Development and Evaluation of an Optimal Human Single-Chain Variable Fragment-Derived BCMA-Targeted CAR T Cell Vector

Eric L. Smith, Mette Staehr, Reed Masakayan, Ishan J. Tatake, Terence J. Purdon, Xiuyan Wang, Pei Wang, Hong Liu, Yiyang Xu, Sarah C. Garrett-Thomson, Steven C. Almo, Isabelle Riviere, Cheng Liu, Renier J. Brentjens

Research output: Contribution to journalArticlepeer-review

65 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1447-1456
Number of pages10
JournalMolecular Therapy
Issue number6
StatePublished - Jun 6 2018


  • BCMA
  • CAR
  • CAR T cell therapy
  • adoptive cellular therapy
  • cellular therapy
  • chimeric antigen receptor
  • multiple myeloma
  • myeloma

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery


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