CAR T-cell therapy in multiple myeloma: more room for improvement

Teoh, Phaik Ju; Chng, Wee‐Joo

doi:10.1038/s41408-021-00469-5

Cited by 128 publications

(130 citation statements)

References 107 publications

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“…With the latter, cilta-cel compared to ide-cel and orva-cel could increase its binding affinity even in MM cells with low BCMA expression, resulting in lower CAR-T cell doses and in a delay of the median time of onset of CRS, with 1–2 days vs. 7 days (ide-cel vs. cilta-cel). These effects allow the management of cilta-cel infusion in outpatients following hospital admission after 5 days to monitor potential CRS [ 84 , 85 ].…”

Section: Bmca-targeted Treatment In MMmentioning

confidence: 99%

BCMA in Multiple Myeloma—A Promising Key to Therapy

Kleber

Ntanasis‐Stathopoulos

Terpos

2021

JCM

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Despite the discoveries of numerous agents including next generation proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies, multiple myeloma (MM) remains an incurable disease. The field of myeloma treatment in refractory or relapsed patients after standard therapy entered a new era due to the B-cell maturation antigen (BMCA) targeted approach. BCMA is a member of the tumor necrosis factor receptor family with high expression in mature B-lymphocytes and plasma cells. Given the understanding of BCMA mechanism of action in MM, BCMA plays a promising role as a therapeutic target. Several clinical trials are underway to evolve the current BCMA targeted treatment concept such as antibody-drug conjugates (ADCs), bispecific T cell engagers (BITEs) and chimeric antigen receptor (CAR) T cell therapy. Current results of representative BCMA trials may close the gap of the unmet clinical need to further improve the outcome of heavily pretreated MM patients with the potency to change the paradigm in newly diagnosed and refractory MM. This comprehensive review will give an update on various BMCA targeted treatment modalities (ADCs, BITEs, CAR T cell therapy) and its existing results on efficacy and safety from preclinical and clinical trials.

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Section: Bmca-targeted Treatment In MMmentioning

confidence: 99%

BCMA in Multiple Myeloma—A Promising Key to Therapy

Kleber

Ntanasis‐Stathopoulos

Terpos

2021

JCM

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“…BCMA has a crucial role in the survival of long-lived plasma cells in the bone marrow and is not expressed in other vital tissues [93]. There are several BCMA CAR T-cell products in clinical development whose differences and clinical activity are reviewed elsewhere [95,96]. So far, only one of them, idecabtagene vicleucel, has received FDA approval based on recently published results from a phase 2 study (NCT03361748) [97,98], and ciltacabtagene autoleucel has earned FDA priority review [99], both for the indication of relapsed/refractory MM.…”

Section: Anti-bcma Car T-cell Therapymentioning

confidence: 99%

“…The potential risk of relapse due to antigen escape and intratumoral heterogeneity with BCMA-negative subclones underscore the importance of targeting additional multiple myeloma-associated cell surface antigens. Several CAR T-cell products specific for other antigens, such as CD19, CD38, CD138, CD229, SLAMF7, and GPRC5D, are currently being evaluated in preclinical or clinical studies, and are reviewed elsewhere [95,96]. In addition, dual-antigen targeting combining BCMA with some alternative targets in bispecific CAR constructs proved an ability to prevent antigen escape in a mouse model [104,105].…”

Section: Resistance To Anti-bcma Car T-cell Therapymentioning

confidence: 99%

Harnessing the Immune System to Fight Multiple Myeloma

Krejcik

Barnkob

Nyvold

et al. 2021

Cancers

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Multiple myeloma (MM) is a heterogeneous plasma cell malignancy differing substantially in clinical behavior, prognosis, and response to treatment. With the advent of novel therapies, many patients achieve long-lasting remissions, but some experience aggressive and treatment refractory relapses. So far, MM is considered incurable. Myeloma pathogenesis can broadly be explained by two interacting mechanisms, intraclonal evolution of cancer cells and development of an immunosuppressive tumor microenvironment. Failures in isotype class switching and somatic hypermutations result in the neoplastic transformation typical of MM and other B cell malignancies. Interestingly, although genetic alterations occur and evolve over time, they are also present in premalignant stages, which never progress to MM, suggesting that genetic mutations are necessary but not sufficient for myeloma transformation. Changes in composition and function of the immune cells are associated with loss of effective immune surveillance, which might represent another mechanism driving malignant transformation. During the last decade, the traditional view on myeloma treatment has changed dramatically. It is increasingly evident that treatment strategies solely based on targeting intrinsic properties of myeloma cells are insufficient. Lately, approaches that redirect the cells of the otherwise suppressed immune system to take control over myeloma have emerged. Evidence of utility of this principle was initially established by the observation of the graft-versus-myeloma effect in allogeneic stem cell-transplanted patients. A variety of new strategies to harness both innate and antigen-specific immunity against MM have recently been developed and intensively tested in clinical trials. This review aims to give readers a basic understanding of how the immune system can be engaged to treat MM, to summarize the main immunotherapeutic modalities, their current role in clinical care, and future prospects.

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“…Six out of ten demonstrated very good partial response, two achieved partial response, and two did not respond leading to disease progression [ 27 ]. Dual antigen-targeting therapy with anti-CD19/anti-BCMA showed a 100% overall response rate [ 28 ].…”

Section: Reviewmentioning

confidence: 99%

Chimeric Antigen Receptor T Cell Therapy and Its Significance in Multiple Myeloma

Padda¹,

Khalid²,

Zubair³

et al. 2021

Cureus

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Multiple myeloma (MM) has a five-year prevalence worldwide of 230,000 people and is known as the second most common hematological malignancy within the United States. Extensive research has been conducted to gain a wide range of treatment strategies, providing hope to these patients. Combination therapy using chemotherapy, monoclonal antibodies, and immunomodulatory drugs are the current management of choice. After the introduction of chimeric antigen receptor (CAR) T cell therapy, promising results have been evidenced. In this therapy, T cells are derived from the patient and modified in-vitro to induce receptors that later target specific antigens when they are injected into patients. CAR T cells use three mechanisms to kill tumor cells: cytolytic pathways, cytokine release, and Fas/FasL axis. In this review, we highlight the different tumor markers targeted for therapy against multiple myeloma (MM). Target antigens for CAR T cell therapy include B-cell maturation antigen (BCMA), signaling lymphocyte activation molecule F7 (SLAMF7), CD38, CD138, CD19, immunoglobulin kappa light chain, orphan G protein-coupled receptor class C group 5 member D (GPRC5D). With the benefit of improving survival and prognosis, this therapy does carry a risk of some adverse events such as cytokine release syndrome, encephalopathy, infections, hypogammaglobulinemia, and tumor lysis syndrome.

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CAR T-cell therapy in multiple myeloma: more room for improvement

Cited by 128 publications

References 107 publications

BCMA in Multiple Myeloma—A Promising Key to Therapy

BCMA in Multiple Myeloma—A Promising Key to Therapy

Harnessing the Immune System to Fight Multiple Myeloma

Chimeric Antigen Receptor T Cell Therapy and Its Significance in Multiple Myeloma

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