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Mol Ther. 2012 Mar;20(3):633-43. doi: 10.1038/mt.2011.256. Epub 2011 Nov 29.

Redirected antitumor activity of primary human lymphocytes transduced with a fully human anti-mesothelin chimeric receptor.

Author information

1
Department of Obstetrics and Gynecology, Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

Abstract

Cancer regression by gene-modified T cells bearing a chimeric antigen receptor (CAR) exodomain of mouse origin can be limited by the induction of transgene immunogenicity resulting in poor persistence and function in vivo. The development of functionally-active CAR of human origin can address this issue. Here, we constructed and evaluated fully human anti-mesothelin CARs comprised of a human mesothelin-specific single-chain antibody variable fragment (P4 scFv) coupled to T cell signaling domains. Primary human T cells expressing P4 CAR specifically produced proinflammatory cytokines, degranulated and exerted potent cytolytic functions when cultured with mesothelin-expressing tumors in vitro. P4 CAR T cells also mediated bystander killing of mesothelin-negative cancer cells during coculture. CAR reactivity was not abrogated by soluble tumor-secreted or recombinant mesothelin protein even at supraphysiological levels. Importantly, adoptive transfer of P4 CAR-expressing T cells mediated the regression of large, established tumor in the presence of soluble mesothelin in a xenogenic model of human ovarian cancer. Thus, primary human T cells expressing fully human anti-mesothelin CAR efficiently kill mesothelin-expressing tumors in vitro and in vivo and have the potential to overcome the issue of transgene immunogenicity that may limit CAR T cell trials that utilize scFvs of mouse origin.

PMID:
22127019
PMCID:
PMC3293635
DOI:
10.1038/mt.2011.256
[Indexed for MEDLINE]
Free PMC Article

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