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An APRIL-based chimeric antigen receptor for dual targeting of BCMA and TACI in multiple myeloma

التفاصيل البيبلوغرافية
العنوان: An APRIL-based chimeric antigen receptor for dual targeting of BCMA and TACI in multiple myeloma
المؤلفون: Paul Maciocia, Kwee Yong, Manuel Rodriguez-Justo, Dominic Patel, Shimobi Onuoha, Simon Thomas, Martin Pule, Reyisa Bughda, Daria Galas-Filipowicz, Margarida Neves, Melody Chin, Brian Philip, Eva Kokalaki, Lydia Lee, Vania Baldan, James Francis, Benjamin Draper, Neil Chaplin
بيانات النشر: American Society of Hematology, 2018.
سنة النشر: 2018
مصطلحات موضوعية: 0301 basic medicine, Cytotoxicity, Immunologic, Transmembrane Activator and CAML Interactor Protein, Immunology, Tumor Necrosis Factor Ligand Superfamily Member 13, Ligands, Biochemistry, 03 medical and health sciences, Mice, 0302 clinical medicine, Antineoplastic Agents, Immunological, Antigen, Cell Line, Tumor, medicine, Animals, Humans, Molecular Targeted Therapy, B-Cell Maturation Antigen, Receptor, Peptidylprolyl isomerase, Lymphoid Neoplasia, Receptors, Chimeric Antigen, biology, Chemistry, Cell Biology, Hematology, medicine.disease, Primary tumor, Chimeric antigen receptor, Cytolysis, 030104 developmental biology, Cell culture, 030220 oncology & carcinogenesis, biology.protein, Cancer research, Antibody, Multiple Myeloma
الوصف: B-cell maturation antigen (BCMA) is a promising therapeutic target for multiple myeloma (MM), but expression is variable, and early reports of BCMA targeting chimeric antigen receptors (CARs) suggest antigen downregulation at relapse. Dual-antigen targeting increases targetable tumor antigens and reduces the risk of antigen-negative disease escape. "A proliferation-inducing ligand" (APRIL) is a natural high-affinity ligand for BCMA and transmembrane activator and calcium-modulator and cyclophilin ligand (TACI). We quantified surface tumor expression of BCMA and TACI on primary MM cells (n = 50). All cases tested expressed BCMA, and 39 (78%) of them also expressed TACI. We engineered a third-generation APRIL-based CAR (ACAR), which killed targets expressing either BCMA or TACI (P < .01 and P < .05, respectively, cf. control, effector-to-target [E:T] ratio 16:1). We confirmed cytolysis at antigen levels similar to those on primary MM, at low E:T ratios (56.2% ± 3.9% killing of MM.1s at 48 h, E:T ratio 1:32; P < .01) and of primary MM cells (72.9% ± 12.2% killing at 3 days, E:T ratio 1:1; P < .05, n = 5). Demonstrating tumor control in the absence of BCMA, we maintained cytolysis of primary tumor expressing both BCMA and TACI in the presence of a BCMA-targeting antibody. Furthermore, using an intramedullary myeloma model, ACAR T cells caused regression of an established tumor within 2 days. Finally, in an in vivo model of tumor escape, there was complete ACAR-mediated tumor clearance of BCMA+TACI- and BCMA-TACI+ cells, and a single-chain variable fragment CAR targeting BCMA alone resulted in outgrowth of a BCMA-negative tumor. These results support the clinical potential of this approach.
اللغة: English
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e5369fc571019d2d8485611c849aa118Test
https://europepmc.org/articles/PMC5922275Test/
حقوق: OPEN
رقم الانضمام: edsair.doi.dedup.....e5369fc571019d2d8485611c849aa118
قاعدة البيانات: OpenAIRE
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