CAR T-Cell Therapy for Patients with Multiple Myeloma: Current Evidence and Challenges

Rendo, Matthew; Joseph, Jacinth; Phan, Liem; DeStefano, Christin B.

doi:10.2147/blctt.s327016

Cited by 39 publications

(24 citation statements)

References 91 publications

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“…Immunotherapy is thought to be a promising treatment for tumors including MM ( 19 , 20 ). Exploring a suitable tumor-specific antigen, which is expressed in tumors but not in other normal tissues, or a tumor-associated antigen, which is overexpressed in tumors but poorly expressed in normal cells, is crucial in active immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

A novel human multiple myeloma cell line with a 1q21 gain genetic abnormality and CKS1B overexpression

He¹,

Yi²,

Zhang³

et al. 2023

Ann Transl Med

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Background Multiple myeloma (MM) is an incurable hematologic malignancy mainly due to its cytogenetic abnormalities. Therefore, it is important to establish permanent malignant MM cell lines as tools to develop more effective therapies. Methods Pleural effusion cells of a 70-year-old patient was collected to establish the CZ2 cell line. Characterization of CZ2 was determined with nephelometry, flow cytometry, fluorescence in situ hybridization (FISH), and chromosomal microarray analysis (CMA). Western blotting analysis was adopted to determine protein expression. Cell viability was measured by the 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Results We established and characterized a new MM cell line, CZ2. Using nephelometry and flow cytometry, cells with typical plasma cell morphology but not classical plasma cell phenotype were found to be non-immunoglobulin-secretary cells. FISH analysis of cells revealed a unique characteristic, namely, that there was only gain of the 1q21 region (1q21+). No other common cytogenetic abnormalities in MM, such as deletion of 17p (17p-), deletion of 13q (13q-), or translocation of immunoglobulin heavy chain (IgH), were observed. In addition, the original cell line maintains its single cytogenetic abnormality. Meanwhile, we observed through western blotting that CDC28 protein kinase regulatory subunit 1B (CKS1B), an adverse prognostic gene located in the 1q21 region, was highly expressed in CZ2. Knockdown of CKS1B reduced cell viability and also increased the levels of cleaved-poly(ADP-ribose) polymerase (cleaved-PARP) and cleaved-caspase3. Conclusions CZ2 provides a suitable material for cellular and molecular studies of MM with only a 1q21 abnormality. This cell line is characterized by a gain of 1q21, and the high expression of CKS1B is an important model for studies of myeloma cell growth and drug resistance during therapy.

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Section: Discussionmentioning

confidence: 99%

A novel human multiple myeloma cell line with a 1q21 gain genetic abnormality and CKS1B overexpression

He¹,

Yi²,

Zhang³

et al. 2023

Ann Transl Med

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“…Since various pro-inflammatory cytokines affect the integrity of the intestinal mucosa, oncologic conditions associated high levels of these cytokines are expected to be associated with a breach in the intestinal barrier functions. Chimeric Antigen Receptor (CAR T)-cell therapy currently approved by the FDA for treating B-cell acute lymphoblastic leukemia [98], B-cell lymphomas [99], and multiple myeloma [100] and is increasingly being administered to patients is associated with cytokine release syndrome (CRS). Similarly, the increasing use of posttransplant high dose cyclophosphamide as a maneuver to reduce the risks for graft-versus-host disease (GVHD) [101] in patients undergoing allogeneic hematopoietic stem cell transplant, especially in peripheral blood stem cell and haploidentical transplants, is associated with high levels of cytokine release during the first 72 h following infusion of the hematopoietic stem cells.…”

Section: Cytokine-induced Intestinal Injurymentioning

confidence: 99%

Intestinal barrier functions in hematologic and oncologic diseases

et al. 2023

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The intestinal barrier is a complex structure that not only regulates the influx of luminal contents into the systemic circulation but is also involved in immune, microbial, and metabolic homeostasis. Evidence implicating disruption in intestinal barrier functions in the development of many systemic diseases, ranging from non-alcoholic steatohepatitis to autism, or systemic complications of intestinal disorders has increased rapidly in recent years, raising the possibility of the intestinal barrier as a potential target for therapeutic intervention to alter the course and mitigate the complications associated with these diseases. In addition to the disease process being associated with a breach in the intestinal barrier functions, patients with hematologic and oncologic diseases are particularly at high risks for the development of increased intestinal permeability, due to the frequent use of broad-spectrum antibiotics and chemoradiation. They also face a distinct challenge of being intermittently severely neutropenic due to treatment of the underlying conditions. In this review, we will discuss how hematologic and oncologic diseases are associated with disruption in the intestinal barrier and highlight the complications associated with an increase in the intestinal permeability. We will explore methods to modulate the complication. To provide a background for our discussion, we will first examine the structure and appraise the methods of evaluation of the intestinal barrier.

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“…In addition, both BiTE and CAR-T cells are associated with T cell activation, which may induce overactive immune responses, including cytokine release syndrome (CRS) and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). Neurotoxicity is another common serious adverse event induced by this therapy [ 48 ].…”

Section: Bcma-targeted Immunotherapy In MMmentioning

confidence: 99%

Targeting BCMA in Multiple Myeloma: Advances in Antibody-Drug Conjugate Therapy

Xing

Liu

2023

Cancers

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Multiple myeloma (MM) is an incurable cancer of the plasma cells. In the last twenty years, treatment strategies have evolved toward targeting MM cells—from the shotgun chemotherapy approach to the slightly more targeted approach of disrupting important MM molecular pathways to the immunotherapy approach that specifically targets MM cells based on protein expression. Antibody-drug conjugates (ADCs) are introduced as immunotherapeutic drugs which utilize an antibody to deliver cytotoxic agents to cancer cells distinctively. Recent investigations of ADCs for MM treatment focus on targeting B cell maturation antigen (BCMA), which regulates B cell proliferation, survival, maturation, and differentiation into plasma cells (PCs). Given its selective expression in malignant PCs, BCMA is one of the most promising targets in MM immunotherapy. Compared to other BCMA-targeting immunotherapies, ADCs have several benefits, such as lower price, shorter production period, fewer infusions, less dependence on the patient’s immune system, and they are less likely to over-activate the immune system. In clinical trials, anti-BCMA ADCs have shown safety and remarkable response rates in patients with relapsed and refractory MM. Here, we review the properties and clinical applications of anti-BCMA ADC therapies and discuss the potential mechanisms of resistance and ways to overcome them.

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CAR T-Cell Therapy for Patients with Multiple Myeloma: Current Evidence and Challenges

Cited by 39 publications

References 91 publications

A novel human multiple myeloma cell line with a 1q21 gain genetic abnormality and CKS1B overexpression

A novel human multiple myeloma cell line with a 1q21 gain genetic abnormality and CKS1B overexpression

Intestinal barrier functions in hematologic and oncologic diseases

Targeting BCMA in Multiple Myeloma: Advances in Antibody-Drug Conjugate Therapy

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