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

Mol Ther. 2018 Jun 6;26(6):1447-1456. doi: 10.1016/j.ymthe.2018.03.016. Epub 2018 Mar 28.


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.

Keywords: BCMA; CAR; CAR T cell therapy; adoptive cellular therapy; cellular therapy; chimeric antigen receptor; multiple myeloma; myeloma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity / physiology
  • B-Cell Maturation Antigen / metabolism*
  • CD4-Positive T-Lymphocytes / metabolism
  • Herpesvirus 4, Human / immunology
  • Humans
  • Immunotherapy, Adoptive / methods*
  • Receptors, Antigen, T-Cell / metabolism
  • Single-Chain Antibodies / immunology*


  • B-Cell Maturation Antigen
  • Receptors, Antigen, T-Cell
  • Single-Chain Antibodies