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Curated Papers > Recent high-impact research on "CAR-T therapy" (Impact Factor ≥ 30, last 5 years)

Chimeric antigen receptor T cell therapies for multiple myeloma. ​

Literature Information ​

DOI10.1186/s13045-019-0823-5
PMID31752943
JournalJournal of hematology & oncology
Impact Factor40.4
JCR QuartileQ1
Publication Year2019
Times Cited20
KeywordsChimeric antigen receptors, Immunotherapy, Multiple myeloma, Tumor immunology
Literature TypeJournal Article, Research Support, Non-U.S. Gov't, Review
ISSN1756-8722
Pages120
Issue12(1)
AuthorsChao Wu, Lina Zhang, Qierra R Brockman, Fenghuang Zhan, Lijuan Chen

TL;DR ​

This paper discusses the challenges in treating refractory multiple myeloma (MM) and highlights the promising efficacy of chimeric antigen receptor (CAR)-modified T cell therapy as a novel approach, noting its manageable toxicities. It provides an overview of recent advancements in CAR-T therapy, including target selection, new technologies, and potential future directions in research.

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Chimeric antigen receptors · Immunotherapy · Multiple myeloma · Tumor immunology

Abstract ​

Multiple myeloma (MM) is the second most common hematologic malignancy and remains incurable despite the advent of numerous new drugs such as proteasome inhibitors (PIs), immunomodulatory agents (IMiDs), and monoclonal antibodies. There is an unmet need to develop novel therapies for refractory/relapsed MM. In the past few years, chimeric antigen receptor (CAR)-modified T cell therapy for MM has shown promising efficacy in preclinical and clinical studies. Furthermore, the toxicities of CAR-T cell therapy are manageable. This article summarizes recent developments of CAR-T therapy in MM, focusing on promising targets, new technologies, and new research areas. Additionally, a comprehensive overview of antigen selection is presented along with preliminary results and future directions of CAR-T therapy development.

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Primary Questions Addressed ​

  1. What are the specific antigen targets currently being explored for CAR-T therapies in multiple myeloma?
  2. How do the efficacy and safety profiles of CAR-T therapies compare to traditional treatments for multiple myeloma?
  3. What advancements in CAR-T technology could enhance the treatment outcomes for patients with refractory multiple myeloma?
  4. In what ways can the management of toxicities associated with CAR-T therapy be improved for multiple myeloma patients?
  5. What are the implications of recent clinical trial results on the future development of CAR-T therapies for multiple myeloma?

Key Findings ​

Background and Objectives ​

Multiple myeloma (MM) is the second most common hematologic malignancy, characterized by the proliferation of malignant plasma cells in the bone marrow. Despite advancements in treatment options, including proteasome inhibitors and monoclonal antibodies, MM remains largely incurable, particularly in relapsed/refractory cases. This review focuses on the emerging potential of chimeric antigen receptor (CAR) T cell therapy as a novel immunotherapeutic approach for MM, highlighting key targets, technological advancements, and future research directions.

Main Methods/Materials/Experimental Design ​

The review outlines the mechanisms and developments in CAR T cell therapy, emphasizing the importance of antigen selection due to the heterogeneity of MM cells. Various targets for CAR T cell therapy are discussed, particularly B cell maturation antigen (BCMA), which has emerged as a primary focus due to its restricted expression in MM cells.

The following flowchart illustrates the experimental design and progression of CAR T cell therapy for MM:

Mermaid diagram

Key Results and Findings ​

  1. Target Selection: BCMA has shown promise due to its specific expression on malignant plasma cells, minimizing on-target/off-tumor toxicity. Other targets include CD19, SLAMF7, kappa light chain, and CD138, each with varying degrees of clinical validation.

  2. Clinical Trials:

    • The first clinical trial targeting BCMA (NCT02215967) reported an overall response rate (ORR) of 81% at the highest dose.
    • bb2121 and bb21217 trials demonstrated ORRs of 85% and 86%, respectively, with manageable side effects, including cytokine release syndrome (CRS).
    • Other CAR T products like LCAR-B38M and P-BCMA-101 have also shown high efficacy rates in clinical settings.

  3. Safety Profiles: Most trials reported manageable CRS, predominantly grade 1-2, with a minority experiencing severe toxicities.

Main Conclusions/Significance/Innovation ​

CAR T cell therapy represents a significant advancement in the treatment of relapsed/refractory MM, showing high response rates and a manageable safety profile. The specificity of BCMA as a target reduces the risk of collateral damage to normal cells, making it a viable option for patients who have exhausted other treatment avenues. Ongoing research is focused on enhancing CAR T cell persistence, reducing side effects, and exploring combination therapies to improve patient outcomes.

Research Limitations and Future Directions ​

  1. Limitations: The review highlights challenges such as the genetic heterogeneity of MM, potential antigen escape mechanisms, and the need for improved safety measures to manage CRS and neurotoxicity.

  2. Future Directions:

    • Continued exploration of additional antigens and combination therapies to overcome resistance.
    • Development of next-generation CAR T cells with enhanced efficacy and reduced toxicity.
    • Investigation into the timing and sequencing of CAR T cell therapy with other treatment modalities, such as PD-1 inhibitors and cytokine modulators.

In conclusion, CAR T cell therapy holds promise for revolutionizing the treatment landscape for multiple myeloma, with ongoing innovations expected to further refine its application and effectiveness.

References ​

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  2. Preclinical characterization of SGN-70, a humanized antibody directed against CD70. - Julie A McEarchern;Leia M Smith;Charlotte F McDonagh;Kerry Klussman;Kristine A Gordon;Carol A Morris-Tilden;Steven Duniho;Maureen Ryan;Tamar E Boursalian;Paul J Carter;Iqbal S Grewal;Che-Leung Law - Clinical cancer research : an official journal of the American Association for Cancer Research (2008)
  3. Multiple Myeloma: Diagnosis and Treatment. - Thomas C Michels;Keith E Petersen - American family physician (2017)
  4. Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. - Michel de Weers;Yu-Tzu Tai;Michael S van der Veer;Joost M Bakker;Tom Vink;Daniëlle C H Jacobs;Lukas A Oomen;Matthias Peipp;Thomas Valerius;Jerry W Slootstra;Tuna Mutis;Wim K Bleeker;Kenneth C Anderson;Henk M Lokhorst;Jan G J van de Winkel;Paul W H I Parren - Journal of immunology (Baltimore, Md. : 1950) (2011)
  5. Clinical responses with T lymphocytes targeting malignancy-associated κ light chains. - Carlos A Ramos;Barbara Savoldo;Vicky Torrano;Brandon Ballard;Huimin Zhang;Olga Dakhova;Enli Liu;George Carrum;Rammurti T Kamble;Adrian P Gee;Zhuyong Mei;Meng-Fen Wu;Hao Liu;Bambi Grilley;Cliona M Rooney;Malcolm K Brenner;Helen E Heslop;Gianpietro Dotti - The Journal of clinical investigation (2016)
  6. Anti-BCMA CAR-T cells for treatment of plasma cell dyscrasia: case report on POEMS syndrome and multiple myeloma. - Jinhuan Xu;Qiuxiang Wang;Hao Xu;Chaojiang Gu;Lijun Jiang;Jue Wang;Di Wang;Bin Xu;Xia Mao;Jin Wang;Zhiqiong Wang;Yi Xiao;Yicheng Zhang;Chunrui Li;Jianfeng Zhou - Journal of hematology & oncology (2018)
  7. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. - Marco L Davila;Isabelle Riviere;Xiuyan Wang;Shirley Bartido;Jae Park;Kevin Curran;Stephen S Chung;Jolanta Stefanski;Oriana Borquez-Ojeda;Malgorzata Olszewska;Jinrong Qu;Teresa Wasielewska;Qing He;Mitsu Fink;Himaly Shinglot;Maher Youssif;Mark Satter;Yongzeng Wang;James Hosey;Hilda Quintanilla;Elizabeth Halton;Yvette Bernal;Diana C G Bouhassira;Maria E Arcila;Mithat Gonen;Gail J Roboz;Peter Maslak;Dan Douer;Mark G Frattini;Sergio Giralt;Michel Sadelain;Renier Brentjens - Science translational medicine (2014)
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  9. Heparanase-induced shedding of syndecan-1/CD138 in myeloma and endothelial cells activates VEGFR2 and an invasive phenotype: prevention by novel synstatins. - O Jung;V Trapp-Stamborski;A Purushothaman;H Jin;H Wang;R D Sanderson;A C Rapraeger - Oncogenesis (2016)
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Literatures Citing This Work ​

  1. Next-generation immuno-oncology agents: current momentum shifts in cancer immunotherapy. - Chongxian Pan;Hongtao Liu;Elizabeth Robins;Wenru Song;Delong Liu;Zihai Li;Lei Zheng - Journal of hematology & oncology (2020)
  2. Deregulation of Adaptive T Cell Immunity in Multiple Myeloma: Insights Into Mechanisms and Therapeutic Opportunities. - Noémie Leblay;Ranjan Maity;Fajer Hasan;Paola Neri - Frontiers in oncology (2020)
  3. Characterization of novel dual tandem CD19/BCMA chimeric antigen receptor T cells to potentially treat multiple myeloma. - Liqing Kang;Jian Zhang;Minghao Li;Nan Xu;Wei Qi;Jingwen Tan;Xiaoyan Lou;Zhou Yu;Juanjuan Sun;Zhenkun Wang;Chengcheng Fu;Xiaowen Tang;Haiping Dai;Jia Chen;Depei Wu;Lei Yu - Biomarker research (2020)
  4. Overcoming Chimeric Antigen Receptor (CAR) Modified T-Cell Therapy Limitations in Multiple Myeloma. - Estefanía García-Guerrero;Belén Sierro-Martínez;Jose Antonio Pérez-Simón - Frontiers in immunology (2020)
  5. BCMA-targeted immunotherapy for multiple myeloma. - Bo Yu;Tianbo Jiang;Delong Liu - Journal of hematology & oncology (2020)
  6. Targeted-Alpha-Therapy Combining Astatine-211 and anti-CD138 Antibody in A Preclinical Syngeneic Mouse Model of Multiple Myeloma Minimal Residual Disease. - Sébastien Gouard;Catherine Maurel;Séverine Marionneau-Lambot;Delphine Dansette;Clément Bailly;François Guérard;Nicolas Chouin;Ferid Haddad;Cyril Alliot;Joëlle Gaschet;Romain Eychenne;Françoise Kraeber-Bodéré;Michel Chérel - Cancers (2020)
  7. Clinical implication of cellular vaccine in glioma: current advances and future prospects. - Yuanliang Yan;Shuangshuang Zeng;Zhicheng Gong;Zhijie Xu - Journal of experimental & clinical cancer research : CR (2020)
  8. Safety and clinical efficacy of BCMA CAR-T-cell therapy in multiple myeloma. - Gils Roex;Marijke Timmers;Kristien Wouters;Diana Campillo-Davo;Donovan Flumens;Wilfried Schroyens;Yiwei Chu;Zwi N Berneman;Eva Lion;Feifei Luo;Sébastien Anguille - Journal of hematology & oncology (2020)
  9. Chimeric antigen receptor- and natural killer cell receptor-engineered innate killer cells in cancer immunotherapy. - Cai Zhang;Yuan Hu;Weihua Xiao;Zhigang Tian - Cellular & molecular immunology (2021)
  10. Novel strategies for immuno-oncology breakthroughs with cell therapy. - Hongtao Liu;Chongxian Pan;Wenru Song;Delong Liu;Zihai Li;Lei Zheng - Biomarker research (2021)

... (10 more literatures)

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