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

Strategies to overcome tumour relapse caused by antigen escape after CAR T therapy. ​

Literature Information ​

DOI10.1186/s12943-025-02334-6
PMID40289115
JournalMolecular cancer
Impact Factor33.9
JCR QuartileQ1
Publication Year2025
Times Cited3
KeywordsAntigen loss/downregulation, Antigen/epitope spreading, Chimeric antigen receptor, Tumour heterogeneity
Literature TypeJournal Article, Review
ISSN1476-4598
Pages126
Issue24(1)
AuthorsYufei Lu, Fu Zhao

TL;DR ​

This review highlights the challenges of CAR T cell therapy in solid tumors, particularly the issues of tumor antigen heterogeneity and acquired resistance leading to immune escape and relapse. It emphasizes the need for innovative strategies that enhance CAR T cell interactions with the host immune system, aiming to induce broader antitumor responses through antigen spreading to address the limitations of current monospecific therapies.

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Antigen loss/downregulation · Antigen/epitope spreading · Chimeric antigen receptor · Tumour heterogeneity

Abstract ​

Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of B cell and plasma cell malignancies, and numerous promising targets against solid tumours are being explored. Despite their initial therapeutic success in hematological cancers, relapse occurs in a significant fraction of patients, highlighting the need for further innovations in advancing CAR T cell therapy. Tumour antigen heterogeneity and acquired tumour resistance leading to antigen escape (antigen loss/downregulation) have emerged as a crucial factor contributing to immune escape and CAR T cell resistance, particularly in the case of solid tumours with only limited success achieved to date. In this review, we discuss mechanisms of tumour relapse in CAR T cell therapy and the promising strategies that are under development to overcome multiple resistance mechanisms, thereby reducing outgrowth of antigen escape variants. Specifically, we emphasize the importance of designing clinical translational strategies to enhance CAR T cell crosstalk with host immune cells, eliciting endogenous antitumour immune responses through antigen/epitope spreading, which offers a genuine solution to the limitations of targeting tumour antigen heterogeneity in solid tumours with monospecific T cell therapies.

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Primary Questions Addressed ​

  1. What are the current innovative approaches being researched to enhance the efficacy of CAR T cell therapy in solid tumours?
  2. How does tumour antigen heterogeneity specifically contribute to the challenge of CAR T cell therapy effectiveness?
  3. What role do host immune cells play in the development of resistance to CAR T therapy, and how can their interactions be optimized?
  4. In what ways can antigen/epitope spreading be leveraged to improve outcomes in patients experiencing antigen escape after CAR T therapy?
  5. What clinical trials are currently underway to test new strategies aimed at preventing tumour relapse in CAR T therapy patients?

Key Findings ​

Research Background and Objectives ​

Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment landscape for B cell malignancies, showing promising results particularly in hematological cancers. However, a significant number of patients experience relapse due to tumor antigen escape, which is characterized by the loss or downregulation of targeted antigens. This review aims to explore the mechanisms underlying tumor relapse post-CAR T therapy and to discuss emerging strategies to mitigate antigen escape, thereby enhancing the efficacy of CAR T cell treatments, especially for solid tumors.

Main Methods/Materials/Experimental Design ​

The review synthesizes findings from various studies on CAR T therapy, focusing on:

  • Mechanisms of antigen escape in tumors.
  • Strategies to overcome antigen downregulation and loss.
  • Enhancements in CAR T cell design and function.

The following flowchart illustrates the strategies discussed:

Mermaid diagram

Key Results and Findings ​

  1. Antigen Escape Mechanisms: Tumors evade CAR T cell detection through mechanisms such as loss of target antigens, mutations, and downregulation of antigen expression.
  2. Strategies for Overcoming Antigen Downregulation:
    • Increasing Antigen Expression: Pharmacologic agents and epigenetic modulators can enhance surface antigen levels, improving CAR T cell recognition.
    • Sensitizing CAR T Cells: Innovations like chimeric co-stimulatory receptors and optimized CAR designs increase CAR T cell efficacy against low antigen density.
    • Dual and Multi-Targeted CAR T Cells: Targeting multiple antigens reduces the risk of tumor escape.
    • Inducing Epitope Spreading: Promoting interactions between CAR T cells and antigen-presenting cells (APCs) can broaden immune responses against heterogeneous tumor antigens.

Main Conclusions/Significance/Innovativeness ​

The review underscores the necessity of developing multifaceted strategies to enhance CAR T cell therapy's effectiveness against tumors exhibiting antigen escape. By fostering endogenous immune responses and improving CAR T cell design, it is possible to tackle the challenges posed by tumor heterogeneity. The integration of various therapeutic modalities, including immune checkpoint inhibitors, vaccines, and cytokines, alongside CAR T therapy, represents a promising frontier in cancer treatment.

Research Limitations and Future Directions ​

While the review provides a comprehensive overview of current strategies, several limitations remain:

  • Many strategies are still in preclinical stages or early clinical trials, necessitating further validation.
  • The complexity of tumor microenvironments and patient-specific factors may affect the generalizability of findings.

Future research should focus on:

  • Optimizing combination therapies that synergize CAR T cells with other immunotherapeutic approaches.
  • Developing biomarkers to predict which patients are most likely to benefit from specific CAR T cell therapies.
  • Exploring novel targets and mechanisms to further broaden the scope of CAR T therapy in solid tumors.

References ​

  1. Vaccine-boosted CAR T crosstalk with host immunity to reject tumors with antigen heterogeneity. - Leyuan Ma;Alexander Hostetler;Duncan M Morgan;Laura Maiorino;Ina Sulkaj;Charles A Whittaker;Alexandra Neeser;Ivan Susin Pires;Parisa Yousefpour;Justin Gregory;Kashif Qureshi;Jonathan Dye;Wuhbet Abraham;Heikyung Suh;Na Li;J Christopher Love;Darrell J Irvine - Cell (2023)
  2. Correction for Davenport et al., Chimeric antigen receptor T cells form nonclassical and potent immune synapses driving rapid cytotoxicity. - Proceedings of the National Academy of Sciences of the United States of America (2019)
  3. 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)
  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. 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)
  6. Determinant spreading and the dynamics of the autoimmune T-cell repertoire. - P V Lehmann;E E Sercarz;T Forsthuber;C M Dayan;G Gammon - Immunology today (1993)
  7. Transgenic Expression of IL15 Improves Antiglioma Activity of IL13Rα2-CAR T Cells but Results in Antigen Loss Variants. - Giedre Krenciute;Brooke L Prinzing;Zhongzhen Yi;Meng-Fen Wu;Hao Liu;Gianpietro Dotti;Irina V Balyasnikova;Stephen Gottschalk - Cancer immunology research (2017)
  8. 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)
  9. Convergence of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 Immunotherapy. - Elena Sotillo;David M Barrett;Kathryn L Black;Asen Bagashev;Derek Oldridge;Glendon Wu;Robyn Sussman;Claudia Lanauze;Marco Ruella;Matthew R Gazzara;Nicole M Martinez;Colleen T Harrington;Elaine Y Chung;Jessica Perazzelli;Ted J Hofmann;Shannon L Maude;Pichai Raman;Alejandro Barrera;Saar Gill;Simon F Lacey;Jan J Melenhorst;David Allman;Elad Jacoby;Terry Fry;Crystal Mackall;Yoseph Barash;Kristen W Lynch;John M Maris;Stephan A Grupp;Andrei Thomas-Tikhonenko - Cancer discovery (2015)
  10. CLDN6-specific CAR-T cells plus amplifying RNA vaccine in relapsed or refractory solid tumors: the phase 1 BNT211-01 trial. - Andreas Mackensen;John B A G Haanen;Christian Koenecke;Winfried Alsdorf;Eva Wagner-Drouet;Peter Borchmann;Daniel Heudobler;Barbara Ferstl;Sebastian Klobuch;Carsten Bokemeyer;Alexander Desuki;Florian Lüke;Nadine Kutsch;Fabian Müller;Eveline Smit;Peter Hillemanns;Panagiotis Karagiannis;Erol Wiegert;Ying He;Thang Ho;Qing Kang-Fortner;Anna Melissa Schlitter;Catrine Schulz-Eying;Andrew Finlayson;Carina Flemmig;Klaus Kühlcke;Liane Preußner;Benjamin Rengstl;Özlem Türeci;Uğur Şahin - Nature medicine (2023)

Literatures Citing This Work ​

  1. Targets for CAR Therapy in Multiple Myeloma. - Olga A Bezborodova;Galina V Trunova;Elena R Nemtsova;Varvara A Khokhlova;Julia B Venediktova;Natalia B Morozova;Maria S Vorontsova;Anna D Plyutinskaya;Elena P Zharova;Peter V Shegai;Andrey D Kaprin - International journal of molecular sciences (2025)
  2. Tracing the development of CAR-T cell design: from concept to next-generation platforms. - Ahdab A Alsaieedi;Kawther A Zaher - Frontiers in immunology (2025)
  3. Advancing CAR T-Cell Therapy in Solid Tumors: Current Landscape and Future Directions. - Saeed Rafii;Deborah Mukherji;Ashok Sebastian Komaranchath;Charbel Khalil;Faryal Iqbal;Siddig Ibrahim Abdelwahab;Amin Abyad;Ahmad Y Abuhelwa;Lakshmikanth Gandikota;Humaid O Al-Shamsi - Cancers (2025)

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