bims-carter Biomed News
on CAR-T Therapies
Issue of 2025–06–01
nine papers selected by
Luca Bolliger, lxBio
  1. Chimeric antigen receptor T cell immunotherapy‑associated hemophagocytic lymphohistiocytosis: Pathogenesis, clinical manifestation, diagnosis and management compared with cytokine release syndrome (Review).
  2. Chimeric antigen receptor therapy for hematological malignancies: a pediatric perspective from leukapheresis to infusion.
  3. Harmonizing the Gut Microbiome and Cellular Immunotherapies: The Next Leap in Cancer Treatment.
  4. New Challenging Systemic Therapies for Juvenile Scleroderma: A Comprehensive Review.
  5. Setting up a CAR-T Program: A Framework for Delivery from the Worldwide Network for Blood & Marrow Transplantation.
  6. Transient mRNA CAR T cells targeting GD2 provide dose-adjusted efficacy against diffuse midline glioma and high grade glioma models.
  7. A Review on the Stability Challenges of Advanced Biologic Therapeutics.
  8. Big Data Science on T Cell Receptor-mediated Immune Regulation.
  9. Advanced therapy medicinal products development - from guidelines to medicines in the market.
  1. Mol Med Rep. 2025 Aug;pii: 213. [Epub ahead of print]32(2):
    Chimeric antigen receptor T cell immunotherapy‑associated hemophagocytic lymphohistiocytosis: Pathogenesis, clinical manifestation, diagnosis and management compared with cytokine release syndrome (Review).
    Jinglin Hu, Cuicui Feng, Lingbo He, Yini Wang.
      Chimeric antigen receptor (CAR) T cell therapy is used to treat hematological malignancy. However, it carries the risk of life‑threatening inflammatory toxicity, including cytokine release syndrome (CRS) and CAR T cell‑associated hemophagocytic lymphohistiocytosis (CARHLH). CRS is a common side effect of CAR T cell therapy, with fever and multiorgan functional impairment as the primary clinical manifestation. CARHLH and CRS have similar clinical manifestations. However, CARHLH is associated with a high mortality rate. CARHLH was previously considered a specific type of CRS, however, it must be promptly differentiated from CRS for treatment initiation, with management differing from that of CRS. The pathogenesis of CARHLH differs from that of CRS. The present review aimed to summarize the pathogenesis, diagnosis and treatment of CARHLH to assist in its early identification and management.
    Keywords:  chimeric antigen receptor T cell immunotherapy; chimeric antigen receptor T cell‑associated hemophagocytic lymphohistiocytosis; cytokine release syndrome; diagnosis; hemophagocytic lymphohistiocytosis; treatment
    DOI:  https://doi.org/10.3892/mmr.2025.13578
  2. Blood Transfus. 2025 Apr 16.
    Chimeric antigen receptor therapy for hematological malignancies: a pediatric perspective from leukapheresis to infusion.
    Alex Moretti, Chiara Buracchi, Sara Napolitano, Valentina Baldini, Giuseppe Gaipa, Andrea Biondi, Adriana Balduzzi.
      Immunotherapy, particularly chimeric antigen receptor T cells (CAR T)s, has changed the landscape of B-cell malignancy treatment and represents a promising approach to cancer therapy. The use of CAR T-based therapy in pediatric patients presents several critical issues such as the quality of the leukapheresis process and the treatment-related toxicity. Nevertheless, the experience with anti-CD19 CAR Ts in treating pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) demonstrated its feasibility and efficacy with a complete response rate greater than 80%. Although CAR T therapy is still in its infancy, the growing clinical experience and expanding body of literature are gradually enhancing the management of complications and patient monitoring. Yet, in vivo, CAR T persistence issues emerged and highlighted the need for continuous investigations to improve the long-term efficacy of CAR T cell therapy. Concurrently, it is crucial to expand the use of CAR T cells in the treatment of pediatric tumors other than BCP-ALL and to extend access to such therapy. In this review, we outline the journey of treating pediatric patients with CAR T products, covering the process from referral to long-term monitoring, while also addressing key concerns and future perspectives.
    DOI:  https://doi.org/10.2450/BloodTransfus.952
  3. Cells. 2025 05 14. pii: 708. [Epub ahead of print]14(10):
    Harmonizing the Gut Microbiome and Cellular Immunotherapies: The Next Leap in Cancer Treatment.
    Kendall Harrington, Khalid Shah.
      The gut microbiome, a diverse community of microorganisms, plays a key role in shaping the host's immune system and modulating cancer therapies. Emerging evidence highlights its critical influence on the efficacy and toxicity of cell-based immunotherapies, including chimeric antigen receptor T cell, natural killer cell, and stem cell therapies. This review explores the interplay between gut microbiota and cellular immunotherapies, focusing on mechanisms by which microbial metabolites and microbial composition impact treatment outcomes. Furthermore, we discuss strategies to leverage the gut microbiome to optimize therapeutic efficacy and minimize adverse effects. A deeper understanding of the relationship between the gut microbiome and cellular immunotherapies can pave the way for more effective cell-based therapies for cancer.
    Keywords:  T cells; antibiotics; cancer; cellular therapy; gut microbiome; mesenchymal stem cells; natural killer cells; probiotics; short-chain fatty amino acids
    DOI:  https://doi.org/10.3390/cells14100708
  4. Pharmaceuticals (Basel). 2025 Apr 28. pii: 643. [Epub ahead of print]18(5):
    New Challenging Systemic Therapies for Juvenile Scleroderma: A Comprehensive Review.
    Chiara Sassetti, Claudia Borrelli, Martha Mazuy, Cristina Guerriero, Donato Rigante, Susanna Esposito.
      Background: Juvenile scleroderma (JS) comprises a group of rare chronic autoimmune and fibrosing disorders in children, primarily presenting as juvenile localized scleroderma (jLS) or juvenile systemic sclerosis (jSS). While jLS predominantly affects the skin and subcutaneous tissues, jSS may involve multiple internal organs and is associated with increased morbidity and mortality. Due to the scarcity of pediatric-specific clinical trials, the current treatment strategies are largely empirical and often adapted from adult protocols. Objective: This narrative review aims to provide a comprehensive update on emerging systemic therapies for juvenile scleroderma, focusing on biologics, small molecule inhibitors, and advanced cellular interventions, to support the development of more personalized and effective pediatric treatment approaches. Methods: A literature search was conducted through PubMed and a manual bibliographic review, covering publications from 2001 to 2024. Only English-language studies involving pediatric populations were included, comprising randomized controlled trials, reviews, and case reports. Additional searches were performed for drugs that are specifically used in juvenile scleroderma. Results: Biologic agents such as tocilizumab, rituximab, and abatacept, along with small molecules including Janus kinase (JAK) inhibitors and imatinib, have demonstrated potential in managing refractory cases by reducing skin fibrosis and pulmonary involvement. Novel approaches-such as pamrevlumab, nintedanib, and chimeric antigen receptor (CAR-T) cell therapy-target fibrotic and autoimmune pathways but remain investigational in children. Autologous stem cell transplantation (ASCT) has also been explored in severe, treatment-resistant cases, although data are extremely limited. The overall evidence base is constrained by small sample sizes, a lack of controlled pediatric trials, and reliance on adult extrapolation. Conclusions: While innovative systemic therapies show promise for juvenile scleroderma, their widespread clinical application remains limited by insufficient pediatric-specific evidence. Large, multicenter, long-term trials are urgently needed to establish safety, efficacy, and optimal treatment algorithms that are tailored to the pediatric population.
    Keywords:  childhood; innovative biotechnologies; juvenile scleroderma; personalized medicine; systemic sclerosis
    DOI:  https://doi.org/10.3390/ph18050643
  5. Transplant Cell Ther. 2025 May 23. pii: S2666-6367(25)01196-0. [Epub ahead of print]
    Setting up a CAR-T Program: A Framework for Delivery from the Worldwide Network for Blood & Marrow Transplantation.
    Syed Osman Ahmed, Riad El Fakih, Mohamed A Kharfan-Dabaja, Farhatullah Syed, Ghulam Mufti, Christian Chabannon, Damiano Rondelli, Mohamad Mohty, Ali A Al Ahmari, Jordan Gauthier, Marco Ruella, Miguel-Angel Perales, Shahrukh Hashmi, Feras Alfraih, Sarah Ghorashian, Mohsen Alzahrani, Zubair Abba, Mickey Koh, Marcelo Pasquini, Annalisa Ruggeri, Laurent Garderet, Abdulwahab Albabtain, Daniel Weisdorf, Hildegard Greinix, Hadeel Samarkandi, Nada Hamad, Yoshiko Atsuta, Mehdi Hamadani, Parameswaran Hari, Navneet S Majhail, Raffaella Greco, Hazzaa Alzahrani, Anna Sureda, Ibrahim Yakoub-Agha, Ali D Alahmari, Dietger Niederwieser, Mahmoud Aljurf.
      Chimeric antigen receptor therapy (CAR-T therapy) is a genetically engineered cellular therapy that is currently integrated into the management of hematological malignancies. Institutions treating patients with CAR-T therapy need to establish a framework of delivery that covers all the main components of the patient journey including intake of patients into the program from referring centers, patient selection according to established eligibility criteria, apheresis, logistics, bridging therapy, infusion and post-infusion care. A CAR-T therapy program, with its unique requirements, needs to be delivered by a multidisciplinary team (MDT). Prior to the establishment of the program, a well-structured business plan should be developed with a clear financial and/or reimbursement model. Consideration should be given to the overall capacity and staffing requirements. Standard operating procedures and guidelines are vital for ensuring that quality standards are clearly defined and adhered to. Institutions should develop a research plan for CAR-T that may incorporate not only industry sponsored trials but also in-house CAR-T manufacture of investigational CAR-T constructs. This report presents recommendations from a group of international experts highlighting the priorities and considerations when developing a new CAR-T program.
    Keywords:  CART cell; Chimeric Antigen Receptor; Program
    DOI:  https://doi.org/10.1016/j.jtct.2025.05.012
  6. Neuro Oncol. 2025 May 24. pii: noaf115. [Epub ahead of print]
    Transient mRNA CAR T cells targeting GD2 provide dose-adjusted efficacy against diffuse midline glioma and high grade glioma models.
    Jessica B Foster, Peter J Madsen, Kyra Harvey, Crystal Griffin, Allison Stern, Luke Patterson, Nikhil Joshi, Conor Dickson, Olivia McManus, Ezra Beaubien, Cullen Wilson, David R Beale, Valerie Baubet, Payush N Goel P, Nicholas A Vitanza, Javad Nazarian, Mateusz Koptyra, Phillip B Storm, Adam C Resnick.
       BACKGROUND: Diffuse midline glioma (DMG) and high grade glioma are devastating pediatric central nervous system tumors that remain incurable. Recent chimeric antigen receptor (CAR) T cell studies have shown proof of concept and early signs of efficacy against DMG targeting GD2. Prior work and ongoing clinical trials have focused on using viral vectors to create permanent CAR T cells. However, virally transduced GD2-directed CAR T cells have shown significant neurotoxicity in both pre-clinical models and human trials.
    METHODS: We evaluated transient CAR T cells targeting GD2 created with mRNA, assessing for efficacy and safety in cell line, organoid, and in vivo xenograft models with repetitive intratumoral dosing.
    RESULTS: We show that mRNA GD2-directed CAR T cells are active against both cell lines and organoid models of DMG and high grade glioma in vitro. Cytotoxicity consistently abates over 9 days, highlighting the potential to avoid toxicity from persistent T cell activity. In both pontine and thalamic DMG xenograft models, repeated doses of mRNA GD2-directed CAR T cells were titrated down to maintain therapeutic effect without causing neurologic toxicity.
    CONCLUSIONS: Our results demonstrate the utility of transient mRNA CAR T cells delivered intratumorally to provide effective tumor killing with a defined half-life, allowing for modulation of the dose and potential side effects. We anticipate this study will expand the use of CAR T cell therapy for DMG and other central nervous system tumors and non-malignant disorders, where concern for toxicity from permanently expressing CAR T cells may hinder development.
    Keywords:  CAR T cells; brain tumor; diffuse midline glioma; mRNA; pediatric
    DOI:  https://doi.org/10.1093/neuonc/noaf115
  7. Pharmaceutics. 2025 Apr 23. pii: 550. [Epub ahead of print]17(5):
    A Review on the Stability Challenges of Advanced Biologic Therapeutics.
    Sruthi Sarvepalli, Shashank Reddy Pasika, Vartika Verma, Anusha Thumma, Sandeep Bolla, Pavan Kumar Nukala, Arun Butreddy, Pradeep Kumar Bolla.
      Advanced biotherapeutic systems such as gene therapy, mRNA lipid nanoparticles, antibody-drug conjugates, fusion proteins, and cell therapy have proven to be promising platforms for delivering targeted biologic therapeutics. Preserving the intrinsic stability of these advanced therapeutics is essential to maintain their innate structure, functionality, and shelf life. Nevertheless, various challenges and obstacles arise during formulation development and throughout the storage period due to their complex nature and sensitivity to various stress factors. Key stability concerns include physical degradation and chemical instability due to various factors such as fluctuations in pH and temperature, which results in conformational and colloidal instabilities of the biologics, adversely affecting their quality and therapeutic efficacy. This review emphasizes key stability issues associated with these advanced biotherapeutic systems and approaches to identify and overcome them. In gene therapy, the brittleness of viral vectors and gene encapsulation limits their stability, requiring the use of stabilizers, excipients, and lyophilization. Keeping cells viable throughout the whole cell therapy process, from culture to final formulation, is still a major difficulty. In mRNA therapeutics, stabilization strategies such as the optimization of mRNA nucleotides and lipid compositions are used to address the instability of both the mRNA and lipid nanoparticles. Monoclonal antibodies are colloidally and conformationally unstable. Hence, buffers and stabilizers are useful to maintain stability. Although fusion proteins and monoclonal antibodies share structural similarities, they show a similar pattern of instability. Antibody-drug conjugates possess issues with conjugation and linker stability. This review outlines the stability issues associated with advanced biotherapeutics and provides insights into the approaches to address these challenges.
    Keywords:  antibody–drug conjugates (ADCs); biologics; cell therapy; colloidal instability; conformational instability; fusion proteins; gene therapy; mRNA lipid nanoparticles; monoclonal antibodies; non-viral vectors; stability concerns; stabilization mechanisms; stabilization strategies; viral vectors
    DOI:  https://doi.org/10.3390/pharmaceutics17050550
  8. JMA J. 2025 Apr 28. 8(2): 338-344
    Big Data Science on T Cell Receptor-mediated Immune Regulation.
    Kazuyoshi Ishigaki.
      T cell receptors (TCRs) have a highly diverse sequence pattern resulting from the random recombination of gene components in the thymus. This diversity enables TCRs to distinguish between a wide range of self and non-self-antigens, thereby shaping the reactivity of the acquired immune system. Self-responsiveness arising from impaired TCR-based self-discrimination is a crucial trigger for the development of autoimmune diseases. The immunological importance of TCR research is evident, yet traditional experimental and analytical techniques have not fully captured the vast information contained within the TCR repertoire. However, recent advancements in massive parallel sequencing, efficient library preparation pipelines, single-cell experiment platforms, and genome engineering are poised to transform our understanding of TCR diversity, sparking interest in the field. These advancements have made it possible to "read through" the entire TCR repertoire and partially identify their cognate antigens. In parallel, methods for efficiently analyzing large datasets of comprehensive TCR sequences have also progressed. These innovations in experimental and analytical techniques are leading TCR research in new directions, such as using TCR as a real-time biomarker, exploring the link between TCR and T cell differentiation, and investigating TCR genetic regulation. This review will cover recent updates on big data science related to TCR-mediated immune regulation.
    Keywords:  HLA polymorphisms; T-cell receptor; autoimmune diseases; regulatory T cells; thymic selection
    DOI:  https://doi.org/10.31662/jmaj.2024-0304
  9. Biotechnol Adv. 2025 May 22. pii: S0734-9750(25)00098-9. [Epub ahead of print]83 108612
    Advanced therapy medicinal products development - from guidelines to medicines in the market.
    Catarina Frederico, André Conceição, Clévio Nóbrega, Liliana S Mendonça.
      In Europe, Advanced Therapy Medicinal Products (ATMPs) include medicines based on gene therapy, somatic-cell therapy, tissue-engineered products, and combined ATMPs. ATMPs constitute an emerging and innovative class of medicines used to treat multiple pathologies and are particularly relevant in pathologies where therapeutic options are limited and require high medical needs. These therapies act, among others, through the insertion of recombinant nucleic acids, including genes, to promote a therapeutic effect and through the restoration of cell functions, and repairing or replacing damaged cells and tissues impaired in pathological conditions. Despite their unique potential, these therapies face challenges related to scientific complexity, production processes, regulatory approval, and market access that hinder their development and availability. Based on official European guidelines, the present review explores the current regulatory framework for the non-clinical and clinical development of advanced therapies. We aimed to discuss the regulations applied to the different types of ATMPs, as well as the challenges associated with their development until these therapies reach the market. Accordingly, topics such as the implementation of proof-of-concept studies to provide evidence supporting the potential clinical effect; biodistribution studies to evaluate tissue distribution and persistence; and toxicology studies to assess potential undesirable effects, integration potential of viral vectors, tumorigenicity, and germline transmission, are discussed. This work also covers some of the ATMPs available to patients on the EU market.
    Keywords:  ATMPs in the market; Advanced therapy medicinal products; Clinical development; EU legislation; Non-clinical development; Quality and safety standards
    DOI:  https://doi.org/10.1016/j.biotechadv.2025.108612
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