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Cancer Immunology Research
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Research Articles

Treatment of Multiple Myeloma Using Chimeric Antigen Receptor T Cells with Dual Specificity

Anat Globerson Levin, Moran Rawet Slobodkin, Tova Waks, Galit Horn, Lihi Ninio-Many, Naamit Deshet Unger, Yaara Ohayon, Shimrit Suliman, Yael Cohen, Boris Tartakovsky, Ella Naparstek, Irit Avivi and Zelig Eshhar
Anat Globerson Levin
1Tel Aviv Sourasky Medical Center (TASMC), Tel Aviv, Israel.
2Weizmann Institute of Science, Rehovot, Israel.
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  • For correspondence: anatgl@tlvmc.gov.il
Moran Rawet Slobodkin
1Tel Aviv Sourasky Medical Center (TASMC), Tel Aviv, Israel.
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Tova Waks
1Tel Aviv Sourasky Medical Center (TASMC), Tel Aviv, Israel.
2Weizmann Institute of Science, Rehovot, Israel.
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Galit Horn
1Tel Aviv Sourasky Medical Center (TASMC), Tel Aviv, Israel.
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Lihi Ninio-Many
1Tel Aviv Sourasky Medical Center (TASMC), Tel Aviv, Israel.
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Naamit Deshet Unger
1Tel Aviv Sourasky Medical Center (TASMC), Tel Aviv, Israel.
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Yaara Ohayon
1Tel Aviv Sourasky Medical Center (TASMC), Tel Aviv, Israel.
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  • ORCID record for Yaara Ohayon
Shimrit Suliman
1Tel Aviv Sourasky Medical Center (TASMC), Tel Aviv, Israel.
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Yael Cohen
1Tel Aviv Sourasky Medical Center (TASMC), Tel Aviv, Israel.
3Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
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Boris Tartakovsky
1Tel Aviv Sourasky Medical Center (TASMC), Tel Aviv, Israel.
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  • ORCID record for Boris Tartakovsky
Ella Naparstek
1Tel Aviv Sourasky Medical Center (TASMC), Tel Aviv, Israel.
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Irit Avivi
1Tel Aviv Sourasky Medical Center (TASMC), Tel Aviv, Israel.
3Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
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Zelig Eshhar
1Tel Aviv Sourasky Medical Center (TASMC), Tel Aviv, Israel.
2Weizmann Institute of Science, Rehovot, Israel.
3Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
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DOI: 10.1158/2326-6066.CIR-20-0118 Published December 2020
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Abstract

Chimeric antigen receptor (CAR) T-cell therapy has shown remarkable successes in fighting B-cell leukemias/lymphomas. Promising response rates are reported in patients treated with B-cell maturation antigen (BCMA) CAR T cells for multiple myeloma. However, responses appear to be nondurable, highlighting the need to expand the repertoire of multiple myeloma–specific targets for immunotherapy and to generate new CAR T cells. Here, we developed a “dual-CAR” targeting two multiple myeloma–associated antigens and explored its safety and efficacy. To reduce the “off-target” toxicity, we used the recognition of paired antigens that were coexpressed by the tumor to induce efficient CAR T-cell activation. The dual-CAR construct presented here was carefully designed to target the multiple myeloma–associated antigens, taking into consideration the distribution of both antigens on normal human tissues. Our results showed that the CD138/CD38-targeted dual CAR (dCAR138-38) elicited a potent anti–multiple myeloma response both in vitro and in vivo. NSG mice transplanted with a multiple myeloma cell line and treated with dCAR138-38 showed median survival of 97 days compared with 31 days in the control group treated with mock-lymphocytes. The dCAR138-38 showed increased specificity toward cells expressing both targeted antigens compared with single-antigen–expressing cells and low activity toward primary cells from healthy tissues. Our findings indicated that the dCAR138-38 may provide a potent and safe alternative therapy for patients with multiple myeloma.

Footnotes

  • Cancer Immunol Res 2020;8:1485–95

  • Received February 6, 2020.
  • Revision received August 4, 2020.
  • Accepted September 29, 2020.
  • Published first October 2, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Immunology Research: 8 (12)
December 2020
Volume 8, Issue 12
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Treatment of Multiple Myeloma Using Chimeric Antigen Receptor T Cells with Dual Specificity
Anat Globerson Levin, Moran Rawet Slobodkin, Tova Waks, Galit Horn, Lihi Ninio-Many, Naamit Deshet Unger, Yaara Ohayon, Shimrit Suliman, Yael Cohen, Boris Tartakovsky, Ella Naparstek, Irit Avivi and Zelig Eshhar
Cancer Immunol Res December 1 2020 (8) (12) 1485-1495; DOI: 10.1158/2326-6066.CIR-20-0118

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Treatment of Multiple Myeloma Using Chimeric Antigen Receptor T Cells with Dual Specificity
Anat Globerson Levin, Moran Rawet Slobodkin, Tova Waks, Galit Horn, Lihi Ninio-Many, Naamit Deshet Unger, Yaara Ohayon, Shimrit Suliman, Yael Cohen, Boris Tartakovsky, Ella Naparstek, Irit Avivi and Zelig Eshhar
Cancer Immunol Res December 1 2020 (8) (12) 1485-1495; DOI: 10.1158/2326-6066.CIR-20-0118
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