Assessment of normal plasma cell biomarkers after arlocabtagene autoleucel (arlo-cel) treatment in patients with ≥3L relapsed refractory multiple myeloma (MM).

Activation of B-Cell Maturation Antigen (BCMA) on Human Multiple Myeloma Cells by a Proliferation-Inducing Ligand (APRIL) Promotes Myeloma Cell Function in the Bone Marrow Microenvironment.

A Novel and Highly Potent CAR T Cell Drug Product for Treatment of BCMA-Expressing Hematological Malignances

Development and Evaluation of an Optimal Human Single-Chain Variable Fragment-Derived BCMA-Targeted CAR T Cell Vector.

New Antibcma-CAR for Multiple Myeloma

Steric Hindrance By APRIL in Binding of BCMA-Directed Bispecific Antibodies: A Novel Refractory Mechanism of BCMA-Directed Immunotherapies in Multiple Myeloma

Introduction Multiple myeloma (MM) is the second most prevalent hematopoietic malignancy with an overall 5-year survival rate of 58%. B cell maturation antigen (BCMA) is selectively expressed on normal and malignant plasma cells, making it an attractive MM target. Anti-BCMA chimeric antigen receptor (CAR) T cell therapy and T cell engagers have shown promise as treatment options for certain MM patients; however, potential toxicities associated with these anti-BCMA therapies, such as cytokine release syndrome (CRS), have limited broader utilization. Much like T cells, natural killer (NK) cells are cytolytic and have demonstrated an innate capacity to reduce tumor burden while exhibiting a more favorable safety profile in clinical testing. To that end, we developed a cryopreserved allogeneic cell therapy comprised of genetically modified human umbilical cord blood-derived (CB) NK cells transduced with a gammaretroviral vector, which incorporates genes for an anti-BCMA CAR and soluble human interleukin-15 (sIL-15). Referred to hereafter as anti-BCMA CAR-NK, it exhibits both innate NK- and CAR-mediated killing in vitro and robust in vivo activity against established MM tumors. Methods CBNK cells were isolated from donor cord blood units, propagated using feeder cells, transduced with a gammaretroviral vector to express an anti-BCMA CAR and soluble human IL-15, and propagated further before harvest and cryopreservation. Donor-equivalent untransduced (UTD) NK cells were generated via the same process but without the transduction step. Cryopreserved anti-BCMA CAR-NK and UTD NK cells were used for in vitro studies, including short-term killing, as well as for evaluation of activity against established MM tumors in vivo using the MM.1S-Luc4 model. Results The anti-BCMA CAR was successfully expressed across all batches of anti-BCMA CAR-NK generated. Results from an in vitro cytotoxicity assay indicated that anti-BCMA CAR-NK kills BCMA expressing MM.1S-Luc4 tumor cells and secretes IFNγ, TNFα, and granzyme B at greater amounts compared to donor-equivalent UTD NK. Anti-BCMA CAR-NK and UTD NK cells also demonstrated equivalent cytotoxicity towards BCMA non-expressing cell lines, JJN3-Luc BCMA KO and NCI-H520, in an effector:target cancer cell dependent manner, highlighting the potential for treatment with anti-BCMA CAR-NK post-prior BCMA therapy. In in vivo studies, anti-BCMA CAR-NK exhibited robust anti-tumor activity in an MM.1S-Luc4 NSG mouse xenograft model, with no signs of anti-BCMA CAR-NK related body weight loss. Conclusion A cryopreserved allogeneic anti-BCMA CAR-NK cellular therapy exhibits both innate and CAR-mediated killing in vitro and robust in vivo activity in MM tumor models. Preclinical data supports future clinical evaluation in relapsed/refractory MM patients who have received prior BCMA therapy and IND enabling studies are ongoing. Citation Format: LeeAnn Talarico, Christina Wong, Chunyan Pang, Taylor Hickman, Chenqi Hu, Amy Shaw, Emily Wisniewski, Shao-Chiang (Michael) Lai, Pranjal Sharma, Shaun Moore, Luan Nguyen, Kayla Rhuda, Saurin Patel, Paul Lin, Rafet Basar, Shawn Cogan, Kat Sofjan, Arun Ramamurthy, Aaron Handler, Kathryn Fraser, Yana Wang, Katayoun Rezvani, Michael D. Curley. A cryopreserved allogeneic anti-BCMA CAR-NK cellular therapy exhibits both innate and CAR-mediated MM cell killing in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1322.

ATRA Augments BCMA Expression on Myeloma Cells and Enhances Recognition By BCMA-CAR T-Cells

Efficacy and Safety of Fully Human Bcma CAR T Cells in Combination with a Gamma Secretase Inhibitor to Increase Bcma Surface Expression in Patients with Relapsed or Refractory Multiple Myeloma

Background: Multiple myeloma (MM), the second most common hematologic malignancy in the US, is characterized by the proliferation and accumulation of clonal malignant plasma cells in the bone marrow, associated with hypercalcemia, renal dysfunction and bone disease. Despite recent advances in treatment including novel therapeutics in combination with transplantation, MM still remains incurable. We have recently developd a highly immunogenic HLA-A2-specific multipeptide cancer vaccine targeting XBP1 (X-box binding protein 1), CD138 (Syndecan-1) and CS1 (SLAMF7) antigens. In both pre-clinical studies and Phase 1/2a clinical trials in patients with smoldering multiple myeloma and triple negative breast cancer, vaccination with this multi-peptide based cancer vaccine induced antigen-specific and Th1-type anti-tumor immune responses, which were maintained for long-term within tetramer+/memory (CD45RO+) CD8 cytotoxic T lymphocytes (CTL). The immune responses were further enhanced in patients who received vaccination in combination with lenalidomide or checkpoint inhibitor. To allow for vaccination against additional tumor-associated antigens, we have recently investigated B Cell Maturation Antigen (BCMA), a cell surface antigen restricted to MM and normal plasma cells, as well as accessory dendritic cells. As the receptor for binding of B cell activating factor (BAFF) and of a proliferation-inducing ligand (APRIL), BCMA promotes MM cell growth, drug resistance, as well as survival of long lived plasma cells. Due to its restricted expression pattern, targeting of this antigen with antibodies, immunotoxins, and CAR T-cells is already ongoing in MM at present. Objective: We aimed to identify immunogenic BCMA peptides in order to generate antigen-specific CD8+ effector cytotoxic T lymphocytes against MM cells. Findings: We identified novel immunogenic HLA-A2 native and engineered heteroclitic BCMA peptides that induce tumor-specific CTL against MM. The engineered heteroclitic BCMA72-80 and BCMA54-62 peptides have improved HLA-A2 binding affinity and stability compared to their native BCMA72-80 and BCMA54-62 peptides. In preclinical studies, each of the heteroclitic BCMA peptide induced antigen specific CTL, which expressed increased T-cell activation (CD38, CD69) and co-stimulatory (CD40L, OX40, GITR) molecules. The engineered heteroclitic BCMA72-80 triggered a more robust immune response than BCMA54-62 peptide, associated with increased HLA-A2 binding affinity and stability. Importantly, the heteroclitic BCMA72-80 peptide-specific CTL induced selective and robust proliferative and cytolytic activities in response to MM patients’ tumor cells. Specifically, these tetramer+ CD8+ CTL demonstrated HLA-A2-restricted immune responses against MM, associated with CD107a degranulation, proliferation, Th-1 cytokine (IFN-γ/IL-2/TNF-α) cytokine production, perforin/granzyme B up-regulation, and increased 41BB expression. Furthermore, the heteroclitic BCMA72-80 peptide has demonstrated its immunogenicity through development central memory and effector memory CTL, which showed polyfunctional antitumor activities against MM including patients’ primary tumor cells and cell lines. This novel engineered heteroclitic BCMA72-80 peptide may therefore be useful for generation of antigen-specific and tumor-selective CTL in MM. Significance: We have identified BCMA-specific native and engineered heteroclitic peptides which induce BCMA antigen specific CD8+ CTL with robust anti-MM activity. This immunogenic BCMA peptide will be utlized in clinical protocols of vaccination and/or adoptive T-cells immunotherapy to trigger antigen-specific central and effector memory CTL anti-MM immunity. Citation Format: Jooeun Bae, Teru Hideshima, Yu-Tzu Tai, Nikhil Munshi, Kenneth Anderson. Development of fargeted multiple myeloma cancer vaccine and antigen-specific T-cell immunotherapy using novel Immunogenic-engineered heteroclitic BCMA peptides [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B100.

APRIL/B Cell Maturation Antigen (BCMA) Signaling Cascades Promote Human Multiple Myeloma Growth and Mediate Immunosuppression in the Bone Marrow Microenvironment Via IL-10, TGF-b, and PD-L1

Safety and Efficacy of Fully Human BCMA CAR T Cells in Combination with a Gamma Secretase Inhibitor to Increase BCMA Surface Expression in Patients with Relapsed or Refractory Multiple Myeloma

BackgroundCD38 is a transmembrane glycoprotein that is relatively highly expressed on multiple myeloma (MM) cells, and CD38-targeting antibodies use pleiotropic mechanisms to kill MM cells. Immunotherapy, with an increased quality of response and acceptable toxicity, shows tremendous potential for treating MM. This research field study aimed to analyze all the relevant literature via bibliometrics to identify its course of development and structural relationships.MethodsA total of 1,030 relevant articles were retrieved from the Web of Science Core Collection (WoSCC) from 1985 to June 21, 2021. CiteSpace was employed to map authors/references/countries with nodes and links, extract highly cited keywords, analyze the time trends of keywords, recognize cocited authors/references, set timezone or timeline views, analyze burstness and generate a dual map. VOSviewer was used to recognize connections among journals and construct collaboration networks. bibliometric.com was utilized to trace advanced countries/regions in the research field.ResultsAll of the articles were cited 24,332 times in total, with an average of 23.62 times. Most articles were published in the United States of America (USA), far outweighing other countries/regions. The current hotspots in this field are related to the following keywords: “monoclonal antibody”, “refractory MM”, “idecabtagene vicleucel”, and “B cell maturation antigen (BCMA)”. Ten significant clusters, namely, “flow cytometry”, “daratumumab”, “BCMA”, “cell line”, “antitumor activity”, “gene”, “non-Hodgkin’s lymphoma”, “peripheral blood”, “survival” and “anti-CD38”, were extracted. The mechanism and effectiveness of CD38-targeting antibodies in treating MM have been studied. Future research hotspots will focus on new therapies for relapsed and refractory multiple myeloma (RRMM) patients.ConclusionsIn the past, efforts were applied to elucidate the mechanism and effectiveness of CD38-targeting antibodies in treating MM. Future research hotspots will focus on anti-BCMA chimeric antigen receptor T cell (CAR-T) immunotherapy for patients with RRMM. According to this article, new researchers can discover its course of development and structural relationships in this field.

Background: Multiple myeloma (MM) is a usually fatal malignancy of plasma cells, with no current therapy considered curative. About 15% of patients diagnosed with MM are stratified as high risk with poor treatment outcomes and short (2-3 years) survival from diagnosis. Standard risk patients tend to live longer but undergo chronic and/or high intensity therapy and likely experience a relapsing and remitting disease pattern. Therefore, there is still a considerable unmet need for innovative therapies that improve outcomes in MM. One such approach is to use adoptive transfer of engineered autologous T cells expressing a chimeric antigen receptor (CAR) directed against malignant cells. The efficacy of CAR T cells directed against hematological malignancies, particularly CD19-expressing B cell leukemia and lymphomas, has been demonstrated in multiple clinical studies. KITE-585 was developed as a CAR T cell immunotherapy product candidate directed against B cell maturation antigen (BCMA). BCMA is nearly ubiquitously expressed on MM cells, plasma cells and subsets of mature B cells, but with limited or absent expression on other tissues. Methods: We generated >50 fully human IgGs directed against BCMA using the BCMA protein as antigen and selection criteria including affinity, cross-reactivity and poly-specificity. Following assessment of the binding of the IgGs to a MM cell line known to express BCMA, >10 IgGs were identified that met the criteria for affinity and selectivity and had a >50-fold binding over background. The 8 IgGs that demonstrated the highest specific binding were then sequence-converted to single-chain variable fragments (scFvs) and incorporated into CARs. Results: In all but one case, human T cells engineered to express these CAR constructs exhibited specific cytolytic activity against MM cell lines (NCI-H929 and MM.1s). These CAR T cells demonstrated killing efficiencies of >95% at effector:target ratios of 1:1 over a 24-hour period. Similarly antigen-specific production of inflammatory cytokines was observed in response to target cell lines in vitro. Assessment of antigen-dependent proliferation over a 5 day period revealed >80% proliferation in the 7 constructs that showed cytolytic activity in vitro. Multiple different anti-BCMA CAR constructs representing distinct epitope binding bins of BCMA were then selected for in vivo evaluation. In two disseminated tumor models of luciferase labeled NCI-H929 or MM.1s cells injected intravenously (i.v.), a single i.v. injection of anti-BCMA CAR T-cells delayed the progression of disease and significantly increased survival when compared to control treatment. Conclusions: The results of these studies highlight the potential of targeting BCMA with adoptive transfer of engineered T cells for the treatment of MM. Given these positive findings, progress towards Phase 1 clinical studies in MM patients with KITE-585 is continuing. Citation Format: Gregor B. Adams, Jun Feng, Atefah Ghogha, Armen Mardiros, Jodi Murakami, Tammy Phung, Ruben Rodriguez, Stuart Sievers, Tassja J. Spindler, Jed Wiltzius, Clare Yarka, Sean C. Yoder, Tony Polverino. Development of KITE-585: A fully human BCMA CAR T-cell therapy for the treatment of multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4979. doi:10.1158/1538-7445.AM2017-4979

Impacts of a Proliferation-Inducing Ligand on Current Therapeutic Monoclonal Antibody-Induced Cytotoxicity Against Human Multiple Myeloma Cells

The Impact of Soluble BCMA and BCMA Gain on Anti-BCMA Immunotherapies in Multiple Myeloma