Challenges in the preclinical design and assessment of CAR-T cells
The advent of immunotherapy in the treatment of cancer has opened a new dimension in the management of this complex multifaceted disease, bringing hope to many patients whose tumors have failed to respond to conventional therapies. The adoptive T cell therapy has since been extended to the treatment...
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Frontiers Media S.A.
2025-08-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1564998/full |
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| author | Radu Tomai Radu Tomai Javier De Las Rivas Bogdan Fetica Bogdan Fetica Rui Bergantim Rui Bergantim Rui Bergantim Rui Bergantim Brankica Filipic Zarko Gagic Katarina Nikolic Diana Gulei Diana Gulei David Kegyes David Kegyes Madalina Nistor Madalina Nistor Ximena Maria Muresan Ximena Maria Muresan Diana Cenariu Diana Cenariu Richard Feder Richard Feder Mariana Pavel-Tanasa Andrei Cianga Adrian Bogdan Tigu Adrian Bogdan Tigu Raluca Munteanu Raluca Munteanu Alina Tanase Hermann Einsele Hermann Einsele Hermann Einsele Ciprian Tomuleasa Ciprian Tomuleasa |
| author_facet | Radu Tomai Radu Tomai Javier De Las Rivas Bogdan Fetica Bogdan Fetica Rui Bergantim Rui Bergantim Rui Bergantim Rui Bergantim Brankica Filipic Zarko Gagic Katarina Nikolic Diana Gulei Diana Gulei David Kegyes David Kegyes Madalina Nistor Madalina Nistor Ximena Maria Muresan Ximena Maria Muresan Diana Cenariu Diana Cenariu Richard Feder Richard Feder Mariana Pavel-Tanasa Andrei Cianga Adrian Bogdan Tigu Adrian Bogdan Tigu Raluca Munteanu Raluca Munteanu Alina Tanase Hermann Einsele Hermann Einsele Hermann Einsele Ciprian Tomuleasa Ciprian Tomuleasa |
| author_sort | Radu Tomai |
| collection | DOAJ |
| description | The advent of immunotherapy in the treatment of cancer has opened a new dimension in the management of this complex multifaceted disease, bringing hope to many patients whose tumors have failed to respond to conventional therapies. The adoptive T cell therapy has since been extended to the treatment of several hematologic malignancies, initially in relapsed settings and more recently at the forefront of treatment due to high response rates. Despite exciting initial results, the preclinical antitumor effects of the first long-term studies show that CAR (Chimeric Antigen Receptor)-T cells have been slow to translate to the clinical setting, with early clinical trials showing suboptimal responses. The main reasons for the limited clinical performance seemed to be related to the low activation and short persistence of CAR-T cells. Thus, began a journey to improve the initial CAR structure, leading to the development of more complex constructs, which are grouped into five CAR generations. In this review, we describe the main challenges and potential solutions for the evaluation of CAR T-cell-based therapies in the preclinical setting. |
| format | Article |
| id | doaj-art-49e94a953b2649e0ad8a7a877ecab390 |
| institution | DOAJ |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-49e94a953b2649e0ad8a7a877ecab3902025-08-20T02:55:09ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-08-011610.3389/fimmu.2025.15649981564998Challenges in the preclinical design and assessment of CAR-T cellsRadu Tomai0Radu Tomai1Javier De Las Rivas2Bogdan Fetica3Bogdan Fetica4Rui Bergantim5Rui Bergantim6Rui Bergantim7Rui Bergantim8Brankica Filipic9Zarko Gagic10Katarina Nikolic11Diana Gulei12Diana Gulei13David Kegyes14David Kegyes15Madalina Nistor16Madalina Nistor17Ximena Maria Muresan18Ximena Maria Muresan19Diana Cenariu20Diana Cenariu21Richard Feder22Richard Feder23Mariana Pavel-Tanasa24Andrei Cianga25Adrian Bogdan Tigu26Adrian Bogdan Tigu27Raluca Munteanu28Raluca Munteanu29Alina Tanase30Hermann Einsele31Hermann Einsele32Hermann Einsele33Ciprian Tomuleasa34Ciprian Tomuleasa35Department of Hematology - Medfuture Institute for Biomedical Research, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, RomaniaDepartment of Personalized Medicine and Rare Diseases - Medfuture Institute for Biomedical Research, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, RomaniaBioinformatics and Functional Genomics Group, Cancer Research Center (CiC-IBMCC, CSIC/USAL), Consejo Superior de Investigaciones Cientificas (CSIC) & University of Salamanca (USAL), Salamanca, SpainDepartment of Hematology - Medfuture Institute for Biomedical Research, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, RomaniaDepartment of Personalized Medicine and Rare Diseases - Medfuture Institute for Biomedical Research, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, RomaniaHematology Department, University Hospital Sao Joao Porto São João (ULS), Porto, Portugali3S Instituto de Investigação e Inovação em Saúde University of Porto, Porto, PortugalCancer Drug Resistance Group, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, PortugalClinical Hematology Department, Faculty of Medicine of the University of Porto (FMUP), Porto, PortugalDepartment of Microbiology and Immunology, Faculty of Pharmacy, University of Belgrade, Belgrade, SerbiaDepartment of Pharmaceutical Chemistry, Faculty of Medicine, University of Banja Luka, Banja Luka, Bosnia and Herzegovina0Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, SerbiaDepartment of Hematology - Medfuture Institute for Biomedical Research, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, RomaniaDepartment of Personalized Medicine and Rare Diseases - Medfuture Institute for Biomedical Research, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, RomaniaDepartment of Hematology - Medfuture Institute for Biomedical Research, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, RomaniaDepartment of Personalized Medicine and Rare Diseases - Medfuture Institute for Biomedical Research, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, RomaniaDepartment of Hematology - Medfuture Institute for Biomedical Research, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, RomaniaDepartment of Personalized Medicine and Rare Diseases - Medfuture Institute for Biomedical Research, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, RomaniaDepartment of Hematology - Medfuture Institute for Biomedical Research, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, RomaniaDepartment of Personalized Medicine and Rare Diseases - Medfuture Institute for Biomedical Research, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, RomaniaDepartment of Hematology - Medfuture Institute for Biomedical Research, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, RomaniaDepartment of Personalized Medicine and Rare Diseases - Medfuture Institute for Biomedical Research, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, RomaniaDepartment of Hematology - Medfuture Institute for Biomedical Research, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, RomaniaDepartment of Personalized Medicine and Rare Diseases - Medfuture Institute for Biomedical Research, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania1Department of Immunology, Grigore T. Popa University of Medicine and Pharmacy, Iasi, Romania1Department of Immunology, Grigore T. Popa University of Medicine and Pharmacy, Iasi, RomaniaDepartment of Hematology - Medfuture Institute for Biomedical Research, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, RomaniaDepartment of Personalized Medicine and Rare Diseases - Medfuture Institute for Biomedical Research, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, RomaniaDepartment of Hematology - Medfuture Institute for Biomedical Research, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, RomaniaDepartment of Personalized Medicine and Rare Diseases - Medfuture Institute for Biomedical Research, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania2Department of Stem Cell Transplantation, Fundeni Clinical Institute, Bucharest, RomaniaDepartment of Hematology - Medfuture Institute for Biomedical Research, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, RomaniaDepartment of Personalized Medicine and Rare Diseases - Medfuture Institute for Biomedical Research, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania3Julius Maximilians University of Würzburg, Würzburg, GermanyDepartment of Hematology - Medfuture Institute for Biomedical Research, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, RomaniaDepartment of Personalized Medicine and Rare Diseases - Medfuture Institute for Biomedical Research, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, RomaniaThe advent of immunotherapy in the treatment of cancer has opened a new dimension in the management of this complex multifaceted disease, bringing hope to many patients whose tumors have failed to respond to conventional therapies. The adoptive T cell therapy has since been extended to the treatment of several hematologic malignancies, initially in relapsed settings and more recently at the forefront of treatment due to high response rates. Despite exciting initial results, the preclinical antitumor effects of the first long-term studies show that CAR (Chimeric Antigen Receptor)-T cells have been slow to translate to the clinical setting, with early clinical trials showing suboptimal responses. The main reasons for the limited clinical performance seemed to be related to the low activation and short persistence of CAR-T cells. Thus, began a journey to improve the initial CAR structure, leading to the development of more complex constructs, which are grouped into five CAR generations. In this review, we describe the main challenges and potential solutions for the evaluation of CAR T-cell-based therapies in the preclinical setting.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1564998/fullCAR-T cell trackingtumor organoidsantigen escapesolid tumor immunotherapymetabolic reprogrammingHDAC inhibitors |
| spellingShingle | Radu Tomai Radu Tomai Javier De Las Rivas Bogdan Fetica Bogdan Fetica Rui Bergantim Rui Bergantim Rui Bergantim Rui Bergantim Brankica Filipic Zarko Gagic Katarina Nikolic Diana Gulei Diana Gulei David Kegyes David Kegyes Madalina Nistor Madalina Nistor Ximena Maria Muresan Ximena Maria Muresan Diana Cenariu Diana Cenariu Richard Feder Richard Feder Mariana Pavel-Tanasa Andrei Cianga Adrian Bogdan Tigu Adrian Bogdan Tigu Raluca Munteanu Raluca Munteanu Alina Tanase Hermann Einsele Hermann Einsele Hermann Einsele Ciprian Tomuleasa Ciprian Tomuleasa Challenges in the preclinical design and assessment of CAR-T cells Frontiers in Immunology CAR-T cell tracking tumor organoids antigen escape solid tumor immunotherapy metabolic reprogramming HDAC inhibitors |
| title | Challenges in the preclinical design and assessment of CAR-T cells |
| title_full | Challenges in the preclinical design and assessment of CAR-T cells |
| title_fullStr | Challenges in the preclinical design and assessment of CAR-T cells |
| title_full_unstemmed | Challenges in the preclinical design and assessment of CAR-T cells |
| title_short | Challenges in the preclinical design and assessment of CAR-T cells |
| title_sort | challenges in the preclinical design and assessment of car t cells |
| topic | CAR-T cell tracking tumor organoids antigen escape solid tumor immunotherapy metabolic reprogramming HDAC inhibitors |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1564998/full |
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