4.6 Article

CD30-Redirected Chimeric Antigen Receptor T Cells Target CD30+ and CD30- Embryonal Carcinoma via Antigen-Dependent and Fas/FasL Interactions

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CANCER IMMUNOLOGY RESEARCH
卷 6, 期 10, 页码 1274-1287

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AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2326-6066.CIR-18-0065

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资金

  1. Gertrude B. Elion Mentored Medical Student Research Award of the Triangle Community Foundation
  2. NCI Cancer Core Grant [P30-CA016086-40]
  3. UNC UCRF funds
  4. NHLBI grant [R01HL114564]
  5. Hyundai Hope on Wheels grant

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Tumor antigen heterogeneity limits success of chimeric antigen receptor (CAR) T-cell therapies. Embryonal carcinomas (EC) and mixed testicular germ cell tumors (TGCT) containing EC, which are the most aggressive TGCT subtypes, are useful for dissecting this issue as ECs express the CD30 antigen but also contain CD30(-/dim) cells. We found that CD30-redirected CAR T cells (CD30. CAR T cells) exhibit antitumor activity in vitro against the human EC cell lines Tera-1, Tera-2, and NCCIT and putative EC stem cells identified by Hoechst dye staining. Cytolytic activity of CD30. CAR T cells was complemented by their sustained proliferation and proinflammatory cytokine production. CD30. CAR T cells also demonstrated antitumor activity in an in vivo xenograft NOD/SCID/gamma cnull (NSG) mouse model of metastatic EC. We observed that CD30. CAR T cells, while targeting CD30(+) EC tumor cells through the CAR (i.e., antigen-dependent targeting), also eliminated surrounding CD30 - EC cells in an antigen-independent manner, via a cell-cell contact-dependent Fas/FasL interaction. In addition, ectopic Fas (CD95) expression in CD30(+) Fas(-) EC was sufficient to improve CD30. CAR T-cell antitumor activity. Overall, these data suggest that CD30. CAR T cells might be useful as an immunotherapy for ECs. Additionally, Fas/FasL interaction between tumor cells and CAR T cells can be exploited to reduce tumor escapedue to heterogeneous antigen expression or to improve CAR T-cell antitumor activity.

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