Tumor-targeted human T cells expressing CD28-based chimeric antigen receptors circumvent CTLA-4 inhibition Journal Article
| Authors: | Condomines, M.; Arnason, J.; Benjamin, R.; Gunset, G.; Plotkin, J.; Sadelain, M. |
| Article Title: | Tumor-targeted human T cells expressing CD28-based chimeric antigen receptors circumvent CTLA-4 inhibition |
| Abstract: | Adoptive T cell therapy represents a promising treatment for cancer. Human T cells engineered to express a chimeric antigen receptor (CAR) recognize and kill tumor cells in a MHC-unrestricted manner and persist in vivo when the CAR includes a CD28 costimulatory domain. However, the intensity of the CAR-mediated CD28 activation signal and its regulation by the CTLA-4 checkpoint are unknown. We investigated whether T cells expressing an anti-CD19, CD3 zeta and CD28-based CAR (19-28z) displayed the same proliferation and anti-tumor abilities than T cells expressing a CD3 zeta-based CAR (19z1) costimulated through the CD80/CD28, ligand/receptor pathway. Repeated in vitro antigen-specific stimulations indicated that 19-28z+ T cells secreted higher levels of Th1 cytokines and showed enhanced proliferation compared to those of 19z1+ or 19z1-CD80+ T cells. In an aggressive pre-B cell leukemia model, mice treated with 19-28z+ T cells had 10-fold reduced tumor progression compared to those treated with 19z1+ or 19z1-CD80+ T cells. shRNA-mediated CTLA-4 down-regulation in 19z1-CD80+ T cells significantly increased their in vivo expansion and anti-tumor properties, but had no effect in 19-28z+ T cells. Our results establish that CTLA-4 down-regulation may benefit human adoptive T cell therapy and demonstrate that CAR design can elude negative checkpoints to better sustain T cell function. © 2015 Condomines et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
| Keywords: | signal transduction; controlled study; protein expression; unclassified drug; human cell; nonhuman; cd8 antigen; antigen expression; lymphocyte proliferation; protein analysis; animal cell; mouse; animal tissue; mus; interleukin 2; animal experiment; animal model; in vivo study; antineoplastic activity; in vitro study; cancer inhibition; tumor necrosis factor alpha; gamma interferon; antigen specificity; protein induction; chimeric antigen receptor; adoptive transfer; down regulation; cd4 antigen; th1 cell; cytotoxic t lymphocyte antigen 4; cytokine release; short hairpin rna; cell expansion; t lymphocyte activation; cd28 antigen; b7 antigen; lymphocyte function; b cell leukemia; lymphocyte antigen; cd19 antibody; human; article; cd3 zeta antigen |
| Journal Title: | PLoS ONE |
| Volume: | 10 |
| Issue: | 6 |
| ISSN: | 1932-6203 |
| Publisher: | Public Library of Science |
| Date Published: | 2015-06-25 |
| Start Page: | e0130518 |
| Language: | English |
| DOI: | 10.1371/journal.pone.0130518 |
| PROVIDER: | scopus |
| PMCID: | PMC4482147 |
| PUBMED: | 26110267 |
| DOI/URL: | |
| Notes: | Export Date: 2 September 2015 -- Source: Scopus |
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