A novel BCMA CAR-T-cell therapy with optimized human scFv for treatment of relapsed/refractory multiple myeloma: results from phase I clinical trials

Yang, Min; Zhang, Wenhao; Kang, Yu; Wang, Peng; Jiang, Hua; Chen, Linjun; Meng, Haitao; Weng, Yiqin; Tao, Rong; Huang, Xin; Xing, Chongyun; Wang, Huamao; Wan, Jing; Wang, Shasha; Dai, Lihui; Hendrix, Amanda Y; Xiao, Jun; Wang, Wei; Ma, Hong; Hao, Siguo; Jin, Jie; Li, Zonghai; Jiang, Songfu

doi:10.3324/haematol.2022.280629

Cited by 8 publications

(4 citation statements)

References 13 publications

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“…In the phase I studies (NCT03302403, NCT03380039, NCT03716856), 24 patients received a dose ranging from 0.5 to 1.8 × 10^6 CT053 cells, the ORR was 87.5%, indicating a high rate of response to CT053 treatment, with 79.2% patients achieved CR (12.5%) or sCR (66.7%), demonstrating deep and durable responses, and the median follow-up time was 17.4 months, the mPFS was 18.8 months and the mDOR was 21.8 months. Anti-drug antibody (ADA) was not detected in patients after infusion, suggesting no significant immunogenicity associated with CT053 treatment, and CT053 demonstrated strong efficacy and a good safety profile for patients with RRMM [ 250 ].…”

Section: Targeted Immunotherapymentioning

confidence: 99%

Multiple myeloma: signaling pathways and targeted therapy

Lu,

Yang,

et al. 2024

Mol Biomed

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Multiple myeloma (MM) is the second most common hematological malignancy of plasma cells, characterized by osteolytic bone lesions, anemia, hypercalcemia, renal failure, and the accumulation of malignant plasma cells. The pathogenesis of MM involves the interaction between MM cells and the bone marrow microenvironment through soluble cytokines and cell adhesion molecules, which activate various signaling pathways such as PI3K/AKT/mTOR, RAS/MAPK, JAK/STAT, Wnt/β-catenin, and NF-κB pathways. Aberrant activation of these pathways contributes to the proliferation, survival, migration, and drug resistance of myeloma cells, making them attractive targets for therapeutic intervention. Currently, approved drugs targeting these signaling pathways in MM are limited, with many inhibitors and inducers still in preclinical or clinical research stages. Therapeutic options for MM include non-targeted drugs like alkylating agents, corticosteroids, immunomodulatory drugs, proteasome inhibitors, and histone deacetylase inhibitors. Additionally, targeted drugs such as monoclonal antibodies, chimeric antigen receptor T cells, bispecific T-cell engagers, and bispecific antibodies are being used in MM treatment. Despite significant advancements in MM treatment, the disease remains incurable, emphasizing the need for the development of novel or combined targeted therapies based on emerging theoretical knowledge, technologies, and platforms. In this review, we highlight the key role of signaling pathways in the malignant progression and treatment of MM, exploring advances in targeted therapy and potential treatments to offer further insights for improving MM management and outcomes.

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Section: Targeted Immunotherapymentioning

confidence: 99%

Multiple myeloma: signaling pathways and targeted therapy

Lu,

Yang,

et al. 2024

Mol Biomed

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“…Reduction of CRS using optimized L17 CD19 CAR T cells generated via studies of ScFv activity shows a potential tool for tumor therapy. To treat MM optimized fully human ScFv CT053 has been studied along with clinical trials [ 34 ] proving the fact that ScFv could optimize the activity of CAR T cells. KHYG-1 NK/T cell line is important in case of cell culture and gene transduction.…”

Section: Scfv Modifications Using Crisprmentioning

confidence: 99%

“…which proves the above mentioned fact. By using CRISPR ScFv can be modified to optimize the activity of CAR T cells [14,20,34,37].…”

Section: Scfv Modifications Using Crisprmentioning

confidence: 99%

Molecular and therapeutic effect of CRISPR in treating cancer

2023

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Cancer has become one of the common causes of mortality around the globe due to mutations in the genome which allows rapid growth of cells uncontrollably without repairing DNA errors. Cancers could arise due alterations in DNA repair mechanisms (errors in mismatch repair genes), activation of oncogenes and inactivation of tumor suppressor genes. Each cancer type is different and each individual has a unique genetic change which leads them to cancer. Studying genetic and epigenetic alterations in the genome leads to understanding the underlying features. CAR T therapy over other immunotherapies such as monoclonal antibodies, immune checkpoint inhibitors, cancer vaccines and adoptive cell therapies has been widely used to treat cancer in recent days and gene editing has now become one of the promising treatments for many genetic diseases. This tool allows scientists to change the genome by adding, removing or altering genetic material of an organism. Due to advance in genetics and novel molecular techniques such as CRISPR, TALEN these genes can be edited in such a way that their original function could be replaced which in turn improved the treatment possibilities and can be used against malignancies and even cure cancer in future along with CAR T cell therapy due to the specific recognition and attacking of tumor.

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“…Fully humanized CAR constructs targeting BCMA include orvacabtagene autoleucel (JCARH125, orva-cel, no longer under development), FHVH-BCMA-T, zevorcabtagene autoleucel (CT053), CT103A, and CC- 98633 ( 55 – 61 ). In two phase 1 trials of CT053 ( n = 24) and CT103A ( n = 71) respectively, ADAs have been reported in fewer than 5% of patients ( 59 , 60 ). Another promising CAR-T therapy under early investigation is CART-ddBCMA, where the BCMA-binding domain has been chosen from a synthetic protein library followed by subsequent mutagenesis and testing to minimize rates of ex vivo immunogenicity ( 62 ).…”

Section: Better Mileage: Longer Duration Of Responsesmentioning

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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A novel BCMA CAR-T-cell therapy with optimized human scFv for treatment of relapsed/refractory multiple myeloma: results from phase I clinical trials

Abstract: Not available.

Cited by 8 publications

References 13 publications

Multiple myeloma: signaling pathways and targeted therapy

Multiple myeloma: signaling pathways and targeted therapy

Molecular and therapeutic effect of CRISPR in treating cancer

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

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