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Curated Papers > Highly Cited Authoritative Literature on "CAR-T Therapy"

CAR-T cell therapy: current limitations and potential strategies. ​

Literature Information ​

DOI10.1038/s41408-021-00459-7
PMID33824268
JournalBlood cancer journal
Impact Factor11.6
JCR QuartileQ1
Publication Year2021
Times Cited1221
KeywordsCAR-T cell therapy, tumor microenvironment, anti-tumor activity
Literature TypeJournal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review
ISSN2044-5385
Pages69
Issue11(4)
AuthorsRobert C Sterner, Rosalie M Sterner

TL;DR ​

This review highlights the revolutionary potential of chimeric antigen receptor (CAR)-T cell therapy in treating cancers, particularly B cell leukemia and lymphoma, while addressing significant challenges such as toxicities, limited anti-tumor activity, and interactions with the tumor microenvironment that hinder its efficacy in solid tumors and hematological malignancies. The authors emphasize the need for innovative engineering strategies to enhance CAR-T cell function, improve clinical outcomes, and mitigate associated risks in cancer treatment.

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CAR-T cell therapy · tumor microenvironment · anti-tumor activity

Abstract ​

Chimeric antigen receptor (CAR)-T cell therapy is a revolutionary new pillar in cancer treatment. Although treatment with CAR-T cells has produced remarkable clinical responses with certain subsets of B cell leukemia or lymphoma, many challenges limit the therapeutic efficacy of CAR-T cells in solid tumors and hematological malignancies. Barriers to effective CAR-T cell therapy include severe life-threatening toxicities, modest anti-tumor activity, antigen escape, restricted trafficking, and limited tumor infiltration. In addition, the host and tumor microenvironment interactions with CAR-T cells critically alter CAR-T cell function. Furthermore, a complex workforce is required to develop and implement these treatments. In order to overcome these significant challenges, innovative strategies and approaches to engineer more powerful CAR-T cells with improved anti-tumor activity and decreased toxicity are necessary. In this review, we discuss recent innovations in CAR-T cell engineering to improve clinical efficacy in both hematological malignancy and solid tumors and strategies to overcome limitations of CAR-T cell therapy in both hematological malignancy and solid tumors.

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Primary Questions Addressed ​

  1. What specific engineering innovations have shown promise in enhancing the efficacy of CAR-T cell therapy for solid tumors?
  2. How do the interactions between CAR-T cells and the tumor microenvironment affect the overall success of the therapy?
  3. What are the latest strategies being researched to minimize the toxicities associated with CAR-T cell therapy?
  4. In what ways can the complexity of the workforce involved in CAR-T cell therapy development be streamlined to improve treatment outcomes?
  5. How does antigen escape impact the long-term effectiveness of CAR-T cell therapy in hematological malignancies, and what strategies are being proposed to address this issue?

Key Findings ​

Research Background and Purpose ​

Chimeric antigen receptor (CAR)-T cell therapy has emerged as a transformative approach in cancer treatment, particularly for certain B cell malignancies. However, its effectiveness is limited by several challenges, including severe toxicities, modest anti-tumor activity, antigen escape, and difficulties in tumor infiltration. This review aims to discuss these limitations and explore innovative strategies to enhance CAR-T cell efficacy against both hematological malignancies and solid tumors.

Main Methods/Materials/Experimental Design ​

The review synthesizes recent advancements in CAR-T cell engineering and therapeutic strategies. Key components of CAR design are discussed, including the antigen-binding domain, hinge region, transmembrane domain, and intracellular signaling domains. The authors outline various approaches to improve CAR-T cell function, focusing on overcoming the following limitations:

  1. Antigen Escape: Targeting multiple antigens using dual or tandem CARs.
  2. On-target Off-tumor Effects: Targeting tumor-restricted post-translational modifications.
  3. CAR-T Cell Trafficking and Tumor Infiltration: Exploring local administration and expressing chemokine receptors on CAR-T cells.
  4. Immunosuppressive Microenvironment: Combining CAR-T cells with checkpoint blockade therapies.
  5. CAR-T Cell-associated Toxicities: Engineering CAR structures to reduce toxicity.
Mermaid diagram

Key Results and Findings ​

  1. Antigen Escape: The review highlights that antigen loss is a common mechanism of resistance in CAR-T therapies. Strategies such as dual-target CARs have shown promise in clinical trials, improving response rates.
  2. On-target Off-tumor Effects: Targeting antigens that are restricted to tumor cells can minimize toxicity to normal tissues, which is crucial for improving patient safety.
  3. Tumor Infiltration: Local administration of CAR-T cells and engineering them to express chemokine receptors can significantly enhance their ability to infiltrate tumors.
  4. Immunosuppressive Microenvironment: Combining CAR-T cell therapy with immune checkpoint inhibitors has demonstrated improved outcomes in both hematological and solid tumors.
  5. Toxicities: Strategies to modify CAR structure, including altering the affinity of antigen-binding domains and employing "off-switches," have been proposed to mitigate adverse effects.

Main Conclusions/Significance/Innovativeness ​

The review underscores the revolutionary potential of CAR-T cell therapy while also acknowledging the significant hurdles that remain. Innovations in CAR engineering and combination therapies are essential to improve clinical outcomes and expand the applicability of CAR-T cells beyond hematological malignancies to solid tumors. This work emphasizes the importance of a multidisciplinary approach in addressing the complexities of CAR-T therapy.

Research Limitations and Future Directions ​

The review identifies several limitations, including the complexity of CAR-T cell design and the need for a trained workforce to implement these therapies effectively. Future research should focus on:

  • Developing more effective dual-targeting strategies to prevent antigen escape.
  • Enhancing CAR-T cell infiltration in solid tumors.
  • Exploring combination therapies to counteract immunosuppressive microenvironments.
  • Further engineering of CAR constructs to minimize toxicity while maintaining efficacy.

This comprehensive approach is vital for advancing CAR-T cell therapy into a broader range of cancers and improving patient outcomes.

References ​

  1. CAR T cell immunotherapy for human cancer. - Carl H June;Roddy S O'Connor;Omkar U Kawalekar;Saba Ghassemi;Michael C Milone - Science (New York, N.Y.) (2018)
  2. The basic principles of chimeric antigen receptor design. - Michel Sadelain;Renier Brentjens;Isabelle Rivière - Cancer discovery (2013)
  3. 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)
  4. 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)
  5. Chimeric Antigen Receptor T Cells in Refractory B-Cell Lymphomas. - Stephen J Schuster;Jakub Svoboda;Elise A Chong;Sunita D Nasta;Anthony R Mato;Özlem Anak;Jennifer L Brogdon;Iulian Pruteanu-Malinici;Vijay Bhoj;Daniel Landsburg;Mariusz Wasik;Bruce L Levine;Simon F Lacey;Jan J Melenhorst;David L Porter;Carl H June - The New England journal of medicine (2017)
  6. A Graduate-Level Interdisciplinary Curriculum in CAR-T Cell Therapy. - Rosalie M Sterner;Karen E Hedin;Richard E Hayden;Grzegorz S Nowakowski;Saranya P Wyles;Alexandra J Greenberg-Worisek;Andre Terzic;Saad S Kenderian - Mayo Clinic proceedings. Innovations, quality & outcomes (2020)
  7. The association of heavy and light chain variable domains in antibodies: implications for antigen specificity. - Anna Chailyan;Paolo Marcatili;Anna Tramontano - The FEBS journal (2011)
  8. Affinity-Tuned ErbB2 or EGFR Chimeric Antigen Receptor T Cells Exhibit an Increased Therapeutic Index against Tumors in Mice. - Xiaojun Liu;Shuguang Jiang;Chongyun Fang;Shiyu Yang;Devvora Olalere;Edward C Pequignot;Alexandria P Cogdill;Na Li;Melissa Ramones;Brian Granda;Li Zhou;Andreas Loew;Regina M Young;Carl H June;Yangbing Zhao - Cancer research (2015)
  9. Tuning Sensitivity of CAR to EGFR Density Limits Recognition of Normal Tissue While Maintaining Potent Antitumor Activity. - Hillary G Caruso;Lenka V Hurton;Amer Najjar;David Rushworth;Sonny Ang;Simon Olivares;Tiejuan Mi;Kirsten Switzer;Harjeet Singh;Helen Huls;Dean A Lee;Amy B Heimberger;Richard E Champlin;Laurence J N Cooper - Cancer research (2015)
  10. The nonsignaling extracellular spacer domain of chimeric antigen receptors is decisive for in vivo antitumor activity. - Michael Hudecek;Daniel Sommermeyer;Paula L Kosasih;Anne Silva-Benedict;Lingfeng Liu;Christoph Rader;Michael C Jensen;Stanley R Riddell - Cancer immunology research (2015)

Literatures Citing This Work ​

  1. Adoptive Natural Killer Cell Immunotherapy for Canine Osteosarcoma. - William C Kisseberth;Dean A Lee - Frontiers in veterinary science (2021)
  2. CAR T cells: Building on the CD19 paradigm. - Anat Globerson Levin;Isabelle Rivière;Zelig Eshhar;Michel Sadelain - European journal of immunology (2021)
  3. The "Magic Bullet" Is Here? Cell-Based Immunotherapies for Hematological Malignancies in the Twilight of the Chemotherapy Era. - Nina Miazek-Zapala;Aleksander Slusarczyk;Aleksandra Kusowska;Piotr Zapala;Matylda Kubacz;Magdalena Winiarska;Malgorzata Bobrowicz - Cells (2021)
  4. In vitro selection of DNA aptamers against human osteosarcoma. - Khaliunsarnai Tsogtbaatar;Diana A Sousa;Debora Ferreira;Atakan Tevlek;Halil Murat Aydın;Eda Çelik;Ligia Rodrigues - Investigational new drugs (2022)
  5. The Promise of Personalized TCR-Based Cellular Immunotherapy for Cancer Patients. - Marion Arnaud;Sara Bobisse;Johanna Chiffelle;Alexandre Harari - Frontiers in immunology (2021)
  6. Structure-Dependent Stability of Lipid-Based Polymer Amphiphiles Inserted on Erythrocytes. - Chunsong Yu;Myunggi An;Meng Li;Charles Manke;Haipeng Liu - Membranes (2021)
  7. Nanoparticles Targeting Innate Immune Cells in Tumor Microenvironment. - Hochung Jang;Eun Hye Kim;Sung-Gil Chi;Sun Hwa Kim;Yoosoo Yang - International journal of molecular sciences (2021)
  8. Ubiquitination in T-Cell Activation and Checkpoint Inhibition: New Avenues for Targeted Cancer Immunotherapy. - Shubhangi Gavali;Jianing Liu;Xinyi Li;Magdalena Paolino - International journal of molecular sciences (2021)
  9. Improving CAR T-Cell Persistence. - Violena Pietrobon;Lauren Anne Todd;Anghsumala Goswami;Ofir Stefanson;Zhifen Yang;Francesco Marincola - International journal of molecular sciences (2021)
  10. Implications of Antigen Selection on T Cell-Based Immunotherapy. - Faye A Camp;Jill E Slansky - Pharmaceuticals (Basel, Switzerland) (2021)

... (1211 more literatures)

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