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Curated Papers > High-impact authoritative literature on "CAR-T therapy"

Advances in Universal CAR-T Cell Therapy. ​

Literature Information ​

DOI10.3389/fimmu.2021.744823
PMID34691052
JournalFrontiers in immunology
Impact Factor5.9
JCR QuartileQ1
Publication Year2021
Times Cited102
KeywordsCRISPR/Cas9, cellular immunotherapy, chimeric antigen receptor T cell therapy, gene editing, universal chimeric antigen receptor T cell therapy
Literature TypeJournal Article, Research Support, Non-U.S. Gov't, Review
ISSN1664-3224
Pages744823
Issue12()
AuthorsHaolong Lin, Jiali Cheng, Wei Mu, Jianfeng Zhou, Li Zhu

TL;DR ​

This paper reviews the advancements and challenges of chimeric antigen receptor T (CAR-T) cell therapy, particularly highlighting the potential of universal CAR-T (UCAR-T) cell therapy to address issues such as high costs and limited cell sources associated with traditional autologous CAR-T therapies. By comparing UCAR-T with original CAR-T, the authors emphasize its promise in enhancing safety and efficacy, while also considering the role of other immune cells as complementary therapies.

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CRISPR/Cas9 · cellular immunotherapy · chimeric antigen receptor T cell therapy · gene editing · universal chimeric antigen receptor T cell therapy

Abstract ​

Chimeric antigen receptor T (CAR-T) cell therapy achieved extraordinary achievements results in antitumor treatments, especially against hematological malignancies, where it leads to remarkable, long-term antineoplastic effects with higher target specificity. Nevertheless, some limitations persist in autologous CAR-T cell therapy, such as high costs, long manufacturing periods, and restricted cell sources. The development of a universal CAR-T (UCAR-T) cell therapy is an attractive breakthrough point that may overcome most of these drawbacks. Here, we review the progress and challenges in CAR-T cell therapy, especially focusing on comprehensive comparison in UCAR-T cell therapy to original CAR-T cell therapy. Furthermore, we summarize the developments and concerns about the safety and efficiency of UCAR-T cell therapy. Finally, we address other immune cells, which might be promising candidates as a complement for UCAR-T cells. Through a detailed overview, we describe the current landscape and explore the prospect of UCAR-T cell therapy.

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Primary Questions Addressed ​

  1. What are the specific challenges that UCAR-T cell therapy faces compared to traditional CAR-T therapies?
  2. How does the safety profile of UCAR-T cell therapy compare to that of autologous CAR-T cell therapy?
  3. In what ways could other immune cells enhance the effectiveness of UCAR-T cell therapy?
  4. What advancements in manufacturing processes are being explored to reduce the costs and time associated with UCAR-T cell therapy?
  5. How do the long-term outcomes of patients treated with UCAR-T cell therapy differ from those treated with conventional CAR-T therapies?

Key Findings ​

Research Background and Objectives ​

Chimeric antigen receptor T (CAR-T) cell therapy has revolutionized the treatment of hematological malignancies, offering significant long-term antitumor effects. However, challenges such as high costs, lengthy manufacturing times, and limited cell sources persist. This review discusses the advancements and challenges of universal CAR-T (UCAR-T) cell therapy, which aims to address these limitations and improve the efficacy and safety of CAR-T treatments.

Main Methods/Materials/Experimental Design ​

The authors conducted a comprehensive review of the existing literature on CAR-T and UCAR-T therapies, comparing their methodologies, safety profiles, and clinical outcomes. They also examined various gene-editing technologies used in UCAR-T development.

Mermaid diagram

Key Results and Findings ​

  • Efficacy of UCAR-T Cells: UCAR-T cells have shown promise in clinical trials, with significant complete response rates observed in patients with hematological malignancies.
  • Safety Concerns: While UCAR-T cells can reduce some adverse effects like graft-versus-host disease (GVHD), risks such as cytokine release syndrome (CRS) and neurotoxicity remain.
  • Gene Editing Innovations: Technologies like CRISPR/Cas9 and TALEN are being employed to enhance the specificity and reduce the immunogenicity of UCAR-T cells.

Main Conclusions/Significance/Innovation ​

UCAR-T cell therapy represents a significant advancement in the field of immunotherapy, potentially offering a more accessible and effective treatment option for cancer patients. The development of universal, off-the-shelf CAR-T cells could transform patient care by reducing manufacturing times and costs. Innovations in gene editing and modular CAR designs are crucial for improving the efficacy and safety of these therapies.

Research Limitations and Future Directions ​

  • Limitations: The review acknowledges the ongoing challenges in achieving optimal persistence and expansion of UCAR-T cells in vivo, as well as the complexities associated with allogeneic cell therapies.
  • Future Directions: Continued research into gene editing, alternative cell sources (such as NK and gdT cells), and the modularization of CAR structures is essential. There is also a need for larger clinical trials to better understand the long-term effects and potential of UCAR-T therapies in both hematological and solid tumors.
AspectAutologous CAR-T TherapyUniversal CAR-T Therapy
Cell SourcePatient-derivedAllogeneic (from healthy donors)
Manufacturing CostHighLower potential cost
Safety RisksCRS, neurotoxicityCRS, neurotoxicity, potential GVHD
PersistenceLongerShorter, ongoing research needed
Gene EditingLimitedAdvanced (CRISPR/Cas9, TALEN)

In conclusion, the review emphasizes the transformative potential of UCAR-T cell therapy in oncology, paving the way for future advancements in cancer treatment.

References ​

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  2. The promise and potential pitfalls of chimeric antigen receptors. - Michel Sadelain;Renier Brentjens;Isabelle Rivière - Current opinion in immunology (2009)
  3. TRUCKs: the fourth generation of CARs. - Markus Chmielewski;Hinrich Abken - Expert opinion on biological therapy (2015)
  4. A Multidrug-resistant Engineered CAR T Cell for Allogeneic Combination Immunotherapy. - Julien Valton;Valérie Guyot;Alan Marechal;Jean-Marie Filhol;Alexandre Juillerat;Aymeric Duclert;Philippe Duchateau;Laurent Poirot - Molecular therapy : the journal of the American Society of Gene Therapy (2015)
  5. Allogeneic CAR Cell Therapy-More Than a Pipe Dream. - Kenneth J Caldwell;Stephen Gottschalk;Aimee C Talleur - Frontiers in immunology (2020)
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  7. Proof of concept for a rapidly switchable universal CAR-T platform with UniCAR-T-CD123 in relapsed/refractory AML. - Martin Wermke;Sabrina Kraus;Armin Ehninger;Ralf C Bargou;Maria-Elisabeth Goebeler;Jan Moritz Middeke;Carla Kreissig;Malte von Bonin;Jan Koedam;Michael Pehl;Martin Bornhäuser;Hermann Einsele;Gerhard Ehninger;Marc Cartellieri - Blood (2021)
  8. Genome-edited, donor-derived allogeneic anti-CD19 chimeric antigen receptor T cells in paediatric and adult B-cell acute lymphoblastic leukaemia: results of two phase 1 studies. - Reuben Benjamin;Charlotte Graham;Deborah Yallop;Agnieszka Jozwik;Oana C Mirci-Danicar;Giovanna Lucchini;Danielle Pinner;Nitin Jain;Hagop Kantarjian;Nicolas Boissel;Marcela V Maus;Matthew J Frigault;André Baruchel;Mohamad Mohty;Athos Gianella-Borradori;Florence Binlich;Svetlana Balandraud;Fabien Vitry;Elisabeth Thomas;Anne Philippe;Sylvain Fouliard;Sandra Dupouy;Ibtissam Marchiq;Maria Almena-Carrasco;Nicolas Ferry;Sylvain Arnould;Cyril Konto;Paul Veys;Waseem Qasim; - Lancet (London, England) (2020)
  9. Induction of resistance to chimeric antigen receptor T cell therapy by transduction of a single leukemic B cell. - Marco Ruella;Jun Xu;David M Barrett;Joseph A Fraietta;Tyler J Reich;David E Ambrose;Michael Klichinsky;Olga Shestova;Prachi R Patel;Irina Kulikovskaya;Farzana Nazimuddin;Vijay G Bhoj;Elena J Orlando;Terry J Fry;Hans Bitter;Shannon L Maude;Bruce L Levine;Christopher L Nobles;Frederic D Bushman;Regina M Young;John Scholler;Saar I Gill;Carl H June;Stephan A Grupp;Simon F Lacey;J Joseph Melenhorst - Nature medicine (2018)
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Literatures Citing This Work ​

  1. Targeting BCMA to Treat Multiple Myeloma: Updates From the 2021 ASH Annual Meeting. - Ruiting Guo;Wenyi Lu;Yi Zhang;Xinping Cao;Xin Jin;Mingfeng Zhao - Frontiers in immunology (2022)
  2. Donor T cells for CAR T cell therapy. - Tiffany C Y Tang;Ning Xu;Robert Nordon;Michelle Haber;Kenneth Micklethwaite;Alla Dolnikov - Biomarker research (2022)
  3. Hurdles to breakthrough in CAR T cell therapy of solid tumors. - Faroogh Marofi;Harun Achmad;Dmitry Bokov;Walid Kamal Abdelbasset;Zeid Alsadoon;Supat Chupradit;Wanich Suksatan;Siavash Shariatzadeh;Zahra Hasanpoor;Mahboubeh Yazdanifar;Navid Shomali;Farhad Motavalli Khiavi - Stem cell research & therapy (2022)
  4. A Bibliometric and Knowledge-Map Analysis of CAR-T Cells From 2009 to 2021. - Lele Miao;Juan Zhang;Zhengchao Zhang;Song Wang;Futian Tang;Muzhou Teng;Yumin Li - Frontiers in immunology (2022)
  5. Pharmacotherapeutic Treatment of Glioblastoma: Where Are We to Date? - Lidia Gatto;Vincenzo Di Nunno;Enrico Franceschi;Alicia Tosoni;Stefania Bartolini;Alba Ariela Brandes - Drugs (2022)
  6. Claudin18.2 is a novel molecular biomarker for tumor-targeted immunotherapy. - Weijie Cao;Haizhou Xing;Yingmei Li;Wenliang Tian;Yongping Song;Zhongxing Jiang;Jifeng Yu - Biomarker research (2022)
  7. Efficacy and safety of CD19 CAR-T cell therapy for acute lymphoblastic leukemia patients relapsed after allogeneic hematopoietic stem cell transplantation. - Xing-Yu Cao;Jing-Jing Li;Pei-Hua Lu;Kai-Yan Liu - International journal of hematology (2022)
  8. Influence of Culture Conditions on Ex Vivo Expansion of T Lymphocytes and Their Function for Therapy: Current Insights and Open Questions. - Harish Sudarsanam;Raymund Buhmann;Reinhard Henschler - Frontiers in bioengineering and biotechnology (2022)
  9. Immunogenic Cell Death Enhances Immunotherapy of Diffuse Intrinsic Pontine Glioma: From Preclinical to Clinical Studies. - Guohao Liu;Yanmei Qiu;Po Zhang;Zirong Chen;Sui Chen;Weida Huang;Baofeng Wang;Xingjiang Yu;Dongsheng Guo - Pharmaceutics (2022)
  10. Current progress in CAR-T cell therapy for tumor treatment. - Lei Chen;Ting Xie;Bing Wei;Da-Lin Di - Oncology letters (2022)

... (92 more literatures)

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