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 journalArticle

21 Citations (Scopus)

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.

Original languageEnglish (US)
JournalMolecular Therapy
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

B-Cell Maturation Antigen
Single-Chain Antibodies
Antigen Receptors
T-Cell Antigen Receptor
Cell- and Tissue-Based Therapy
Tumor Burden
Multiple Myeloma
Antigens
Heterografts
Bacteriophages
Clone Cells
Growth Factor Receptors
Human Engineering
Libraries
Lymphoma
Neoplasms
B-Lymphocytes
T-Lymphocytes

Keywords

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

ASJC Scopus subject areas

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

Cite this

Smith, E. L., Staehr, M., Masakayan, R., Tatake, I. J., Purdon, T. J., Wang, X., ... Brentjens, R. J. (Accepted/In press). Development and Evaluation of an Optimal Human Single-Chain Variable Fragment-Derived BCMA-Targeted CAR T Cell Vector. Molecular Therapy. https://doi.org/10.1016/j.ymthe.2018.03.016

Development and Evaluation of an Optimal Human Single-Chain Variable Fragment-Derived BCMA-Targeted CAR T Cell Vector. / Smith, Eric L.; Staehr, Mette; Masakayan, Reed; Tatake, Ishan J.; Purdon, Terence J.; Wang, Xiuyan; Wang, Pei; Liu, Hong; Xu, Yiyang; Garrett-Thomson, Sarah C.; Almo, Steven C.; Riviere, Isabelle; Liu, Cheng; Brentjens, Renier J.

In: Molecular Therapy, 01.01.2018.

Research output: Contribution to journalArticle

Smith, EL, Staehr, M, Masakayan, R, Tatake, IJ, Purdon, TJ, Wang, X, Wang, P, Liu, H, Xu, Y, Garrett-Thomson, SC, Almo, SC, Riviere, I, Liu, C & Brentjens, RJ 2018, 'Development and Evaluation of an Optimal Human Single-Chain Variable Fragment-Derived BCMA-Targeted CAR T Cell Vector', Molecular Therapy. https://doi.org/10.1016/j.ymthe.2018.03.016
Smith, Eric L. ; Staehr, Mette ; Masakayan, Reed ; Tatake, Ishan J. ; Purdon, Terence J. ; Wang, Xiuyan ; Wang, Pei ; Liu, Hong ; Xu, Yiyang ; Garrett-Thomson, Sarah C. ; Almo, Steven C. ; Riviere, Isabelle ; Liu, Cheng ; Brentjens, Renier J. / Development and Evaluation of an Optimal Human Single-Chain Variable Fragment-Derived BCMA-Targeted CAR T Cell Vector. In: Molecular Therapy. 2018.
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