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A fully human chimeric antigen receptor with potent activity against cancer cells but reduced risk for off-tumor toxicity.


ABSTRACT: Chimeric antigen receptors (CARs) can redirect T cells against antigen-expressing tumors in an HLA-independent manner. To date, various CARs have been constructed using mouse single chain antibody variable fragments (scFvs) of high affinity that are immunogenic in humans and have the potential to mediate "on-target" toxicity. Here, we developed and evaluated a fully human CAR comprised of the human C4 folate receptor-alpha (?FR)-specific scFv coupled to intracellular T cell signaling domains. Human T cells transduced to express the C4 CAR specifically secreted proinflammatory cytokine and exerted cytolytic functions when cultured with ?FR-expressing tumors in vitro. Adoptive transfer of C4 CAR T cells mediated the regression of large, established human ovarian cancer in a xenogeneic mouse model. Relative to a murine MOv19 scFv-based ?FR CAR, C4 CAR T cells mediated comparable cytotoxic tumor activity in vitro and in vivo but had lower affinity for ?FR protein and exhibited reduced recognition of normal cells expressing low levels of ?FR. Thus, T cells expressing a fully human CAR of intermediate affinity can efficiently kill antigen-expressing tumors in vitro and in vivo and may overcome issues of transgene immunogenicity and "on-target off-tumor" toxicity that plague trials utilizing CARs containing mouse-derived, high affinity scFvs.

SUBMITTER: Song DG 

PROVIDER: S-EPMC4673284 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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A fully human chimeric antigen receptor with potent activity against cancer cells but reduced risk for off-tumor toxicity.

Song De-Gang DG   Ye Qunrui Q   Poussin Mathilde M   Liu Lin L   Figini Mariangela M   Powell Daniel J DJ  

Oncotarget 20150801 25


Chimeric antigen receptors (CARs) can redirect T cells against antigen-expressing tumors in an HLA-independent manner. To date, various CARs have been constructed using mouse single chain antibody variable fragments (scFvs) of high affinity that are immunogenic in humans and have the potential to mediate "on-target" toxicity. Here, we developed and evaluated a fully human CAR comprised of the human C4 folate receptor-alpha (αFR)-specific scFv coupled to intracellular T cell signaling domains. Hu  ...[more]

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