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Biomedicines
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Advances in CAR-T Cell Therapy
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Advances in CAR-T Cell Therapy

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Gene and Cell Therapy".

Deadline for manuscript submissions: 30 June 2025 | Viewed by 8144

Special Issue Editor

Dr. Anand Rotte

E-Mail Website
Guest Editor
Clinical and Regulatory Affairs, Arcellx, Gaithersburg, MD, USA
Interests: clinical research; clinical development (early and late); immunotherapy; melanoma; oxidative stress; type 2 diabetes and neuropathic pain
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In recent decades, we have witnessed the potential of targeting the immune system and the clinical impact of modulating immune response in the treatment of cancer. Research on immune checkpoints such as PD-1 and CTLA-4 has laid this foundation, with multiple approvals of anti-PD-1 and anti-CTLA-4 blockers as monotherapy and combination therapy for the treatment of cancer. The need for further improvement in response and survival rates has led to the development of cell therapies such as tumor-specific chimeric antigen receptor (CAR-) T cell therapy, NK cell therapy, and γδ-T-cell therapy. Among the different cell therapies, CAR-T cell therapy has seen significant success as the structure of CAR evolved from the first generation that had no intracellular signaling domain to CARs with one or two intracellular signaling domains with or without the ability to secrete cytokines or blocking proteins. Impressive clinical outcomes such as objective response rates (ORRs) as high as 100% in certain hematological cancers and responses durable over 10 years in some patients were seen with CAR-T cell therapy. To date, six CAR-T cell therapies, including axicabtagene ciloleucel (Yescarta), brexucabtagene autoleucel (Tecartus), tisagenlecleucel (Kymriah), lisocabtagene maraleucel (Breyanzi), idecabtagene vicleucel (Abecma), and ciltacabtagene autoleucel (Carvykti), have been approved by the US FDA for different hematological cancers.

However, CAR-T cells are limited by several challenges like low responses in solid tumors, the development of resistance due to antigen loss, exhaustion of CAR-T cells due to tonic signaling, waiting time for the manufacture of CAR-T cells, and manufacturing inconsistencies and failures. Preclinical, translational, and clinical research aiming to improve the durability of responses, extending the success to solid tumors, and addressing concerns related to time to manufacture cell therapy is currently underway.

This Special Issue aims to broadly attract research focused on CAR-T cell therapy. Clinical prospective, retrospective, and observational real-world studies and preclinical and translational studies are welcome to be submitted. Case reports may be considered on a case-by-case basis if they include the detailed elucidation of molecular mechanisms or comprehensive literature-based discussions. While we expect to receive articles related to cancer treatment, non-oncology applications of CAR-T cells such as autoimmune disorders are also considered to be within the scope of this Special Issue.

Dr. Anand Rotte
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • chimeric antigen receptors
  • CAR-T cells
  • binding domains
  • T cells redirected for universal cytokine-mediated killing (TRUCKs)
  • response
  • CRS
  • ICANS
  • safety
  • cancer
  • solid tumors
  • hematological malignancies and autoimmune disorders

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Published Papers (5 papers)

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Research

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15 pages, 2349 KiB  
Article
Novel mRNA-Engineered Fully Human CAR-T Cells Targeting AXL in Solid Tumors
by Bo Zou, Mengge Wang, Shimeng Bai, Ning Li, Zhongyi Fan, Yuanzheng Peng, Mingshu Han, Chen Zeng, Hongzhou Lu, Lin Qi, Xingding Zhang, Xiaohua Tan and Qibin Liao
Biomedicines 2025, 13(4), 844; https://doi.org/10.3390/biomedicines13040844 - 1 Apr 2025
Viewed by 377
Abstract
Background/Objectives: The AXL receptor tyrosine kinase is a promising therapeutic target in solid tumors, yet conventional viral vector-engineered CAR-T cells face critical limitations, including risks of insertional mutagenesis and immunogenicity from murine-derived single-chain variable fragments (scFvs). This study aimed to develop and evaluate [...] Read more.
Background/Objectives: The AXL receptor tyrosine kinase is a promising therapeutic target in solid tumors, yet conventional viral vector-engineered CAR-T cells face critical limitations, including risks of insertional mutagenesis and immunogenicity from murine-derived single-chain variable fragments (scFvs). This study aimed to develop and evaluate mRNA-engineered fully human AXL CAR-T (mfhAXL CAR-T) cells as a safer, scalable alternative for solid tumor immunotherapy. Methods:mfhAXL CAR-T cells were generated via electroporation-mediated delivery of in vitro transcribed mRNA encoding a fully human AXL-specific CAR. CAR expression kinetics and T-cell viability were quantified by flow cytometry. Antitumor activity was assessed through in vitro co-cultures with AXL-positive lung and pancreatic cancer cells, measuring cytotoxicity, cytokine secretion, and specificity. In vivo efficacy was evaluated in a lung cancer xenograft mouse model, with tumor volume and body weight monitored over 14 days. Results: Flow cytometry confirmed transient but high CAR expression (>90% at 24 h) with preserved T-cell viability (>90%). In vitro, mfhAXL CAR-T cells exhibited dose-dependent cytotoxicity and antigen-specific cytokine secretion. In vivo, four administrations of mfhAXL CAR-T cells suppressed tumor growth without body weight loss. Conclusions: The mRNA-electroporated mfhAXL CAR-T platform enables cost-effective, large-scale production, offering a safer alternative to viral vector-based approaches by eliminating risks of insertional mutagenesis and immunogenicity. Full article
(This article belongs to the Special Issue Advances in CAR-T Cell Therapy)
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20 pages, 26367 KiB  
Article
Exploring CAR-PBMCs: A Novel Strategy Against EGFR-Positive Tumor Cells
by Alexandru Tîrziu, Oana-Isabella Gavriliuc, Maria-Florina Bojin and Virgil Păunescu
Biomedicines 2025, 13(2), 264; https://doi.org/10.3390/biomedicines13020264 - 22 Jan 2025
Viewed by 1832
Abstract
Background: Chimeric antigen receptor (CAR) T cell therapy has shown significant promise in treating hematological malignancies, yet its application in solid tumors, particularly those expressing the epidermal growth factor receptor (EGFR), remains limited. This study investigates the potential of CAR-engineered peripheral blood mononuclear [...] Read more.
Background: Chimeric antigen receptor (CAR) T cell therapy has shown significant promise in treating hematological malignancies, yet its application in solid tumors, particularly those expressing the epidermal growth factor receptor (EGFR), remains limited. This study investigates the potential of CAR-engineered peripheral blood mononuclear cells (PBMCs) as a novel adoptive cell therapy against EGFR-positive cancers. Methods: Lentiviral transduction at an MOI of 50 was performed to generate specific anti-EGFR second generation CAR-effector cells. The transduced PBMCs were stimulated with cytokines and CD3/CD28 beads to enhance their proliferation and activation. Flow cytometric and real-time cell analysis were performed at various effector-to-target ratios to explore the cytotoxic potential of CAR-PBMCs. Results: CAR-PBMCs exhibited improved targeting and cytotoxicity against EGFR-positive cancer cell lines MDA-MB-468 and SK-BR-3, compared to untransduced controls, with unsignificant effects on allogeneic PBMCs. Conclusion: CAR-PBMCs hold considerable potential as a therapeutic strategy for EGFR-positive solid tumors, warranting further clinical investigation. Full article
(This article belongs to the Special Issue Advances in CAR-T Cell Therapy)
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11 pages, 1542 KiB  
Article
The Kinetics of Inflammation-Related Proteins and Cytokines in Children Undergoing CAR-T Cell Therapy—Are They Biomarkers of Therapy-Related Toxicities?
by Paweł Marschollek, Karolina Liszka, Monika Mielcarek-Siedziuk, Iwona Dachowska-Kałwak, Natalia Haze, Anna Panasiuk, Igor Olejnik, Tomasz Jarmoliński, Jowita Frączkiewicz, Zuzanna Gamrot, Anna Radajewska, Iwona Bil-Lula and Krzysztof Kałwak
Biomedicines 2024, 12(7), 1622; https://doi.org/10.3390/biomedicines12071622 - 21 Jul 2024
Cited by 2 | Viewed by 1546
Abstract
CD19-targeted CAR-T cell therapy has revolutionized the treatment of relapsed/refractory (r/r) pre-B acute lymphoblastic leukemia (ALL). However, it can be associated with acute toxicities related to immune activation, particularly cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Cytokines released from [...] Read more.
CD19-targeted CAR-T cell therapy has revolutionized the treatment of relapsed/refractory (r/r) pre-B acute lymphoblastic leukemia (ALL). However, it can be associated with acute toxicities related to immune activation, particularly cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Cytokines released from activated immune cells play a key role in their pathophysiology. This study was a prospective analysis of proinflammatory proteins and cytokines in children treated with tisagenlecleucel. Serial measurements of C-reactive protein, fibrinogen, ferritin, IL-6, IL-8, IL-10, IFNγ, and TNFα were taken before treatment and on consecutive days after infusion. The incidence of CRS was 77.8%, and the incidence of ICANS was 11.1%. No CRS of grade ≥ 3 was observed. All complications occurred within 14 days following infusion. Higher biomarker concentrations were found in children with CRS grade ≥ 2. Their levels were correlated with disease burden and CAR-T cell dose. While cytokine release syndrome was common, most cases were mild, primarily due to low disease burden before lymphodepleting chemotherapy (LDC). ICANS occurred less frequently but exhibited various clinical courses. None of the toxicities were fatal. All of the analyzed biomarkers rose within 14 days after CAR-T infusion, with most reaching their maximum around the third day following the procedure. Full article
(This article belongs to the Special Issue Advances in CAR-T Cell Therapy)
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Review

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16 pages, 301 KiB  
Review
Updates on Chimeric Antigen Receptor T-Cells in Large B-Cell Lymphoma
by Khalil Saleh, Nadine Khalife, Ahmadreza Arbab, Rita Khoury, Claude Chahine, Rebecca Ibrahim, Zamzam Tikriti, Nohad Masri, Mohamad Hachem and Axel Le Cesne
Biomedicines 2024, 12(12), 2810; https://doi.org/10.3390/biomedicines12122810 - 11 Dec 2024
Viewed by 1399
Abstract
CD19-targeting chimeric antigen receptor (CAR) T-cells have changed the treatment paradigm of patients with large B-cell lymphoma (LBCL). Three CAR T-cells were approved by the Food and Drug Administration (FDA) for patients with relapsed and/or refractory (R/R) LBCL in the third-line setting: tisagenlecleucel [...] Read more.
CD19-targeting chimeric antigen receptor (CAR) T-cells have changed the treatment paradigm of patients with large B-cell lymphoma (LBCL). Three CAR T-cells were approved by the Food and Drug Administration (FDA) for patients with relapsed and/or refractory (R/R) LBCL in the third-line setting: tisagenlecleucel (tisa-cel), axicabtagene ciloleucel (axi-cel), and lisocabtagene maraleucel (liso-cel), with an ORR ranging from 58% to 82%. More recently, axi-cel and liso-cel were approved as second-line treatments for patients with R/R disease up to 12 months after the completion of first-line chemo-immunotherapy. The safety profile was acceptable with cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome being the two most frequent acute adverse events. Potential long-term toxicities of CD19-targeting CAR T-cells have also been described. Overall, 30% to 40% of patients are cured with a single infusion of CAR T-cells. However, 60% to 70% of patients relapse after being treated with CAR T-cells and have a dismal prognosis. The advent of bispecific antibodies (BsAb) offers an additional treatment modality for patients with R/R LBCL. The aim of this review is to describe the clinical efficacy of the three CAR T-cells, as well as their safety profile. We also compare these three CAR T-cells in terms of their efficacy and safety profile as well as evaluating the place of CAR T-cells and BsAb in the treatment arsenal of patients with R/R LBCL. Full article
(This article belongs to the Special Issue Advances in CAR-T Cell Therapy)
16 pages, 817 KiB  
Review
Cell-Based Treatment in Acute Myeloid Leukemia Relapsed after Allogeneic Stem Cell Transplantation
by Martina Canichella and Paolo de Fabritiis
Biomedicines 2024, 12(8), 1721; https://doi.org/10.3390/biomedicines12081721 - 1 Aug 2024
Cited by 1 | Viewed by 1775
Abstract
Allogeneic stem cell transplant (ASCT) remains the only treatment option for patients with high-risk acute myeloid leukemia (AML). Recurrence of leukemic cells after ASCT represents a dramatic event associated with a dismal outcome, with a 2-year survival rate of around 20%. Adoptive cell [...] Read more.
Allogeneic stem cell transplant (ASCT) remains the only treatment option for patients with high-risk acute myeloid leukemia (AML). Recurrence of leukemic cells after ASCT represents a dramatic event associated with a dismal outcome, with a 2-year survival rate of around 20%. Adoptive cell therapy (ACT) is a form of cell-based strategy that has emerged as an effective therapy to treat and prevent post-ASCT recurrence. Lymphocytes are the principal cells used in this therapy and can be derived from a hematopoietic stem cell donor, the patient themselves, or healthy donors, after being engineered to express the chimeric antigen receptor (CAR-T and UniCAR-T). In this review, we discuss recent advances in the established strategy of donor lymphocyte infusion (DLI) and the progress and challenges of CAR-T cells. Full article
(This article belongs to the Special Issue Advances in CAR-T Cell Therapy)
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