell-surface PSMA, retrovirally transduced lymphocytes undergo robust proliferation, expanding by more than 2 logs in three weeks, and produce large amounts of interleukin-2 (IL-2). Importantly, the amplified cell populations retain their antigen-specific cytolytic activity. These data demonstrate that fusion receptors containing both TCR and CD28 signaling moieties are potent molecules able to redirect and amplify human T-cell responses. These findings have important implications for adoptive immunotherapy of cancer, especially in the context of tumor cells that fail to express major histocompatibility complex antigens and co-stimulatory molecules.
Keywords: signal transduction; controlled study; protein expression; unclassified drug; human cell; nonhuman; flow cytometry; lymphocyte proliferation; t-lymphocytes; cells, cultured; cell division; interleukin 2; cancer immunotherapy; protein binding; membrane proteins; biotechnology; time factors; genetic transduction; transduction, genetic; t lymphocyte receptor; immunology; prostate specific membrane antigen; dna modification; antigens; recombinant fusion proteins; antigen specificity; receptors, antigen, t-cell; tumors; rna viruses; t-lymphocytes, cytotoxic; tumor immunity; cytokine production; cytolysis; adoptive immunotherapy; t lymphocyte activation; cd28 antigen; antigens, cd28; retrovirus; retroviridae; interleukin-2; chimeric protein; gene transfer techniques; cells; unidentified retrovirus; humans; human; priority journal; article; cytolytic activities; t lymphocyte receptor zeta chain
Journal Title: Nature Biotechnology
Volume: 20
Issue: 1
ISSN: 1087-0156
Publisher: Nature Publishing Group  
Date Published: 2002-01-01
Start Page: 70
End Page: 75
Language: English
DOI: 10.1038/nbt0102-70
PUBMED: 11753365
PROVIDER: scopus
Notes: Export Date: 14 November 2014 -- Source: Scopus
Citation Impact
MSK Authors
  1. John Maher
    2 Maher
  2. Renier J Brentjens
    279 Brentjens
  3. Michel W J Sadelain
    540 Sadelain
  4. Isabelle C Riviere
    222 Riviere
  5. Gertrude Mary Gunset
    16 Gunset