“Off-the-shelf” immunotherapies for multiple myeloma

Mohammed, Turab; Mailankody, Sham

doi:10.1053/j.seminoncol.2022.01.001

Cited by 4 publications

(6 citation statements)

References 64 publications

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“…However, each therapeutic modality has unique pros and cons which could be more or less suitable for different patient populations. Bispecific antibodies offer the advantage of being "off the shelf" products that can be used promptly to treat MM, whereas CAR T administration involves a 4-6 week process of lymphocyte collection, manufacturing, and infusion (119). During these 4-6 weeks "bridging" chemotherapy or immunotherapy may need to be used to prevent disease progression while patients are waiting (120).…”

Section: Discussionmentioning

confidence: 99%

Harnessing the T Cell to Treat Multiple Myeloma: Dawn of a New Therapeutic Paradigm

Keller

Sherbenou²,

Forsberg³

et al. 2022

Front. Oncol.

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Multiple myeloma is an incurable hematologic malignancy. The typical disease course for myeloma patients is characterized by initial response to treatment followed by eventual development of resistance. Subsequent cycles of remission and relapse proceed as long as patients have new lines of therapy available to them. This reality has prompted development of many novel immunotherapeutics. Many of these drugs exploit the cytotoxic capabilities of the patients’ own T cells, effectively redirecting them to myeloma cells that are otherwise evading immune attack. Approaches including CAR T cell therapy and bispecific antibodies have displayed impressive efficacy in clinical trials for myeloma patients. This review examines the different approaches that utilize T cells in multiple myeloma therapy and investigates the benefits and risks of these exciting new strategies.

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Section: Discussionmentioning

confidence: 99%

Harnessing the T Cell to Treat Multiple Myeloma: Dawn of a New Therapeutic Paradigm

Keller

Sherbenou²,

Forsberg³

et al. 2022

Front. Oncol.

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“…Other investigational allogeneic BCMA CAR-T therapies include PBCAR269A, in which proprietary ARCUS gene editing is used to simultaneously knock out the native TCR and ‘knock in’ the anti-BCMA CAR ( 117 ). A Phase 1/2a trial (clinicaltrials.gov ID: NCT04171843) of PBCAR269A with or without the addition of nirogacestat, a GSI discussed earlier in this review in the context of BCMA targeting, is currently under way ( 24 – 26 ).…”

Section: Hassle-free Delivery: Minimization Of Brain-to-vein Timementioning

confidence: 99%

Innovation in BCMA CAR-T therapy: Building beyond the Model T

2022

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Autologous chimeric antigen receptor T-cell (CAR-T) therapies targeting B-cell maturation antigen (BCMA) have revolutionized the field of multiple myeloma in the same way that the Ford Model T revolutionized the original CAR world a century ago. However, we are only beginning to understand how to improve the efficacy and usability of these cellular therapies. In this review, we explore three automotive analogies for innovation with BCMA CAR-T therapies: stronger engines, better mileage, and hassle-free delivery. Firstly, we can build stronger engines in terms of BCMA targeting: improved antigen binding, tools to modulate antigen density, and armoring to better reach the antigen itself. Secondly, we can improve “mileage” in terms of response durability through ex vivo CAR design and in vivo immune manipulation. Thirdly, we can implement hassle-free delivery through rapid manufacturing protocols and off-the-shelf products. Just as the Model T set a benchmark for car manufacturing over 100 years ago, idecabtagene vicleucel and ciltacabtagene autoleucel have now set the starting point for BCMA CAR-T therapy with their approvals. As with any emerging technology, whether automotive or cellular, the best in innovation and optimization is yet to come.

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“…2 To address this area of unmet need, the focus has shifted toward new approaches, such as chi me ric anti gen recep tor (CAR) Tcell ther a pies, anti bodydrug con ju gates (ADCs), and bispecific antibodies (BsAbs). 3 Although CAR Tcell ther apy has shown remark able over all effi cacy of greater than 70% across var i ous earlyphase stud ies-lead ing to the approv als of idecabtagene vicleucel and ciltacabtagene autoleucel-delays in drug admin is tra tion due to manufactur ing time and grade 3/4 adverse events (AEs) from cyto kine release syn drome (CRS), neu ro tox ic ity, and cytopenias remain major con cerns. 3 The desire for safe "offtheshelf" immunotherapies has strength ened inter est in ADCs and BsAbs, which them selves have dem on strated prom is ing effi cacy in relapsed/refrac tory MM (RRMM).…”

Section: Introductionmentioning

confidence: 99%

“…3 Although CAR Tcell ther apy has shown remark able over all effi cacy of greater than 70% across var i ous earlyphase stud ies-lead ing to the approv als of idecabtagene vicleucel and ciltacabtagene autoleucel-delays in drug admin is tra tion due to manufactur ing time and grade 3/4 adverse events (AEs) from cyto kine release syn drome (CRS), neu ro tox ic ity, and cytopenias remain major con cerns. 3 The desire for safe "offtheshelf" immunotherapies has strength ened inter est in ADCs and BsAbs, which them selves have dem on strated prom is ing effi cacy in relapsed/refrac tory MM (RRMM). 3 In this review we pres ent the state of devel op ment of each class of anti bodydirected ther apy in MM, with an empha sis on the rap idly advanc ing ADC and BsAb ther a peu tic arma men tar ium.…”

Section: Introductionmentioning

confidence: 99%

“…3 The desire for safe "offtheshelf" immunotherapies has strength ened inter est in ADCs and BsAbs, which them selves have dem on strated prom is ing effi cacy in relapsed/refrac tory MM (RRMM). 3 In this review we pres ent the state of devel op ment of each class of anti bodydirected ther apy in MM, with an empha sis on the rap idly advanc ing ADC and BsAb ther a peu tic arma men tar ium.…”

Section: Introductionmentioning

confidence: 99%

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Antibodies and bispecifics for multiple myeloma: effective effector therapy

2022

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The therapeutic landscape in multiple myeloma (MM) has changed dramatically over the last 2 decades. With the introduction of novel immunotherapies, patients with MM can expect deeper responses, longer remissions, and improved overall survival. Since its approval by the US Food and Drug Administration in 2015, the monoclonal antibody specific for CD38, daratumumab, has been incorporated into both frontline and relapsed treatment regimens. Its role as a maintenance therapy is currently being explored. Subsequently, a variety of novel antibody therapeutics have evolved from the success of daratumumab, using similar concepts to target the malignant plasma cell clone. Noteworthy naked monoclonal antibodies include isatuximab, another agent directed against CD38, and elotuzumab, an agent directed against SLAM family member 7. Antibody-drug conjugates, complex molecules composed of an antibody tethered to a cytotoxic drug, target malignant cells and deliver a lethal payload. The first to market is belantamab mafodotin, which targets B-cell maturation antigen (BCMA) on malignant plasma cells and delivers a potent microtubule inhibitor, monomethyl auristatin F. Additionally, bispecific T-cell antibodies are in development that engage the immune system directly by simultaneously binding CD3 on T cells and a target epitope—such as BCMA, G-protein coupled receptor family C group 5 member D (GPRC5d), and Fc receptor homologue 5 (FcRH5)—on malignant cells. Currently, teclistamab, an anti-BCMA bispecific, is closest to approval for commercial use. In this review, we explore the evolving landscape of antibodies in the treatment of MM, including their role in frontline and relapse settings.

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“Off-the-shelf” immunotherapies for multiple myeloma

Cited by 4 publications

References 64 publications

Harnessing the T Cell to Treat Multiple Myeloma: Dawn of a New Therapeutic Paradigm

Harnessing the T Cell to Treat Multiple Myeloma: Dawn of a New Therapeutic Paradigm

Innovation in BCMA CAR-T therapy: Building beyond the Model T

Antibodies and bispecifics for multiple myeloma: effective effector therapy

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