Development and evaluation of an optimal human single-chain variable fragment-derived BCMA-targeted CAR T cell vector Journal Article
| Authors: | Smith, E. L.; Staehr, M.; Masakayan, R.; Tatake, I. J.; Purdon, T. J.; Wang, X.; Wang, P.; Liu, H.; Xu, Y.; Garrett-Thomson, S. C.; Almo, S. C.; Riviere, I.; Liu, C.; Brentjens, R. J. |
| Article Title: | Development and evaluation of an optimal human single-chain variable fragment-derived BCMA-targeted CAR T cell vector |
| Abstract: | B cell maturation antigen (BCMA) has recently been identified as an important multiple myeloma (MM)-specific target for chimeric antigen receptor (CAR) T cell therapy. In CAR T cell therapy targeting CD19 for lymphoma, host immune anti-murine CAR responses limited the efficacy of repeat dosing and possibly long-term persistence. This clinically relevant concern can be addressed by generating a CAR incorporating a human single-chain variable fragment (scFv). We screened a human B cell-derived scFv phage display library and identified a panel of BCMA-specific clones from which human CARs were engineered. Despite a narrow range of affinity for BCMA, dramatic differences in CAR T cell expansion were observed between unique scFvs in a repeat antigen stimulation assay. These results were confirmed by screening in a MM xenograft model, where only the top preforming CARs from the repeat antigen stimulation assay eradicated disease and prolonged survival. The results of this screening identified a highly effective CAR T cell therapy with properties, including rapid in vivo expansion (>10,000-fold, day 6), eradication of large tumor burden, and durable protection to tumor re-challenge. We generated a bicistronic construct including a second-generation CAR and a truncated-epithelial growth factor receptor marker. CAR T cell vectors stemming from this work are under clinical investigation. Human-scFv phage display library screening identified BCMA-specific clones for engineering human CARs. Repeat antigen stimulation predicted differential in vivo efficacy of CARs incorporating unique scFvs. Smith and colleagues’ lead CAR, which induced rapid T cell expansion, eradicated large tumor burden, and protected from tumor re-challenge in myeloma xenografts, is now under clinical investigation. © 2018 The American Society of Gene and Cell Therapy |
| Keywords: | multiple myeloma; chimeric antigen receptor; myeloma; adoptive cellular therapy; cellular therapy; car; bcma; car t cell therapy |
| Journal Title: | Molecular Therapy |
| Volume: | 26 |
| Issue: | 6 |
| ISSN: | 1525-0016 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2018-06-06 |
| Start Page: | 1447 |
| End Page: | 1456 |
| Language: | English |
| DOI: | 10.1016/j.ymthe.2018.03.016 |
| PROVIDER: | scopus |
| PMCID: | PMC5986730 |
| PUBMED: | 29678657 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 July 2018 -- Source: Scopus |
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