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      CAR-T Cells Based on Novel BCMA Monoclonal Antibody Block Multiple Myeloma Cell Growth

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          Abstract

          The cell-surface protein B cell maturation antigen (BCMA, CD269) has emerged as a promising target for CAR-T cell therapy for multiple myeloma. In order to create a novel BCMA CAR, we generated a new BCMA monoclonal antibody, clone 4C8A. This antibody exhibited strong and selective binding to human BCMA. BCMA CAR-T cells containing the 4C8A scFv were readily detected with recombinant BCMA protein by flow cytometry. The cells were cytolytic for RPMI8226, H929, and MM1S multiple myeloma cells and secreted high levels of IFN-γ in vitro. BCMA-dependent cytotoxicity and IFN-γ secretion were also observed in response to CHO (Chinese Hamster Ovary)-BCMA cells but not to parental CHO cells. In a mouse subcutaneous tumor model, BCMA CAR-T cells significantly blocked RPMI8226 tumor formation. When BCMA CAR-T cells were given to mice with established RPMI8226 tumors, the tumors experienced significant shrinkage due to CAR-T cell activity and tumor cell apoptosis. The same effect was observed with 3 humanized BCMA-CAR-T cells in vivo. These data indicate that novel CAR-T cells utilizing the BCMA 4C8A scFv are effective against multiple myeloma and warrant future clinical development.

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          CD22-CAR T Cells Induce Remissions in CD19-CAR Naïve and Resistant B-ALL

          Terry Fry, Nirali Shah, Rimas Orentas … (2017)
          Chimeric antigen receptor (CAR) T-cells targeting CD19 mediate potent effects in relapsed/refractory pre-B cell acute lymphoblastic leukemia (B-ALL) but antigen loss is a frequent cause of resistance to CD19-targeted immunotherapy. CD22 is also expressed on most B-ALL and usually retained following CD19 loss. We report results from a phase I trial testing a novel CD22-CAR in twenty-one children and adults, including 17 previously treated with CD19-directed immunotherapy. Dose dependent anti-leukemic activity was observed with complete remission in 73% (11/15) of patients receiving ≥ 1 × 106 CD22-CART cells/kg, including 5/5 patients with CD19dim/neg B-ALL. Median remission duration was 6 months. Relapses were associated with diminished CD22 site density that likely permitted escape from killing by CD22-CART cells. These results are the first to eastablish the clinical activity of a CD22-CAR in pre-B cell ALL, including in leukemia resistant to anti-CD19 immunotherapy, demonstrating comparable potency to CD19-CART at biologically active doses in B-ALL. They also highlight the critical role played by antigen density in regulating CAR function. (Funded by NCI Intramural Research Program)
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            T Cells Expressing CD19/CD20 Bispecific Chimeric Antigen Receptors Prevent Antigen Escape by Malignant B Cells.

            Eugenia Zah, Meng-Yin Lin, Anne Silva-Benedict … (2016)
            The adoptive transfer of T cells expressing anti-CD19 chimeric antigen receptors (CARs) has shown remarkable curative potential against advanced B-cell malignancies, but multiple trials have also reported patient relapses due to the emergence of CD19-negative leukemic cells. Here, we report the design and optimization of single-chain, bispecific CARs that trigger robust cytotoxicity against target cells expressing either CD19 or CD20, two clinically validated targets for B-cell malignancies. We determined the structural parameters required for efficient dual-antigen recognition, and we demonstrate that optimized bispecific CARs can control both wild-type B-cell lymphoma and CD19(-) mutants with equal efficiency in vivo To our knowledge, this is the first bispecific CAR capable of preventing antigen escape by performing true OR-gate signal computation on a clinically relevant pair of tumor-associated antigens. The CD19-OR-CD20 CAR is fully compatible with existing T-cell manufacturing procedures and implementable by current clinical protocols. These results present an effective solution to the challenge of antigen escape in CD19 CAR T-cell therapy, and they highlight the utility of structure-based rational design in the development of receptors with higher-level complexity. Cancer Immunol Res; 4(6); 498-508. ©2016 AACRSee related Spotlight by Sadelain, p. 473.
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              BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone.

              Cécile Lugagne, Karin Tarte, Bernard Klein … (2004)
              Identification of growth factors in neoplasias may be a target for future therapies by blocking either growth factor receptor interaction or the induced pathway. Using gene expression profiling, we identified overexpression of 2 receptors for a proliferation-inducing ligand (APRIL) and B-cell activating factor (BAFF) in malignant plasma cells compared with normal plasma cells. APRIL and BAFF are involved in a variety of tumor and autoimmune diseases, including B-cell malignancies. We confirmed the expression of BAFF and APRIL receptors (B-cell maturation antigen [BCMA], transmembrane activator and calcium modulator and cyclophilin ligand interactor [TACI], and BAFF-R) in a majority of 13 myeloma cell lines and in the purified primary myeloma cells of 11 patients. APRIL and BAFF were potent survival factors for exogenous cytokine-dependent myeloma cell lines and were autocrine growth factors for the RPMI8226 and L363 autonomously growing cell lines. These factors activated nuclear factor (NF)-kappaB, phosphatidylinositol-3 (PI-3) kinase/AKT, and mitogen-activated protein kinase (MAPK) kinase pathways and induced a strong up-regulation of the Mcl-1 and Bcl-2 antiapoptotic proteins in myeloma cells. BAFF or APRIL was also involved in the survival of primary myeloma cells cultured with their bone-marrow environment, and protected them from dexamethasone (DEX)-induced apoptosis. Finally, the serum levels of BAFF and APRIL were increased about 5-fold in patients with multiple myeloma (MM) as compared with healthy donors. Altogether, these data suggest that APRIL/BAFF inhibitors may be of clinical value in MM.
              Article 0 comments Cited 140 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cancers (Basel)
                Journal ID (iso-abbrev): Cancers (Basel)
                Journal ID (publisher-id): cancers
                Title: Cancers
                Publisher: MDPI
                ISSN (Electronic): 2072-6694
                Publication date (Electronic): 11 September 2018
                Publication date Collection: September 2018
                Volume: 10
                Issue: 9
                Electronic Location Identifier: 323
                Affiliations
                [1 ]ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA; robert.berahovich@ 123456promab.com (R.B.); huazhou369@ 123456gmail.com (H.Z.); shirley.xu@ 123456promab.com (S.X.); yuehua.wei@ 123456promab.com (Y.W.); jasper.guan@ 123456promab.com (J.G.); jian.guan@ 123456promab.com (J.G.); hizkia.harto@ 123456promab.com (H.H.); simon.li@ 123456promab.com (L.L.); john@ 123456promab.com (L.W.)
                [2 ]Forevertek Biotechnology Co., Ltd., Building M0, Oversea Graduate Park National High-Tech Industrial Zone, Changsha 410003, China; promab8807@ 123456126.com (S.F.); yangkaihuai520@ 123456126.com (K.Y.); shuying256@ 123456163.com (S.Z.)
                Author notes
                [* ]Correspondence: vita.gol@ 123456promab.com ; Tel.: +1-510-974-0697
                Article
                Publisher ID: cancers-10-00323
                DOI: 10.3390/cancers10090323
                PMC ID: 6162381
                PubMed ID: 30208593
                SO-VID: 6783875b-9993-4d05-8ded-112e60322796
                Copyright © © 2018 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 27 July 2018
                Date accepted : 04 September 2018
                Categories
                Subject: Article

                Keywords: chimeric antigen receptor,car-t cells,multiple myeloma,immunotherapy,cell therapy,tumor antigen,cancer,xenograft
                Data availability:
                Keywords: chimeric antigen receptor, car-t cells, multiple myeloma, immunotherapy, cell therapy, tumor antigen, cancer, xenograft

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