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Preclinical evaluation of CD38 chimeric antigen receptor engineered T cells for the treatment of multiple myeloma
© Drent et al. 2015
Published: 4 November 2015
Adoptive transfer of T cells transduced with tumor-reactive Chimeric Antigen Receptors (CARs) is a promising strategy for cancer immunotherapy. The CD38 molecule, with its high and homogenous expression on Multiple Myeloma (MM) cells, appears a suitable target for antibody therapy. Prompted by this, we evaluated the feasibility of targeting MM with CD38-CAR-transduced (CD38-CAR) T cells.
We generated three retroviral CAR constructs based on huCD38 antibodies, CD3ζ and 4-1BB signaling domains and transduced them into T cells of healthy donors and MM patients to test the in vitro and in vivo efficacy.
Irrespective of the donor, CD38-CAR T cells lost CD38 expression, expanded readily and lysed MM and other malignant cell lines in a cell dose-, and CD38-dependent manner. They also lysed primary malignant cells from acute myeloid leukemia, and multi-drug resistant MM patients. Also in a xenotransplant model, i.v. injected CD38-CAR T cells were effective against MM tumors growing in a human bone marrow-like microenvironment, thus demonstrating their ability to properly migrate and infiltrate into the tumor niche to lyse malignant cells. Although CD38-CAR T cells lysed CD38+ monocytes, NK cells, CD34+ cells and to a lesser extent CD38+ T and B cells, they did not hamper the outgrowth progenitor cells into various myeloid lineages. Furthermore, CD38-CART cells were controllable with a caspase-9-based suicide gene.
These results signify the potential importance of CD38-CAR T cells as therapeutic tools for CD38+ malignancies, including MM, and warrant further safety and efficacy evaluation in appropriate models.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.