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CAR T therapies in multiple myeloma: unleashing the future. ​

Literature Information ​

DOI10.1038/s41417-024-00750-2
PMID38438559
JournalCancer gene therapy
Impact Factor5.0
JCR QuartileQ1
Publication Year2024
Times Cited62
KeywordsCAR T-cell therapy, multiple myeloma, antigen-targeted therapy
Literature TypeJournal Article, Review
ISSN0929-1903
Pages667-686
Issue31(5)
AuthorsMohsen Sheykhhasan, Amirhossein Ahmadieh-Yazdi, Rosario Vicidomini, Naresh Poondla, Hamid Tanzadehpanah, Ashkan Dirbaziyan, Hanie Mahaki, Hamed Manoochehri, Naser Kalhor, Paola Dama

TL;DR ​

This paper discusses the transformative impact of CAR T-cell therapy in treating multiple myeloma (MM), highlighting its effectiveness compared to traditional treatments and recent FDA approvals. It emphasizes the potential of CAR T-cells to improve treatment responses and reduce side effects, while also addressing the challenges and limitations that need to be overcome to optimize their application in patients with relapsed/refractory MM.

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CAR T-cell therapy · multiple myeloma · antigen-targeted therapy

Abstract ​

In recent years, the field of cancer treatment has witnessed remarkable breakthroughs that have revolutionized the landscape of care for cancer patients. While traditional pillars such as surgery, chemotherapy, and radiation therapy have long been available, a cutting-edge therapeutic approach called CAR T-cell therapy has emerged as a game-changer in treating multiple myeloma (MM). This novel treatment method complements options like autologous stem cell transplants and immunomodulatory medications, such as proteasome inhibitors, by utilizing protein complexes or anti-CD38 antibodies with potent complement-dependent cytotoxic effects. Despite the challenges and obstacles associated with these treatments, the recent approval of the second FDA multiple myeloma CAR T-cell therapy has sparked immense promise in the field. Thus far, the results indicate its potential as a highly effective therapeutic solution. Moreover, ongoing preclinical and clinical trials are exploring the capabilities of CAR T-cells in targeting specific antigens on myeloma cells, offering hope for patients with relapsed/refractory MM (RRMM). These advancements have shown the potential for CAR T cell-based medicines or combination therapies to elicit greater treatment responses and minimize side effects. In this context, it is crucial to delve into the history and functions of CAR T-cells while acknowledging their limitations. We can strategize and develop innovative approaches to overcome these barriers by understanding their challenges. This article aims to provide insights into the application of CAR T-cells in treating MM, shedding light on their potential, limitations, and strategies employed to enhance their efficacy.

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Primary Questions Addressed ​

  1. What are the specific mechanisms by which CAR T-cell therapy targets myeloma cells compared to traditional therapies?
  2. How do the side effects of CAR T-cell therapies in multiple myeloma patients compare to those of autologous stem cell transplants?
  3. What advancements are being made in the development of combination therapies that include CAR T-cells for treating relapsed/refractory multiple myeloma?
  4. In what ways can the limitations of CAR T-cell therapies be addressed to improve their efficacy in multiple myeloma treatment?
  5. What role do preclinical and clinical trials play in shaping the future of CAR T-cell therapies for multiple myeloma patients?

Key Findings ​

Research Background and Objectives ​

Multiple myeloma (MM) is a prevalent hematological malignancy characterized by the uncontrolled proliferation of plasma cells, contributing significantly to cancer-related mortality. Traditional treatments, including chemotherapy and stem cell transplants, have limitations, particularly for high-risk patients. Chimeric Antigen Receptor (CAR) T-cell therapy has emerged as a promising approach, offering targeted immunotherapy for MM, particularly through the targeting of B-cell maturation antigen (BCMA). This article reviews the advancements, challenges, and future directions of CAR T-cell therapies in treating MM.

Main Methods/Materials/Experimental Design ​

The development of CAR T-cell therapies involves several key steps:

  1. Patient Leukapheresis: Collection of patient T cells.
  2. T Cell Activation and Transduction: The collected T cells are activated and genetically modified to express CARs that target specific antigens on myeloma cells.
  3. Expansion and Cryopreservation: The modified T cells are expanded in culture and cryopreserved.
  4. Reinfusion: The engineered T cells are infused back into the patient to target and eliminate cancer cells.

The following flowchart illustrates the CAR T-cell manufacturing process:

Mermaid diagram

Key Results and Findings ​

  • Efficacy: CAR T-cell therapies targeting BCMA have shown promising results, with clinical trials reporting overall response rates (ORR) of up to 85% in relapsed/refractory MM patients.
  • Safety: While effective, CAR T therapies are associated with side effects, including cytokine release syndrome (CRS) and neurotoxicity, which require careful management.
  • Emerging Therapies: Next-generation CAR T-cells, including dual-targeting approaches (e.g., BCMA/CD19), have been developed to improve efficacy and reduce the risk of antigen escape.

Main Conclusions/Significance/Innovativeness ​

CAR T-cell therapy represents a transformative advancement in the treatment of multiple myeloma, offering hope for improved outcomes in patients with limited treatment options. The innovative design of CARs, particularly those targeting BCMA, demonstrates the potential for personalized immunotherapy in oncology. However, challenges such as tumor heterogeneity and the immunosuppressive tumor microenvironment must be addressed to enhance treatment efficacy and safety.

Research Limitations and Future Directions ​

  • Limitations: The durability of responses to CAR T-cell therapy remains a concern, with a significant proportion of patients experiencing relapse due to antigen loss or downregulation.
  • Future Directions: Research is ongoing to explore new target antigens, enhance CAR T-cell persistence, and integrate maintenance therapies. The use of CRISPR technology to edit T cells and improve their functionality is also a promising avenue for future studies.
AspectDetails
Main FindingsHigh ORR in clinical trials, significant safety concerns (CRS, neurotoxicity).
InnovationsDevelopment of dual-targeting CAR T-cells, use of suicide switches for safety.
LimitationsAntigen escape, limited durability of responses, and challenges in the tumor microenvironment.
Future ResearchExplore novel antigens, improve CAR T-cell persistence, and utilize CRISPR for T-cell editing.

References ​

  1. The basic principles of chimeric antigen receptor design. - Michel Sadelain;Renier Brentjens;Isabelle Rivière - Cancer discovery (2013)
  2. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. - Jesus G Berdeja;Deepu Madduri;Saad Z Usmani;Andrzej Jakubowiak;Mounzer Agha;Adam D Cohen;A Keith Stewart;Parameswaran Hari;Myo Htut;Alexander Lesokhin;Abhinav Deol;Nikhil C Munshi;Elizabeth O'Donnell;David Avigan;Indrajeet Singh;Enrique Zudaire;Tzu-Min Yeh;Alicia J Allred;Yunsi Olyslager;Arnob Banerjee;Carolyn C Jackson;Jenna D Goldberg;Jordan M Schecter;William Deraedt;Sen Hong Zhuang;Jeffrey Infante;Dong Geng;Xiaoling Wu;Marlene J Carrasco-Alfonso;Muhammad Akram;Farah Hossain;Syed Rizvi;Frank Fan;Yi Lin;Thomas Martin;Sundar Jagannath - Lancet (London, England) (2021)
  3. Mechanisms of antigen escape from BCMA- or GPRC5D-targeted immunotherapies in multiple myeloma. - Holly Lee;Sungwoo Ahn;Ranjan Maity;Noemie Leblay;Bachisio Ziccheddu;Marietta Truger;Monika Chojnacka;Anthony Cirrincione;Michael Durante;Remi Tilmont;Elie Barakat;Mansour Poorebrahim;Sarthak Sinha;John McIntyre;Angela M Y Chan;Holly Wilson;Shari Kyman;Amrita Krishnan;Ola Landgren;Wencke Walter;Manja Meggendorfer;Claudia Haferlach;Torsten Haferlach;Hermann Einsele;Martin K Kortüm;Stefan Knop;Jean Baptiste Alberge;Andreas Rosenwald;Jonathan J Keats;Leo Rasche;Francesco Maura;Paola Neri;Nizar J Bahlis - Nature medicine (2023)
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  5. The loss of neoantigens is an important reason for immune escape in multiple myeloma patients with high intratumor heterogeneity. - Yue Wang;Jiadai Xu;Tianwei Lan;Chi Zhou;Peng Liu - Cancer medicine (2023)
  6. 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)
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Literatures Citing This Work ​

  1. Role of Immune Cells and Immunotherapy in Multiple Myeloma. - Vijay Radhakrishnan;Upendarrao Golla;Avinash Kundadka Kudva - Life (Basel, Switzerland) (2024)
  2. Genetic Susceptibility in Endothelial Injury Syndromes after Hematopoietic Cell Transplantation and Other Cellular Therapies: Climbing a Steep Hill. - Paschalis Evangelidis;Nikolaos Evangelidis;Panagiotis Kalmoukos;Maria Kourti;Athanasios Tragiannidis;Eleni Gavriilaki - Current issues in molecular biology (2024)
  3. Clinician and administrator perspectives on outpatient administration of ciltacabtagene autoleucel in relapsed or refractory multiple myeloma. - Doris K Hansen;Binod Dhakal;Mehdi Hamadani;David Dingli;Tania Jain;Carol Ann Huff;Murali Janakiram;Yi-Hsuan Liu;Kevin C De Braganca;Nicole Lodowski;Jennifer Sander;Peter Okorozo;Lindsay McFarland;Matthew Perciavalle;Stephen Huo;Zaina P Qureshi;Krina K Patel - Frontiers in immunology (2024)
  4. The Interplay between the DNA Damage Response (DDR) Network and the Mitogen-Activated Protein Kinase (MAPK) Signaling Pathway in Multiple Myeloma. - Panagiotis Malamos;Christina Papanikolaou;Maria Gavriatopoulou;Meletios A Dimopoulos;Evangelos Terpos;Vassilis L Souliotis - International journal of molecular sciences (2024)
  5. Pathways to therapy resistance: The sheltering effect of the bone marrow microenvironment to multiple myeloma cells. - Kuntal Bhowmick;Max von Suskil;Omar S Al-Odat;Weam Othman Elbezanti;Subash C Jonnalagadda;Tulin Budak-Alpdogan;Manoj K Pandey - Heliyon (2024)
  6. Review of CAR T-Cell Therapy in Multiple Myeloma: A Canadian Perspective. - Steven Chun-Min Shih;Sita Bhella - Current oncology (Toronto, Ont.) (2024)
  7. The next frontier in immunotherapy: potential and challenges of CAR-macrophages. - Jing Li;Ping Chen;Wenxue Ma - Experimental hematology & oncology (2024)
  8. Targeting B-cell maturation antigen for treatment and monitoring of relapsed/refractory multiple myeloma patients: a comprehensive review. - David Yashar;Bernard Regidor;Marissa-Skye Goldwater;Sean Bujarski;Ashley Del Dosso;James R Berenson - Therapeutic advances in hematology (2024)
  9. CAR T-cell therapy in cancer: Integrating nursing perspectives for enhanced patient care. - Ashna Gupta;Gunjan Dagar;Mohd Umar Rehmani;Chandra Prakash Prasad;Deepak Saini;Mayank Singh;Abhishek Shankar - Asia-Pacific journal of oncology nursing (2024)
  10. Galectin-9 - ligand axis: an emerging therapeutic target for multiple myeloma. - Rajib K Shil;Norhan B B Mohammed;Charles J Dimitroff - Frontiers in immunology (2024)

... (52 more literatures)

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