Chimeric antigen receptors combining 4-1BB and CD28 signaling domains augment PI 3 kinase/AKT/Bcl-X L activation and CD8 T cell-mediated tumor eradication

Xiao Song Zhong, Maiko Matsushita, Jason Plotkin, Isabelle Riviere, Michel Sadelain

Research output: Contribution to journalArticle

265 Citations (Scopus)

Abstract

To enhance the strength of activation afforded by tumor antigen-specific receptors, we investigated the effect of adding combined CD28 and 4-1BB costimulatory signaling domains to a chimeric antigen receptor (CAR) specific for prostate-specific membrane antigen (PSMA). Having transferred receptors encompassing the CD28, 4-1BB, and/or CD3 cytoplasmic domains in primary human CD8 T cells, we find that the P28BBz receptor, which includes all three signaling domains, is superior to receptors that only include one or two of these domains in promoting cytokine release, in vivo T-cell survival and tumor elimination following intravenous T-cell administration to tumor-bearing severe combined immunodeficient (SCID)/beige mice. Upon in vitro exposure to PSMA, the P28BBZ receptor-induced the strongest PI 3 Kinase/Akt activation and Bcl-X L expression, and the least apoptosis in transduced peripheral blood CD8 T cells. These findings further support the concept of integrating optimized costimulatory properties into recombinant antigen receptors to augment the survival and function of genetically targeted T cells within the tumor microenvironment.

Original languageEnglish
Pages (from-to)413-420
Number of pages8
JournalMolecular Therapy
Volume18
Issue number2
DOIs
Publication statusPublished - 2010 Feb 1
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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