Article open access publication

Pre-clinical evaluation of CD38 chimeric antigen receptor engineered T cells for the treatment of multiple myeloma

Haematologica, Ferrata Storti Foundation (Haematologica), ISSN 1466-4860

Volume 101, 5, 2016

DOI:10.3324/haematol.2015.137620, Dimensions: pub.1017029739, PMC: PMC5004365, PMID: 26858358,

Affiliations

Organisations

  1. (1) Departments of Clinical Chemistry and Hematology, Utrecht, the Netherlands
  2. (2) VU University Medical Center, grid.16872.3a
  3. (3) University Medical Center Utrecht, grid.7692.a
  4. (4) Genmab (Netherlands), grid.466767.2
  5. (5) Leiden University Medical Center, grid.10419.3d
  6. (6) University of Southern Denmark, grid.10825.3e, SDU
  7. (7) Xpand Biotechnology (Netherlands), grid.426475.6
  8. (8) Queen Mary University of London, grid.4868.2

Countries

Netherlands

Denmark

United Kingdom

Continents

Europe

Description

Adoptive transfer of chimeric antigen receptor-transduced T cells is a promising strategy for cancer immunotherapy. The CD38 molecule, with its high expression on multiple myeloma cells, appears a suitable target for antibody therapy. Prompted by this, we used three different CD38 antibody sequences to generate second-generation retroviral CD38-chimeric antigen receptor constructs with which we transduced T cells from healthy donors and multiple myeloma patients. We then evaluated the preclinical efficacy and safety of the transduced T cells. Irrespective of the donor and antibody sequence, CD38-chimeric antigen receptor-transduced T cells proliferated, produced inflammatory cytokines and effectively lysed malignant cell lines and primary malignant cells from patients with acute myeloid leukemia and multi-drug resistant multiple myeloma in a cell-dose, and CD38-dependent manner, despite becoming CD38-negative during culture. CD38-chimeric antigen receptor-transduced T cells also displayed significant anti-tumor effects in a xenotransplant model, in which multiple myeloma tumors were grown in a human bone marrow-like microenvironment. CD38-chimeric antigen receptor-transduced T cells also appeared to lyse the CD38(+) fractions of CD34(+) hematopoietic progenitor cells, monocytes, natural killer cells, and to a lesser extent T and B cells but did not inhibit the outgrowth of progenitor cells into various myeloid lineages and, furthermore, were effectively controllable with a caspase-9-based suicide gene. These results signify the potential importance of CD38-chimeric antigen receptor-transduced T cells as therapeutic tools for CD38(+) malignancies and warrant further efforts to diminish the undesired effects of this immunotherapy using appropriate strategies.

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University of Southern Denmark

Dimensions Citation Indicators

Times Cited: 62

Field Citation Ratio (FCR): 11.72

Relative Citation ratio (RCR): 3.25

Open Access Info

Bronze