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Preclinical evaluation of CD38 chimeric antigen receptor engineered T cells for the treatment of multiple myeloma
  1. Esther Drent1,
  2. Richard Groen1,
  3. Willy Noort1,
  4. Jeroen Lammerts van Bueren2,
  5. Paul Parren2,3,4,
  6. Jürgen Kuball5,
  7. Zsolt Sebestyen5,
  8. Niels van de Donk1,
  9. Anton Martens1,
  10. Henk Lokhorst2 and
  11. Tuna Mutis1
  1. Aff1 grid.16872.3a000000040435165XVU University Medical Center Amsterdam Amsterdam the Netherlands
  2. Aff2 grid.466767.20000000406203167Genmab BV, Utrecht Utrecht the Netherlands
  3. Aff3 grid.10825.3e0000000107280170University of Southern Denmark Odense Denmark
  4. Aff4 grid.10419.3d0000000089452978Leiden University Medical Center, Leiden Utrecht the Netherlands
  5. Aff5 grid.7692.a0000000090126352University Medical Center Utrecht Utrecht the Netherlands

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Meeting abstracts

Background

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.

Methods

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.

Results

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.

Conclusions

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.

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