Safety and efficacy of targeting CD138 with a chimeric antigen receptor for the treatment of multiple myeloma
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Chuang Sun1, Aruna Mahendravada2, Brandon Ballard2, Brandon Kale1, Carlos Ramos2,3, John West4, Todd Maguire4, Katie McKay4, Eben Lichtman1,5, Sascha Tuchman1,5, Gianpietro Dotti1,6 and Barbara Savoldo1,7
1Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
2Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, TX, USA
3Department of Medicine, Baylor College of Medicine, Houston, TX, USA
4UNC Lineberger Advanced Cellular Therapeutics Facility, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
5Division of Hematology/Oncology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
6Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
7Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Barbara Savoldo, email: [email protected]
Keywords: chimeric antigen receptor; adoptive cell transfer; multiple myeloma; T cells immunotherapy; syndecan-1
Abbreviations: MM: Multiple myeloma; CAR: chimeric antigen receptor; BCMA: B-cell maturation antigen; IHC: immunohistochemetry; Ctr: control
Received: December 05, 2018 Accepted: March 04, 2019 Published: March 22, 2019
After unprecedented successes in B-cell malignancies, chimeric antigen receptor T cells have recently been investigated for the treatment of multiple myeloma. Chimeric antigen receptor targeting T cells B-cell maturation antigen (BCMA) on malignant plasma cells have led to impressive clinical responses in recent trials. However, BCMA-negative relapses have been observed, supporting the need for complementary treatment strategies. Here, we explored the feasibility of targeting CD138 (syndecan-1), a surface marker expressed on both normal and malignant plasma cells. We showed that T cells from both healthy donors and from multiple myeloma patients, when transduced with a CD138-specific chimeric antigen receptor, can eliminate tumor cell lines and primary myeloma cells both in vitro and in vivo. CD138 is also expressed by putative myeloma stem cells identified by Hoechst staining, and these cells can be eliminated by CD138-specific chimeric antigen receptor T cells. Preclinical analyses did not identify any on target off tumor cytotoxicity against normal epithelial or endothelial cells, further supporting the rationale for the use of adoptively transferred CD138-specific chimeric antigen receptor T cells for the treatment of patients with relapsed/refractory multiple myeloma.
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