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

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, highligh...

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Bibliographic Details
Published in:Cancer immunology research 2020-12, Vol.8 (12), p.1485-1495
Main Authors: Globerson Levin, Anat, Rawet Slobodkin, Moran, Waks, Tova, Horn, Galit, Ninio-Many, Lihi, Deshet Unger, Naamit, Ohayon, Yaara, Suliman, Shimrit, Cohen, Yael, Tartakovsky, Boris, Naparstek, Ella, Avivi, Irit, Eshhar, Zelig
Format: Article
Language:English
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Summary: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 and 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.
ISSN:2326-6066
2326-6074
DOI:10.1158/2326-6066.CIR-20-0118