Myeloid cells in peripheral blood mononuclear cell concentrates inhibit the expansion of chimeric antigen receptor T cells

David F. Stroncek, Jiaqiang Ren, Daniel W. Lee, Minh Tran, Sue Ellen Frodigh, Marianna Sabatino, Hanh Khuu, Melinda S. Merchant, Crystal L. Mackall

Research output: Contribution to journalArticle

Abstract

Background aims Autologous chimeric antigen receptor (CAR) T-cell therapies have shown promising clinical outcomes, but T-cell yields have been variable. CD19- and GD2-CAR T-cell manufacturing records were reviewed to identify sources of variability. Methods CD19-CAR T cells were used to treat 43 patients with acute lymphocytic leukemia or lymphoma and GD2-CAR T cells to treat eight patients with osteosarcoma and three with neuroblastoma. Both types of CAR T cells were manufactured using autologous peripheral blood mononuclear cells (PBMC) concentrates and anti-CD3/CD28 beads for T-cell enrichment and simulation. Results A comparison of the first 6 GD2- and the first 22 CD19-CAR T-cell products manufactured revealed that GD2-CAR T-cell products contained fewer transduced cells than CD19-CAR T-cell products (147 ± 102 × 106 vs 1502 ± 1066 × 106; P = 0.0059), and their PBMC concentrates contained more monocytes (31.4 ± 12.4% vs 18.5 ± 13.7%; P = 0.019). Among the first 28 CD19-CAR T-cell products manufactured, four had poor expansion yielding less than 1 × 106 transduced T cells per kilogram. When PBMC concentrates from these four patients were compared with the 24 others, PBMC concentrates of poorly expanding products contained greater quantities of monocytes (39.8 ± 12.9% vs. 15.3 ± 10.8%, P = 0.0014). Among the patients whose CD19-CAR T cells expanded poorly, manufacturing for two patients was repeated using cryopreserved PBMC concentrates but incorporating a monocyte depleting plastic adherence step, and an adequate dose of CAR T cells was produced for both patients. Conclusions Variability in CAR T-cell expansion is due, at least in part, to the contamination of the starting PBMC concentrates with monocytes.

Original languageEnglish (US)
Pages (from-to)893-901
Number of pages9
JournalCytotherapy
Volume18
Issue number7
DOIs
StatePublished - Jul 1 2016
Externally publishedYes

Keywords

  • acute lymphocytic leukemia
  • adoptive cellular therapy
  • CD19
  • chimeric antigen receptor T cells
  • GD2
  • osteosarcoma

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology
  • Genetics(clinical)
  • Cell Biology
  • Cancer Research
  • Transplantation

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  • Cite this

    Stroncek, D. F., Ren, J., Lee, D. W., Tran, M., Frodigh, S. E., Sabatino, M., Khuu, H., Merchant, M. S., & Mackall, C. L. (2016). Myeloid cells in peripheral blood mononuclear cell concentrates inhibit the expansion of chimeric antigen receptor T cells. Cytotherapy, 18(7), 893-901. https://doi.org/10.1016/j.jcyt.2016.04.003