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Cited by 17CAR-T cell therapy researchImmunotherapy and Immune ResponsesMultiple Myeloma Research and Treatments

The DOI matches its Crossref record; 5 of the 5 references it cites were found in a registry or an index.

Specific Targeting of Multiple Myeloma by Dual Split-signaling Chimeric Antigen Receptor T cells Directed against CD38 and CD138

van der Schans, Jort J., Wang, Ziyu, van Arkel, Jennemiek, van Schaik, Thijs, Katsarou, Afroditi, Ruiter, Ruud, Baardemans, Thomas, Yuan, Huipin, de Bruijn, Joost, Zweegman, Sonja, van de Donk, Niels W.C.J., Groen, Richard W.J., Themeli, Maria, Mutis, Tuna·2023·Clinical Cancer Research
DOI 10.1158/1078-0432.ccr-23-0132

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Abstract

Purpose: The success of B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T cells illustrates the potential of this novel therapy for multiple myeloma. Nonetheless, broadening CAR T-cell therapy beyond BCMA requires inventive strategies as there are only a few multiple myeloma– or plasma cell–specific target antigens. We investigated the feasibility of achieving multiple myeloma specificity by dual-split CD38/CD138 CAR targeting, whereby the stimulatory and costimulatory signals for T-cell activation are split into two separate stimulatory (sCAR) and costimulatory CARs (cCAR). Experimental Design: Using various combinations of CD38 and CD138 sCARs and cCARs with different affinities, we generated several dual-split CAR T cells and analyzed them for multiple myeloma–specific effector functions in vitro. The best-functioning CAR T cells were tested in vivo in a murine xenograft model. Results: We found optimal designs of both CD38sCAR/CD138cCAR and CD138sCAR/CD38cCAR combinations, that effectively lysed multiple myeloma cells but spared single CD38- or CD138-positive healthy hematopoietic cells. While the CD38sCAR/CD138cCAR T cells achieved multiple myeloma–specific activity solely due to the low affinity of the CD38sCARs, the multiple myeloma–specific cytotoxicity, cytokine release, and proliferation of CD138sCAR/CD38cCAR T cells were established through a true combinatorial stimulatory and costimulatory effect. The most optimal combination comprised a low-affinity CD138sCAR combined with a high-affinity CD38cCAR. These CD138sCAR/CD38cCAR T cells also showed dual-antigen specific anti–multiple myeloma effects in vivo. Importantly, they were also effective against multiple myeloma cells from daratumumab pretreated patients with decreased CD38 expression levels. Conclusions: We demonstrate the possibility to specifically target multiple myeloma cells, even after CD38 targeted therapy, with carefully-designed dual-split CARs directed against CD38 and CD138.

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  • CAR-T cells targeting GPRC5D, CD19, CD38, CD138, CS1, and NKG2D are under exploration for MM treatment.

    “Several CAR-T cells targeting antigens, such an GPRC5D [229–231], CD19 [232, 233], CD38 [234–236], CD138 [237], CS1 [238–240] and NKG2D [241, 242] are also under exploration for their efficacy in MM treatment.”

    From Multiple myeloma: signaling pathways and targeted therapy (2024) · cites this paper as [237]

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Metadata

Authors
van der Schans, J. J., Wang, Z., van Arkel, J., van Schaik, T., Katsarou, A., Ruiter, R., Baardemans, T., Yuan, H., de Bruijn, J., Zweegman, S., van de Donk, N. W. C. J., Groen, R. W. J., Themeli, M., & Mutis, T.
Affiliations
  • Amsterdam University Medical Centers (NL)
  • 2Kuros Biosciences BV, Bilthoven, the Netherlands.
Corresponding author
Mutis, Tuna
ORCID
Venue
Clinical Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2023-08-01
Volume
29
Issue
20
Pages
4219-4229
ISSN
  • 1078-0432 (ISSN-L)
  • 1557-3265
DOI
10.1158/1078-0432.ccr-23-0132
OpenAlex
W4385445027
Cited by
17
References
5
Citations by year
2026: 4 · 2025: 6 · 2024: 7
FWCI
2.08
Type
journal article
Language
en
Open access
closed
Locations
  • Clinical Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • KWF (12967)
  • Stichting Kompass
Topics
  • Health Sciences › Medicine › Oncology › CAR-T cell therapy research
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
Keywords
multiple myeloma, chimeric antigen receptor, CD38, syndecan-1, costimulation, CAR T-cell therapy, murine xenograft model
MeSH terms
Receptors, Chimeric Antigen, Animals, Humans, Lymphocyte Activation, Membrane Glycoproteins, Multiple Myeloma, Receptors, Antigen, T-Cell, T-Lymphocytes, Signal Transduction, Immunotherapy, Adoptive, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, ADP-ribosyl Cyclase 1, Syndecan-1

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