title: Pre-clinical evaluation of CD38 chimeric antigen receptor engineered T cells for the treatment of multiple myeloma.
abstract: 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.
authors: Department of Hematology, VU University Medical Center, Amsterdam, the Netherlands Departments of Clinical Chemistry and Hematology, Utrecht, the Netherlands.
authors: Esther
authors: E
authors: Drent
authors: Department of Hematology, VU University Medical Center, Amsterdam, the Netherlands Department of Cell Biology, University Medical Center, Utrecht, the Netherlands.
authors: Richard W J
authors: RW
authors: Groen
authors: Department of Hematology, VU University Medical Center, Amsterdam, the Netherlands Department of Cell Biology, University Medical Center, Utrecht, the Netherlands.
authors: Willy A
authors: WA
authors: Noort
authors: Department of Hematology, VU University Medical Center, Amsterdam, the Netherlands.
authors: Maria
authors: M
authors: Themeli
authors: Genmab, Utrecht, the Netherlands.
authors: Jeroen J
authors: JJ
authors: Lammerts van Bueren
authors: Genmab, Utrecht, the Netherlands Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, the Netherlands.
authors: Paul W H I
authors: PW
authors: Parren
authors: Department of Hematology, University Medical Center, Utrecht, the Netherlands.
authors: Jürgen
authors: J
authors: Kuball
authors: Department of Immunology, University Medical Center Utrecht, the Netherlands.
authors: Zsolt
authors: Z
authors: Sebestyen
authors: Xpand Biotechnology BV, Bilthoven, the Netherlands.
authors: Huipin
authors: H
authors: Yuan
authors: Xpand Biotechnology BV, Bilthoven, the Netherlands The School of Engineering and Materials Science, Queen Mary University of London, UK.
authors: Joost
authors: J
authors: de Bruijn
authors: Department of Hematology, VU University Medical Center, Amsterdam, the Netherlands.
authors: Niels W C J
authors: NW
authors: van de Donk
authors: Department of Hematology, VU University Medical Center, Amsterdam, the Netherlands Department of Cell Biology, University Medical Center, Utrecht, the Netherlands Department of Immunology, University Medical Center Utrecht, the Netherlands.
authors: Anton C M
authors: AC
authors: Martens
authors: Department of Hematology, VU University Medical Center, Amsterdam, the Netherlands Department of Hematology, University Medical Center, Utrecht, the Netherlands.
authors: Henk M
authors: HM
authors: Lokhorst
authors: Department of Hematology, VU University Medical Center, Amsterdam, the Netherlands Departments of Clinical Chemistry and Hematology, Utrecht, the Netherlands t.mutis@vumc.nl.
authors: Tuna
authors: T
authors: Mutis
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D005434:Flow Cytometry; D015870:Gene Expression; D018014:Gene Transfer Techniques; D041722:Genes, Transgenic, Suicide; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009101:Multiple Myeloma / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000637:transplantation; D014161:Transduction, Genetic; D047368:Tumor Burden / Q000235:genetics / Q000276:immunology
chemical_list: D016207:Cytokines; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D051997:ADP-ribosyl Cyclase 1