【AI Explained】Overview of approved CAR-T therapies, ongoing clinical trials, and its impact on clinical practice.

Literature Information

TL;DR

This review discusses the rapid advancement of chimeric antigen receptor T-cell (CAR-T) therapies, particularly their transformative impact on treating non-Hodgkin lymphoma, B-cell acute lymphoblastic leukemia, and multiple myeloma, showing high response rates and potential for durable remissions. It emphasizes the ongoing exploration of CAR-T therapy in earlier treatment lines and its potential to replace traditional methods like autologous hematopoietic cell transplantation, while also highlighting the development of therapies targeting novel tumor-associated antigens to broaden its applications in hematological malignancies.

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CAR‐T cell therapy · acute lymphoblastic leukemia · diffuse large B‐cell lymphoma · multiple myeloma · non‐Hodgkin lymphoma

Abstract

In recent years, we have seen rapid expansion of chimeric antigen receptor T-cell (CAR-T) therapies in multiple malignancies. CAR-T therapy has profoundly altered the treatment landscape of non-Hodgkin lymphoma, B-cell acute lymphoblastic leukemia, and multiple myeloma. Currently available CD19 and B-cell maturation antigen-directed CAR-T therapies have shown high overall response rate and durable remissions in patients who have failed standard therapies. Multiple studies are underway exploring the role of CAR-T-cell therapy as earlier line of treatment. In high-grade B-cell lymphoma, CD19 CAR-T therapy may replace autologous hematopoietic cell transplantation as second line therapy in near future. CAR-T-cell therapy targeting novel tumor-associated antigens will help expand utility of this treatment modality in other hematological malignancies. It may also help overcome limitations of currently approved CAR-T-cell therapies. In this review, we have provided an overview of currently approved CAR-T therapies and upcoming clinical trials which may potentially impact the clinical practice.

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Primary Questions Addressed

1. What are the key differences in efficacy and safety between currently approved CAR-T therapies and those in clinical trials?
2. How might the integration of CAR-T therapy into earlier lines of treatment affect patient outcomes compared to traditional therapies?
3. What novel tumor-associated antigens are being targeted in upcoming CAR-T therapies, and what implications do they have for treatment expansion?
4. In what ways could CAR-T therapy evolve to address the limitations faced by current therapies in terms of patient eligibility and treatment response?
5. How do ongoing clinical trials aim to refine the administration protocols of CAR-T therapies to enhance their effectiveness in diverse patient populations?

Key Findings

Research Background and Purpose

Chimeric antigen receptor T-cell (CAR-T) therapies have emerged as a groundbreaking treatment modality for various hematological malignancies, particularly non-Hodgkin lymphoma (NHL), B-cell acute lymphoblastic leukemia (B-ALL), and multiple myeloma (MM). This review aims to provide a comprehensive overview of currently approved CAR-T therapies, ongoing clinical trials, and their impact on clinical practice, highlighting advancements in CAR-T technology and its potential to alter treatment paradigms.

Main Methods/Materials/Experimental Design

The review systematically discusses FDA-approved CAR-T therapies, focusing on their development, mechanisms of action, clinical trial results, and safety profiles.

Key Results and Findings

1. FDA-Approved Therapies:

   • Axicabtagene ciloleucel (axi-cel): Approved for R/R high-grade B-cell lymphoma with an overall response rate (ORR) of 82% and a complete response (CR) rate of 54%.
   • Tisagenlecleucel (tisa-cel): Approved for R/R B-ALL in pediatric and young adults, showing an ORR of 81% and a CR rate of 75%.
   • Lisocabtagene maraleucel (liso-cel): Achieved a 73% ORR and 54% CR in R/R large B-cell lymphoma.
   • Brexucabtagene autoleucel (brexu-cel): Approved for R/R mantle cell lymphoma with an ORR of 93% and a CR rate of 67%.

2. Ongoing Clinical Trials:

   • Numerous studies are investigating the efficacy of CAR-T therapies in earlier lines of treatment and targeting novel antigens, which may expand the applicability of CAR-T therapies.

Main Conclusions/Significance/Innovation

CAR-T therapies represent a significant advancement in the treatment of hematological malignancies, offering high response rates and durable remissions in patients with limited treatment options. The potential shift towards using CAR-T therapies as first-line treatments and the exploration of novel targets may enhance the effectiveness of these therapies, addressing the limitations of existing treatments. The review emphasizes the transformative impact of CAR-T therapies on clinical practice, with the potential to improve patient outcomes and quality of life.

Research Limitations and Future Directions

While CAR-T therapies have shown promise, challenges remain, including:

• Toxicity Management: New toxicities associated with CAR-T therapies, such as cytokine release syndrome (CRS) and neurotoxicity, require ongoing education and adaptation in clinical practice.
• Access and Infrastructure: The need for specialized centers to manage CAR-T therapy patients and the implications for healthcare systems.
• Long-Term Efficacy: Ongoing research is necessary to determine the long-term efficacy and safety of CAR-T therapies, particularly in diverse patient populations.

Future research should focus on:

• Expanding CAR-T applications to additional hematological malignancies.
• Investigating combination therapies to enhance efficacy and reduce toxicity.
• Developing strategies to manage and mitigate adverse effects associated with CAR-T therapies.

References

1. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. - Shannon L Maude;Theodore W Laetsch;Jochen Buechner;Susana Rives;Michael Boyer;Henrique Bittencourt;Peter Bader;Michael R Verneris;Heather E Stefanski;Gary D Myers;Muna Qayed;Barbara De Moerloose;Hidefumi Hiramatsu;Krysta Schlis;Kara L Davis;Paul L Martin;Eneida R Nemecek;Gregory A Yanik;Christina Peters;Andre Baruchel;Nicolas Boissel;Francoise Mechinaud;Adriana Balduzzi;Joerg Krueger;Carl H June;Bruce L Levine;Patricia Wood;Tetiana Taran;Mimi Leung;Karen T Mueller;Yiyun Zhang;Kapildeb Sen;David Lebwohl;Michael A Pulsipher;Stephan A Grupp - The New England journal of medicine (2018)
2. Ibrutinib improves the efficacy of anti-CD19-CAR T-cell therapy in patients with refractory non-Hodgkin lymphoma. - Meijing Liu;Haobin Deng;Juan Mu;Qing Li;Yedi Pu;Yili Jiang;Qi Deng;Zhengzi Qian - Cancer science (2021)
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4. Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. - Nikhil C Munshi;Larry D Anderson;Nina Shah;Deepu Madduri;Jesús Berdeja;Sagar Lonial;Noopur Raje;Yi Lin;David Siegel;Albert Oriol;Philippe Moreau;Ibrahim Yakoub-Agha;Michel Delforge;Michele Cavo;Hermann Einsele;Hartmut Goldschmidt;Katja Weisel;Alessandro Rambaldi;Donna Reece;Fabio Petrocca;Monica Massaro;Jamie N Connarn;Shari Kaiser;Payal Patel;Liping Huang;Timothy B Campbell;Kristen Hege;Jesús San-Miguel - The New England journal of medicine (2021)
5. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. - Frederick L Locke;Armin Ghobadi;Caron A Jacobson;David B Miklos;Lazaros J Lekakis;Olalekan O Oluwole;Yi Lin;Ira Braunschweig;Brian T Hill;John M Timmerman;Abhinav Deol;Patrick M Reagan;Patrick Stiff;Ian W Flinn;Umar Farooq;Andre Goy;Peter A McSweeney;Javier Munoz;Tanya Siddiqi;Julio C Chavez;Alex F Herrera;Nancy L Bartlett;Jeffrey S Wiezorek;Lynn Navale;Allen Xue;Yizhou Jiang;Adrian Bot;John M Rossi;Jenny J Kim;William Y Go;Sattva S Neelapu - The Lancet. Oncology (2019)
6. Feasibility and efficacy of CD19-targeted CAR T cells with concurrent ibrutinib for CLL after ibrutinib failure. - Jordan Gauthier;Alexandre V Hirayama;Janaki Purushe;Kevin A Hay;James Lymp;Daniel H Li;Cecilia C S Yeung;Alyssa Sheih;Barbara S Pender;Reed M Hawkins;Aesha Vakil;Tinh-Doan Phi;Rachel N Steinmetz;Mazyar Shadman;Stanley R Riddell;David G Maloney;Cameron J Turtle - Blood (2020)
7. Outcomes and management of patients with mantle cell lymphoma after progression on brexucabtagene autoleucel therapy. - Preetesh Jain;Loretta Nastoupil;Jason Westin;Hun Ju Lee;Lucy Navsaria;Raphael E Steiner;Sairah Ahmed;Omar Moghrabi;Onyeka Oriabure;Wendy Chen;Maria Badillo;Christopher R Flowers;Michael L Wang - British journal of haematology (2021)
8. New targets for CAR T therapy in hematologic malignancies. - Malvi Savani;Olalekan Oluwole;Bhagirathbhai Dholaria - Best practice & research. Clinical haematology (2021)
9. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. - Sattva S Neelapu;Frederick L Locke;Nancy L Bartlett;Lazaros J Lekakis;David B Miklos;Caron A Jacobson;Ira Braunschweig;Olalekan O Oluwole;Tanya Siddiqi;Yi Lin;John M Timmerman;Patrick J Stiff;Jonathan W Friedberg;Ian W Flinn;Andre Goy;Brian T Hill;Mitchell R Smith;Abhinav Deol;Umar Farooq;Peter McSweeney;Javier Munoz;Irit Avivi;Januario E Castro;Jason R Westin;Julio C Chavez;Armin Ghobadi;Krishna V Komanduri;Ronald Levy;Eric D Jacobsen;Thomas E Witzig;Patrick Reagan;Adrian Bot;John Rossi;Lynn Navale;Yizhou Jiang;Jeff Aycock;Meg Elias;David Chang;Jeff Wiezorek;William Y Go - The New England journal of medicine (2017)
10. Long-term clinical outcomes of tisagenlecleucel in patients with relapsed or refractory aggressive B-cell lymphomas (JULIET): a multicentre, open-label, single-arm, phase 2 study. - Stephen J Schuster;Constantine S Tam;Peter Borchmann;Nina Worel;Joseph P McGuirk;Harald Holte;Edmund K Waller;Samantha Jaglowski;Michael R Bishop;Lloyd E Damon;Stephen Ronan Foley;Jason R Westin;Isabelle Fleury;P Joy Ho;Stephan Mielke;Takanori Teshima;Murali Janakiram;Jing-Mei Hsu;Koji Izutsu;Marie José Kersten;Monalisa Ghosh;Nina Wagner-Johnston;Koji Kato;Paolo Corradini;Marcela Martinez-Prieto;Xia Han;Ranjan Tiwari;Gilles Salles;Richard T Maziarz - The Lancet. Oncology (2021)

Literatures Citing This Work

1. Targeting CD10 on B-Cell Leukemia Using the Universal CAR T-Cell Platform (UniCAR). - Nicola Mitwasi;Claudia Arndt;Liliana R Loureiro;Alexandra Kegler;Frederick Fasslrinner;Nicole Berndt;Ralf Bergmann;Vaclav Hořejší;Claudia Rössig;Michael Bachmann;Anja Feldmann - International journal of molecular sciences (2022)
2. Overview of approved CAR-T therapies, ongoing clinical trials, and its impact on clinical practice. - Salyka Sengsayadeth;Bipin N Savani;Olalekan Oluwole;Bhagirathbhai Dholaria - EJHaem (2022)
3. Chimeric antigen receptor-T cell therapies: The changing landscape. - Salyka M Sengsayadeth;Bhagirathbhai R Dholaria;Bipin N Savani;Olalekan O Oluwole - EJHaem (2022)
4. Current updates on generations, approvals, and clinical trials of CAR T-cell therapy. - Tadesse Asmamaw Dejenie;Markeshaw Tiruneh G/Medhin;Gashaw Dessie Terefe;Fitalew Tadele Admasu;Wondwossen Wale Tesega;Endeshaw Chekol Abebe - Human vaccines & immunotherapeutics (2022)
5. Mast Cells and Dendritic Cells as Cellular Immune Checkpoints in Immunotherapy of Solid Tumors. - Katerina Kalkusova;Sindija Smite;Elea Darras;Pavla Taborska;Dmitry Stakheev;Luca Vannucci;Jirina Bartunkova;Daniel Smrz - International journal of molecular sciences (2022)
6. A digital platform for the design of patient-centric supply chains. - Niki Triantafyllou;Andrea Bernardi;Matthew Lakelin;Nilay Shah;Maria M Papathanasiou - Scientific reports (2022)
7. Recent Advances in the Development of Anti-FLT3 CAR T-Cell Therapies for Treatment of AML. - Maya Graham Pedersen;Bjarne Kuno Møller;Rasmus O Bak - Biomedicines (2022)
8. Activation of distinct antiviral T-cell immunity: A comparison of bi- and trispecific T-cell engager antibodies with a chimeric antigen receptor targeting HBV envelope proteins. - Bilge Debelec-Butuner;Oliver Quitt;Sophia Schreiber;Frank Momburg;Karin Wisskirchen;Ulrike Protzer - Frontiers in immunology (2022)
9. DNA and mRNA Vaccines for Chronic Viral Infections and Cancer: Rationale, Mechanisms, and Progress. - Margaret A Liu - Cancers (2022)
10. Joining Forces for Cancer Treatment: From “TCR versus CAR” to “TCR and CAR”. - Karin Teppert;Xueting Wang;Kathleen Anders;César Evaristo;Dominik Lock;Annette Künkele - International journal of molecular sciences (2022)

… (61 more literatures)

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