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Immunomodulatory Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
An alternative strategy to combat the consequences of CD19 down-regulation is the manufacture of novel CARs which target different surface antigens. For example, BCMA (B-cell maturation antigen), Mesothelin, CD22, CD20, and CD123 are emerging as popular targets for CAR-T cells. Clinical trials using anti-CD20 CAR-T cells have already generated impressive response rates, similar to that for anti-CD19 CAR-T therapies, in non-Hodgkin’s lymphoma. Similar responses were also observed when evaluating the efficacy of anti-CD22 CAR-T cells in treating patients with B-ALL who had developed resistance to anti-CD19 CAR-T cell therapies. Clinical trials assessing the efficacy of CAR-T therapies in AML are underway, many of which target CD123 and are producing encouraging results. Anti-BCMA CAR-T cells are also being investigated in patients with multiple myeloma (MM).
Multiple Myeloma
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Promising new agents are the anti-BCMA antibodies directed against B cell maturation antigen (BCMA). These include conjugated antibodies and also BITE antibodies that bind CD3 on T cells. BITE antibodies have a short half-life so have to be given continuously and can cause a cytokine release syndrome.
Mucosal B cells and their function
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Jo Spencer, Edward N. Janoff, Per Brandtzaeg
T-cell–independent mechanisms of IgA class-switch recombination in the intestinal tract in mice, and possibly in humans, are mediated by interactions of B cells with relatively homologous CD40L-like molecules, a proliferation-inducing ligand (APRIL), and B-cell–activating factor (BAFF). Both factors favor class-switch recombination to IgA1 and IgA2 in humans when combined with IL-4 and cell division. These molecules are produced locally by GALT dendritic cells, epithelial cells, macrophages, and neutrophils and interact directly with surface receptors on B cells (B-cell maturation antigen, transmembrane activator and calcium-modulator and cyclophilin ligand interactor, or BAFF-R) to induce the upregulation of AID and IgA class switching (see Figure 10.6). TLR-induced activation of dendritic cells enhances APRIL production. Mice deficient in APRIL and humans lacking APRIL receptor exhibit substantially reduced IgA production. However, mice lacking T cells, CD4, or CD40L still develop relatively normal intestinal IgA responses, highlighting the importance of both T–independent and T-dependent class-switch recombination in the generation of intestinal IgA. The microbiome may drive class-switch recombination though both T-dependent and T-independent pathways by activation of CD40L on T cells and engagement of the antigen-specific B-cell receptor and toll-like receptors (e.g., TLR9), respectively.
10th antibody industrial symposium: new developments in antibody and adoptive cell therapies
Published in mAbs, 2023
Ana Antunes, Luis Alvarez-Vallina, Federico Bertoglio, Nicolas Bouquin, Stéphanie Cornen, Francis Duffieux, Pierre Ferré, Raphaëlle Gillet, Christian Jorgensen, Mark B Leick, Bernard Maillère, Hélène Negre, Mireia Pelegrin, Nicolas Poirier, Dietmar Reusch, Bruno Robert, Guy Serre, Alain Vicari, Martin Villalba, Christoph Volpers, Gavin Vuddamalay, Hervé Watier, Thierry Wurch, Lennart Zabeau, Stefan Zielonka, Baolin Zhang, Alain Beck, Pierre Martineau
Dr. Manel Juan (Head of the Immunology Service, Hospital Clínic de Barcelona, Spain) described the generation of a new autologous CAR targeting CD19 (ARI-0001). This CAR obtained similar clinical results than commercial CARs used in the same clinical settings and was approved by the Spanish Agency of Medicines and Medical Devices (AEMPS). ARI-0001 was granted a hospital exemption to be used as advanced therapy medicinal product (ATMP), leading to its marketing authorization under specific conditions. These are: the exemption is only applicable to individual patients treated in the hospital (mainly academic centers that developed the ATMP and are supported by the national competent authority and limited to European Union (EU) member states; the exemption is intended for >25-year-old patients with relapsed or refractory CD19+ acute lymphoblastic leukemia. This authorization is the first step in the development of and access to completely academic CAR T-cell products in the EU and can be used as an intermediate step before obtaining a centralized marketing authorization by the European Medicines Agency (EMA). The cooperation between academic partners, who must follow strict standards of traceability, pharmacovigilance, and quality, should favor the accessibility of this product and the approval of other academic ATMPs. M. Juan’s team is completing a clinical trial on an anti-B-cell maturation antigen (BCMA) CAR-T for multiple myeloma, with a solid clinical response.12
How do nuclear factor kappa B (NF-κB)1 and NF-κB2 defects lead to the incidence of clinical and immunological manifestations of inborn errors of immunity?
Published in Expert Review of Clinical Immunology, 2023
Nazanin Fathi, Hanieh Mojtahedi, Marzieh Nasiri, Hassan Abolhassani, Mahsa Yousefpour Marzbali, Marzie Esmaeili, Fereshte Salami, Furozan Biglari, Nima Rezaei
Activation-induced deaminase (AID) promotes antibody diversity by somatic hypermutation or class switch recombination. NF-κB is significantly involved in these processes because of the implication of both NF-κB1 and NF-κB2 pathways in inducing AID transcription [46]. NF-κB also induces the expression of IRF4, which, along with AID, results in plasma cell (PC) differentiation. B cell maturation antigen (BCMA), a receptor for BAFF, is connected to maintaining long-lived plasma cells. BCMA induces NF-κB activation, showing the critical role of the NF-κB pathway in the survival of long-lived plasma cells [45]. The GC B cells’ recirculation can lead to the production of memory B lymphocytes and plasma cells with high affinity and frequently isotype-switched types that are affected by NF-κBs.
Guidelines for non-transplant chemotherapy for treatment of systemic AL amyloidosis: EHA-ISA working group
Published in Amyloid, 2023
Ashutosh D. Wechalekar, M. Teresa Cibeira, Simon D. Gibbs, Arnaud Jaccard, Shaji Kumar, Giampaolo Merlini, Giovanni Palladini, Vaishali Sanchorawala, Stefan Schönland, Christopher Venner, Mario Boccadoro, Efstathios Kastritis
The B-cell maturation antigen (BCMA) is another cell surface molecule ubiquitously expressed on plasma cell as well as their B-cell progenitors. There have been several unique targeting strategies demonstrating clear anti-plasma cell activity in multiple myeloma [82]. To date, however, the experience specifically in AL amyloidosis is limited. A novel antibody-drug conjugate, Belantamab mafodotin, combines the potent mafodotin toxin with plasma cell targeting anti-BCMA monoclonal antibody [83]. It has demonstrated excellent single agent activity in advanced relapsed and refractory multiple myeloma. Combination studies with various immunomodulating agents and proteasome inhibitors are ongoing. A prospective EMN study (NCT04617925) is examining Belantamab in relapsed AL amyloidosis. An important consideration with this agent is the unique ocular toxicity in the form of keratopathy which has proven to be a challenge in the delivery of this agent. In AL amyloidosis, with the often-lower clonal burden, less frequent and finite dosing strategies built around response adapted approaches may help limit this issue without compromising efficacy.