bims-carter Biomed News
on CAR-T Therapies
Issue of 2025–08–31
twenty-six papers selected by
Luca Bolliger, lxBio



  1. Cells. 2025 Aug 12. pii: 1242. [Epub ahead of print]14(16):
      Chimeric antigen receptor (CAR) T cell immunotherapy has changed the landscape of B cell hematological malignancies' management, while it has recently shown promising results in the treatment of refractory autoimmune rheumatic disorders (ARDs). Targeting B cell antigens such as CD19 and BCMA, CAR-T cell therapy can induce sustained remission by the elimination of autoreactive B cell populations resistant to the standard of care treatment options. Clinical data from case reports and small case series demonstrate profound clinical responses in ARDs, including systemic lupus erythematosus (SLE), systemic sclerosis (SSc), idiopathic inflammatory myopathies (IIMs), rheumatoid arthritis (RA), antiphospholipid syndrome (APS), and primary Sjögren's syndrome (pSS). Treatment outcomes include reduced disease activity, normalization of serologic markers, improved organ function, and drug-free remission, even after B cell reconstitution. Additionally, toxicities, primarily limited to mild cytokine release syndrome (CRS), were generally manageable with supportive care. Encouraging preliminary results have led to the development of several ongoing clinical trials investigating CAR-T cell therapy across multiple ARDs and patient populations, including pediatric patients. This review summarizes the current clinical experience and provides a comprehensive overview of ongoing clinical trials exploring CAR-T cell immunotherapy for ARDs.
    Keywords:  BCMA; CAR-T cell therapy; CD19; autoimmune rheumatic disorders; immunotherapy; systemic lupus erythematosus
    DOI:  https://doi.org/10.3390/cells14161242
  2. Adv Sci (Weinh). 2025 Aug 25. e05822
      Immunotherapy, particularly chimeric antigen receptor T cell (CAR-T) therapy, has revolutionized the treatment of hematological malignancies and autoimmune diseases. However, its efficacy in solid tumors remains limited due to challenges such as tumor heterogeneity, an immunosuppressive microenvironment, and poor T cell infiltration. This review first summarizes the primary causes and challenges that restrict CAR-T therapy in the treatment of solid tumors, followed by an overview of recent advancements in gastric cancer, liver cancer, and glioma, where early trials have demonstrated promising clinical potential. Advances in CRISPR-edited and "off-the-shelf" allogeneic CAR-T cells seek to improve scalability, while artificial intelligence (AI)-driven target discovery, synthetic biology, and cytokine armoring strategies aim to enhance tumor specificity and T-cell persistence. Additionally, the flexible utilization of combination strategies in clinical surgical and medical trials, such as combining CAR-T therapy with immune checkpoint inhibitors, oncolytic viruses, chimeric antigen receptor NK cells (CAR-NK), or chimeric antigen receptor macrophage cells (CAR-M) may further enhance antitumor efficacy. The evolution of CAR-T therapy highlights its potential to reshape precision oncology, offering hope to patients with aggressive solid tumors through ongoing basic research, technological optimization, and clinical refinement.
    Keywords:  artificial intelligence; cell therapy; chimeric antigen receptor T cell; solid malignancies; synthetic biology
    DOI:  https://doi.org/10.1002/advs.202505822
  3. Int J Mol Sci. 2025 Aug 15. pii: 7890. [Epub ahead of print]26(16):
      Chimeric antigen receptor (CAR) cell therapy, encompassing CAR T, CAR NK, and CAR macrophage cells, demonstrates high efficacy in tumor treatment, conferring durable and effective responses, notably in hematologic malignancies. However, challenges persist in the manufacture of CAR cells, and treatment is associated with serious adverse events, notably cytokine release syndrome (CRS), a potentially life-threatening complication. Owing to the inherent properties of exosomes, CAR cell-derived exosomes offer distinct advantages in cancer therapeutics. CAR cells-derived exosomes retain the inherent tumor-killing function of the parent cells while also exhibiting key practical advantages, including wide availability, safety, and ease of storage and transport. Furthermore, CAR cell-derived exosomes can be combined with other tumor therapies; this combinatorial approach significantly enhances efficacy while reducing side effects. To accelerate the clinical translation of CAR cell-derived exosomes in tumor therapy, this paper reviews their biogenesis, engineering strategies, antitumor mechanisms and clinical evidence, including case studies of combination therapies with other antitumor modalities.
    Keywords:  CAR cells-derived exosomes; biogenesis; clinical translation; mechanism; tumor therapy
    DOI:  https://doi.org/10.3390/ijms26167890
  4. Front Immunol. 2025 ;16 1595533
      Immunotherapy has emerged as the established fourth pillar of cancer treatment following surgery, radiotherapy, and chemotherapy, representing a cutting-edge research domain in translational medicine and clinical oncology. Natural killer (NK) cells, a type of innate cytotoxic lymphocyte, possess unique antitumor properties that are independent of major histocompatibility complex (MHC) restrictions, making them promising candidates for "off-the-shelf" therapeutic products. NK cells can eliminate tumor cells through various mechanisms. Genetic engineering of NK cells can enhance their activation signals, promote proliferation, inhibit suppressive signals, and improve tumor homing, all of which are expected to significantly boost their clinical efficacy. Compared to chimeric antigen receptor T (CAR-T) cell therapy, NK cell-based immunotherapy demonstrates superior safety and tolerability. However, the clinical application of NK cells still faces several challenges, including suboptimal expansion efficiency in vitro, limited persistence in vivo, low transduction efficiency of chimeric antigen receptor NK (CAR-NK) cells, and immunosuppressive effects of the tumor microenvironment. These issues require further investigation to achieve significant improvements. This review provides a comprehensive overview of the biological characteristics of NK cells, their antitumor mechanisms, the latest therapeutic strategies in tumor immunotherapy, and the challenges associated with NK cell-based immunotherapy, aiming to offer valuable insights for future research and clinical applications.
    Keywords:  clinical applications; immunotherapy; natural killer cells; tumor; “Off-the-shelf” cell
    DOI:  https://doi.org/10.3389/fimmu.2025.1595533
  5. Front Immunol. 2025 ;16 1564998
      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.
    Keywords:  CAR-T cell tracking; HDAC inhibitors; antigen escape; metabolic reprogramming; solid tumor immunotherapy; tumor organoids
    DOI:  https://doi.org/10.3389/fimmu.2025.1564998
  6. Pathogens. 2025 Aug 05. pii: 774. [Epub ahead of print]14(8):
      Chimeric antigen receptor (CAR)-T immunotherapy has revolutionized the management of patients with relapsed/refractory B-cell hematological malignancies. There is emerging evidence that CAR-engineered cells-not only T cells, but also natural killers and macrophages-might have a crucial role in the treatment of autoimmune disorders and solid tumors. Moreover, given the burden of chronic infectious diseases, the mortality and morbidity of infections in immunocompromised individuals, and the development of multidrug-resistant pathogens, including bacteria, fungi, and mycobacteria, a need for novel and personalized therapeutics in this field is emerging. To this end, the development of CAR cells for the management of chronic infections has been reported. In this literature review, we summarize the ongoing clinical and pre-clinical data about CAR cell products in the field of infectious diseases. Currently, clinical studies on CAR immunotherapy for infections mainly concern human immunodeficiency virus infection treatment, and data regarding other infections largely originate from preclinical in vitro and in vivo models. In the era of personalized medicine, effective and safe therapies for the management of chronic infections and infectious complications in immunocompromised patients are crucial.
    Keywords:  chimeric antigen receptor; human immunodeficiency virus; immunotherapy; infections; invasive fungal diseases; viral infections
    DOI:  https://doi.org/10.3390/pathogens14080774
  7. Biomolecules. 2025 Aug 14. pii: 1166. [Epub ahead of print]15(8):
      CAR-T cell therapy represents a breakthrough in cancer treatment, yet its implementation in developing countries remains challenging due to technical and infrastructural barriers. This study aimed to establish clinical-scale CAR-T production in Kazakhstan, a country with no prior experience in advanced cell and gene therapies. We implemented a complete CAR-T manufacturing pipeline, including in-house lentiviral vector (LV) production and automated CAR-T cell processing using the CliniMACS Prodigy system. Two anti-CD19 CAR LVs were used, one modeled after FDA-approved Kymriah (4-1BB costimulation) and another replicating Yescarta (CD28 costimulation). The vector produced locally achieved functional titers of 1.5 × 1010 TU/mL after concentration. Twelve clinical-scale CAR-T products were manufactured, exhibiting a memory-skewed T-cell phenotype. Functional assessments revealed that CD28-based CAR-T cells produced significantly higher Th1 cytokines (IFN-γ, TNF-α, IL-2; p < 0.05) than 4-1BB-based cells, though both demonstrated comparable cytotoxicity against CD19+ targets. These findings demonstrate the feasibility of establishing CAR-T production in resource-limited settings using a decentralized manufacturing framework. This work provides a scalable model of CAR-T therapy production in developing regions, suitable for clinical implementation using the hospital exemption framework. Critical gaps in access to advanced immunotherapies, including CAR-T, in the Central Eurasia region are addressed.
    Keywords:  CAR-T therapy; CliniMACS Prodigy; academic format; developing economy; hospital exemption; point-of-care
    DOI:  https://doi.org/10.3390/biom15081166
  8. Discov Oncol. 2025 Aug 22. 16(1): 1593
      Cancer immunotherapy has transformed oncology, with CAR-T cell therapy emerging as a cornerstone of personalized treatment for hematologic malignancies. In China, rapid advancements in domestically developed CAR-T therapies have achieved clinical outcomes comparable to global benchmarks, with overall response rates (ORR) of 79-89% in B-cell malignancies and 64% 12-month progression-free survival in multiple myeloma. Despite these successes, CAR-T application in solid tumors remains hindered by antigen heterogeneity, immunosuppressive microenvironments, and on-target/off-tumor toxicity. To address these barriers, China has pioneered innovative strategies, including dual-target CAR-T constructs, armored CAR-Ts secreting immunomodulatory cytokines, and synergistic integration with traditional Chinese medicine, which enhances CAR-T efficacy by inhibiting myeloid-derived suppressor cells and reducing cytokine release syndrome. Notably, preclinical studies demonstrate that Huangqin increases tumor regression rates from 40 to 65% in lung cancer models when combined with CAR-T therapy. Concurrently, China is reshaping accessibility through policy innovations such as the "1 + 3 + N" multi-tiered payment system and regional insurance pilots, which reduce patient costs by 50%. Strategic investments in automated manufacturing and global regulatory harmonization further position China as a leader in cost-effective CAR-T development. However, challenges persist in solid tumor targeting, international market integration, and long-term safety monitoring. Future directions emphasize precision engineering, AI-driven treatment optimization, and cross-border collaborations to advance next-generation therapies. By balancing innovation, affordability, and policy agility, China is poised to drive the global evolution of cancer immunotherapy while addressing unmet needs in both hematologic and solid malignancies.
    Keywords:  Bispecific antibodies; CAR-T; Immune cell therapy; Immune checkpoint therapy; Tumor immunotherapy
    DOI:  https://doi.org/10.1007/s12672-025-03282-9
  9. Cancer. 2025 Sep 01. 131(17): e70069
      Cytokine release syndrome (CRS) is a common and potentially severe complication of cancer immunotherapy, including CAR T-cell therapies, bispecific T-cell engagers, and less commonly immune checkpoint inhibitors. Although extensive research has established guidelines for managing CRS in hematological malignancies, there is a growing need to address CRS in the context of solid organ tumors due to differences in tumor microenvironment, immunotherapy indications, and patient population. This review aims to provide an overview of CRS in solid tumors, outlining its pathophysiology, clinical presentation, and current management strategies. The complexities of CRS in solid tumors arise from challenges such as the immunosuppressive nature of the tumor microenvironment and the overlap of tumor-associated antigens with healthy tissues, potentially increasing the risk of severe on-target off-tumor toxicities. The review emphasizes early detection and grading of CRS as essential for patient safety and effective intervention. Management of CRS involves supportive care for mild cases, whereas severe presentations often require targeted therapies like tocilizumab, corticosteroids, and escalation to the intensive care unit for organ support. The decision to rechallenge or withhold immunotherapy requires careful consideration of patient-specific goals and risks. Emerging treatments such as other cytokine inhibitors, plasma exchange, and suicide gene systems are promising avenues for mitigating severe CRS. Future research focuses on refining risk stratification tools, novel therapeutic agents, and evaluating long-term outcomes. A deeper understanding of CRS in solid tumors will enable more personalized treatment approaches, enhancing the safety and efficacy of immunotherapies for this patient population.
    Keywords:  adoptive; chimeric antigen receptor therapy; cytokine release syndrome; drug‐related side effects and adverse reactions; immune checkpoint inhibitors; immunotherapy; solid tumors
    DOI:  https://doi.org/10.1002/cncr.70069
  10. Front Med (Lausanne). 2025 ;12 1591751
      Decentralized manufacturing has emerged as a promising approach to improve the accessibility and scalability of cell and gene therapy products, particularly for autologous treatments. This paper proposes a comprehensive Quality Management System (QMS) framework tailored to decentralized cell therapy manufacturing, integrating current Good Manufacturing Practice (cGMP) principles and regulatory oversight through a centralized Control Site model. The Control Site serves as the regulatory nexus, maintaining POCare Master Files and ensuring consistency across multiple decentralized manufacturing sites. Decentralized manufacturing has the potential to facilitate accessibility for cell and gene therapies. The proposed model leverages automated, closed-system technologies to minimize process variability and hardware deviations, thereby enhancing product quality and regulatory compliance. The Control Site holds functional roles like primary focus point for interaction with regulatory agencies, provision of quality assurance, qualified person (QP) and oversight systems. It also maintains the POCare Master File for the individual POCare GMP manufacturing sites. A standardized GMP manufacturing platform (e.g., deployable as prefabricated units allowing quick expansion) and an overarching training platform should guarantee quality standards. Key regulatory expectations will be discussed, e.g., the demonstration of consistency and comparability, the central role of QP (as proposed in the context of the European Commission's Pharma strategy), and the Control Site as single point of contact for competent authorities. This approach aims to streamline cell therapy production at or near point of care, supporting rapid and cost-effective clinical implementation.
    Keywords:  GMP compliance; cell and gene therapy; control site; decentralized manufacturing; point of care platform; quality management system; regulatory oversight
    DOI:  https://doi.org/10.3389/fmed.2025.1591751
  11. Int J Hematol Oncol Stem Cell Res. 2025 Apr 01. 19(2): 180-190
      The plethora of advancements in cancer treatment has resulted in designing unique signatures and personalized therapies, tailored to patient-specific needs, using medications that target specific markers on cancer cells or even retrain the body's immune system. Chimeric Antigen Receptor T-cell, also called as CAR T-cell, is one such approach wherein a patient's cells are modulated to kill the cancer cells. Conventional cancer treatments invite issues like low specificity, increased chances of relapse, or issues with radiotoxicity and tolerance in the case of chemotherapy. Currently, CAR T-cell therapy is under clinical investigation, and different countries are still coming up with their guidelines for the pragmatic application of CAR T. In this review, we present all one needs to know about CAR T-cell therapy, its types, components, side effects, current authorization status in different countries, along with the technology being used in the therapy. We also briefly upon the recent regulations or guidelines released by Europe and the USA, the countries that have actively initiated the CAR T idea. This review aims to provide insight into this targeted therapy, which has the potential to boost cancer research and to help researchers develop more such patient-specific treatments to improve clinical outcomes in cancer.
    Keywords:  CAR T-cell therapy; Cancer; Immunology; Immunotherapy
    DOI:  https://doi.org/10.18502/ijhoscr.v19i2.18555
  12. Crit Rev Oncol Hematol. 2025 Aug 21. pii: S1040-8428(25)00300-2. [Epub ahead of print]214 104912
      Natural killer (NK) cells offer distinct advantages over CAR-T therapies, including reduced toxicity and 'off-the-shelf' potential. This review critically evaluates engineered NK innovations (CAR-NK, cytokine armoring, NKCEs) and their clinical translation, with emphasis on overcoming immunosuppression in solid tumors. We highlight the limitations of CAR-T cells-such as cytokine release syndrome (CRS), neurotoxicity, and antigen escape- and detail how NK cell-based therapies address safety challenges (e.g., reduced CRS/GvHD) and offer 'off-the-shelf' applicability. Notably, antigen escape remains a shared limitation for both platforms. Key innovations in engineered NK cell therapies-including CAR-NK, cytokine armoring (e.g., IL-15), and bispecific/trispecific NK cell engagers (NKCEs)-are critically evaluated. We further address translational barriers, including immunosuppression within the tumor microenvironment (TME), metabolic constraints, and NK cell exhaustion, and discuss strategies to enhance homing, infiltration, and durability. Clinical progress in hematologic malignancies and solid tumors is summarized, emphasizing promising trial outcomes (e.g., 83 % remission in lymphoma with CAR19-NK). Finally, we outline future directions: logic-gated CARs, iPSC-derived NK platforms, and combinatorial approaches with immune checkpoint blockade. CAR-NK therapy represents a paradigm shift in immuno-oncology, augmented by strategies like NKCEs and cytokine armoring. These engineered approaches converge to expand treatment options for refractory cancers.
    Keywords:  Adoptive Cell Therapy; CAR-NK; Cancer Immunotherapy; Natural killer cells; Tumor Microenvironment
    DOI:  https://doi.org/10.1016/j.critrevonc.2025.104912
  13. MicroPubl Biol. 2025 ;2025
      CD19-targeting CAR T cell therapy has shown remarkable efficacy in the treatment of relapsed/refractory B cell lymphoma. However, a proportion of patients exhibit resistance to treatment. We investigate the impact of lymphoma-derived Extracellular Vesicles (EV) on CD19-targeting CAR T cell function in vitro . We demonstrate that lymphoma-EV express B cell markers such as CD19 and CD20, which can be transferred to the CAR T cell membrane. In co-culture experiments, lymphoma-EV suppress the tumour-killing capacity of CAR T cells.
    DOI:  https://doi.org/10.17912/micropub.biology.001646
  14. Pharmaceuticals (Basel). 2025 Jul 26. pii: 1115. [Epub ahead of print]18(8):
      The escalating global crisis of antimicrobial resistance, responsible for approximately 1.27 million deaths in 2019, has catalyzed renewed interest in bacteriophage therapy as a viable therapeutic alternative. With projections indicating that drug-resistant bacteria could cause over 39 million deaths worldwide by 2050, developing alternative antimicrobial strategies has become critically urgent. This comprehensive review examines the scientific foundation of bacteriophage therapy, traces its historical development from early Soviet applications through contemporary regulatory frameworks, and provides strategic guidance for developers seeking FDA approval for bacteriophage-based therapeutics. We analyze the current regulatory landscape across major jurisdictions, including manufacturing requirements and clinical development pathways essential for successful market authorization. Approximately 90 clinical trials involving bacteriophages are ongoing worldwide, with 41 studies in the United States demonstrating significant momentum in this field.
    Keywords:  FDA approval; GMP manufacturing; Soviet phage therapy; antimicrobial; antimicrobial resistance; bacteriophage therapy; clinical trials; international regulation; regulatory pathway
    DOI:  https://doi.org/10.3390/ph18081115
  15. Pharmaceutics. 2025 Jul 30. pii: 987. [Epub ahead of print]17(8):
      Nanotechnology is revolutionizing medicine by enabling highly precise diagnostics, targeted therapies, and personalized healthcare solutions. This review explores the multifaceted applications of nanotechnology across medical fields such as oncology and infectious disease control. Engineered nanoparticles (NPs), such as liposomes, polymeric carriers, and carbon-based nanomaterials, enhance drug solubility, protect therapeutic agents from degradation, and enable site-specific delivery, thereby reducing toxicity to healthy tissues. In diagnostics, nanosensors and contrast agents provide ultra-sensitive detection of biomarkers, supporting early diagnosis and real-time monitoring. Nanotechnology also contributes to regenerative medicine, antimicrobial therapies, wearable devices, and theranostics, which integrate treatment and diagnosis into unified systems. Advanced innovations such as nanobots and smart nanosystems further extend these capabilities, enabling responsive drug delivery and minimally invasive interventions. Despite its immense potential, nanomedicine faces challenges, including biocompatibility, environmental safety, manufacturing scalability, and regulatory oversight. Addressing these issues is essential for clinical translation and public acceptance. In summary, nanotechnology offers transformative tools that are reshaping medical diagnostics, therapeutics, and disease prevention. Through continued research and interdisciplinary collaboration, it holds the potential to significantly enhance treatment outcomes, reduce healthcare costs, and usher in a new era of precise and personalized medicine.
    Keywords:  drug delivery system; healthcare; nanobots; nanomedicine; nanozyme
    DOI:  https://doi.org/10.3390/pharmaceutics17080987
  16. J Allergy Clin Immunol. 2025 Aug 21. pii: S0091-6749(25)00869-3. [Epub ahead of print]
      Reconstitution of the T cell compartment is essential in the treatment of several immune disorders. Similarly, individuals with hematological malignancies undergoing allogeneic hematopoietic stem cell transplantation experience prolonged T cell deficiencies, which increase the risk of infections and relapses. Various strategies for addressing T cell deficiencies are based on adoptive T cell therapies. However, challenges related to specificity, safety, scalability, and manufacturing have yet to be overcome. Human T lymphoid progenitor (HTLP)-based immunotherapy might be a valuable, complementary approach for increasing the effectiveness of current treatments for T cell deficiencies. We developed a feeder-free culture system that leverages a human DLL4-Fc fusion protein (Notch ligand) to generate HTLP from CD34+ hematopoietic stem and progenitor cells within 7 days. The cell product, called ProTcell, is mainly constituted of cells expressing CD7, chemokine receptor proteins (e.g. CCR9) and adhesion molecules (e.g. L-selectin). After injection in NSG mice, ProTcell can differentiate and be educated in the thymus to generate simple positive T-cells. Here, we summarize the current state of preclinical and clinical research using this approach, highlighting its potential advantages and current limitations for immune reconstitution therapies.
    Keywords:  DLL4; Hematopoietic stem cell transplantation; Immune reconstitution; Lymphopoiesis; T cell progenitor; T lymphocyte; Thymus
    DOI:  https://doi.org/10.1016/j.jaci.2025.08.004
  17. Clin Microbiol Rev. 2025 Aug 22. e0019824
      SUMMARYViral infections remain a significant and predictable challenge in solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients. Although antiviral drugs are commonly used for prophylaxis or early treatment, their long-term use is limited by toxicity, high costs, and the emergence of drug-resistant viral strains, often leading to treatment failure. Cellular immune therapies, particularly adoptive transfer of virus-specific T cells (VSTs), have emerged as a promising alternative, with proven efficacy in controlling hematological malignancies and severe viral infections. While donor-derived VSTs can effectively suppress viral replication in HSCT and SOT recipients, this approach is not feasible when donors are seronegative or inaccessible. A novel single-platform technology now allows for the rapid generation of multi-virus-specific T cells from healthy donors, broadening the applicability of this strategy. In addition, immune monitoring tools can help identify high-risk patients, enabling earlier and more targeted interventions. Emerging data suggest that adoptive T-cell therapy may be used not only therapeutically but also prophylactically, potentially replacing conventional antivirals and reducing adverse effects in immunocompromised patients. This review provides historical foundations and recent advancements in the use of adoptive T-cell therapies for virus-associated complications in transplant recipients.
    Keywords:  Epstein-Barr virus; T-cell therapy; adenoviruses; adoptive transfer; cytomegalovirus; immunity; polyomavirus
    DOI:  https://doi.org/10.1128/cmr.00198-24
  18. Front Drug Deliv. 2025 ;5 1598145
      Gene therapy, a pivotal cornerstone in biomedical research, has emerged as a transformative approach for addressing a wide spectrum of dermatologic conditions, including hereditary disorders, chronic wounds, and immune related skin diseases. The skin, with its expansive surface area and regenerative capacity, serves as an ideal platform for localized gene delivery. However, conventional gene therapy strategies face critical limitations, such as high costs, suboptimal transfection efficiency, immunogenicity, and off-target effects. In this context, gene hydrogels have emerged as an innovative paradigm, offering tailored physicochemical and biological functionalities to overcome these challenges. Gene hydrogels are distinguished by their tunable morphologies (e.g., particulate or bulk gel configurations), which enable precise control over therapeutic release kinetics and spatial distribution. Their three-dimensional polymeric networks recapitulate the extracellular matrix, functioning as bioactive scaffolds that enhance tissue regeneration, facilitate cell migration, and accelerate wound healing. By integrating stimuli-responsive polymers, these hydrogels achieve spatiotemporal control of gene delivery, improving target specificity while minimizing systemic exposure. Furthermore, their inherent biocompatibility and biodegradability mitigate immunogenic risks and prevent long-term residue accumulation, addressing pivotal safety concerns in clinical translation. This review systematically examines the multifaceted advantages of gene hydrogels, including their ability to bypass the stratum corneum barrier, protect genetic payloads from enzymatic degradation, and sustain localized therapeutic effects over extended periods. Recent advancements in "smart" hydrogels, responsive to pathological cues such as pH fluctuations or matrix metalloproteinase overexpression, further underscore their potential in personalized medicine. By synergizing material science with gene-editing technologies, gene hydrogels represent a revolutionary leap toward precision dermatologic therapies. Future challenges, such as scalable manufacturing and dynamic regulatory mechanisms, are critically analyzed alongside opportunities in intelligent material design and interdisciplinary innovation. This comprehensive analysis positions gene hydrogels as a cornerstone for next-generation dermatologic therapeutics, bridging the gap between laboratory innovation and clinical impact.
    Keywords:  gene delivery; gene hydrogel; hereditary skin disease; immune related skin disease; wound healing
    DOI:  https://doi.org/10.3389/fddev.2025.1598145
  19. Cancer Treat Res. 2025 ;129 293-308
      There have been tremendous advancements in immunotherapy approaches for patients with renal cell carcinoma (RCC) from the initial interleukin-2 era to the current immune checkpoint inhibitor (ICI) combinations. Several ICI-based therapies have greatly improved outcomes for patients with RCC with the potential for durable responses for a subset of patients. In this chapter, we review the data of key frontline ICI-based combinations for RCC in the metastatic setting and recent data on adjuvant immunotherapy. We also discuss recent data on the role of immunotherapy rechallenge following prior ICI treatment as well as emerging novel immunotherapy strategies with chimeric antigen receptor (CAR) T and gut microbiome interventions. Lastly, we highlight a multidisciplinary team-based approach for patients with RCC treated with ICI including management of immune-related adverse events as well as potential role of cytoreductive nephrectomy in an evolving treatment landscape.
    Keywords:  Immunotherapy; Kidney cancer; Microbiome; Renal cell carcinoma
    DOI:  https://doi.org/10.1007/978-3-031-97242-3_13
  20. Int Immunol. 2025 Aug 16. pii: dxaf048. [Epub ahead of print]
      The T cell receptor (TCR) repertoire is a valuable source of information that reflects an individual's immune status and infection history. However, due to the exceptional diversity and complexity of the TCR repertoire, predicting its functional properties remains a challenging task. This review summarizes recent advances in protein language models (PLMs), which apply natural language processing techniques to protein sequences, focusing specifically on TCR repertoire analysis. We begin by outlining the biological basis of the TCR repertoire and its current clinical applications. We then describe the methods used for representing TCR data and the training procedures of the corresponding PLMs. PLMs capture context-dependent features from large unlabeled TCR datasets and achieve high generalization performance even with limited labeled data through transfer learning. In this respect, PLMs offer significant advantages over conventional sequence representation methods. We highlight antigen specificity prediction as a key application, comparing supervised deep learning models with PLM-based approaches. While employment of PLMs is promising, TCR repertoire analysis still faces challenges such as data scarcity, bias, and lack of paired-chain information. Addressing these challenges requires rigorous dataset optimization, integration, and augmentation strategies. Future advances will require better interpretation of the representations learned by PLMs and the development of multimodal approaches that integrate structural information. These advances could enable several clinical applications, including disease diagnosis, vaccine development, and personalized immune profiling.
    Keywords:  AIRR; TCR repertoire; antigen specificity prediction; self-supervised learning; transfer learning
    DOI:  https://doi.org/10.1093/intimm/dxaf048
  21. Cytotherapy. 2025 Jul 23. pii: S1465-3249(25)00784-4. [Epub ahead of print]
       BACKGROUND: Cytokine release syndrome (CRS) is an adverse event associated with T-cell engaging (TCE) immuno-oncology therapies such as chimeric antigen receptor T cells (CAR-T), bispecific TCE antibodies and dual-affinity retargeting proteins.
    OBJECTIVE: To develop a model to predict the preinfusion risk of CRS grade ≥2 for patients with solid tumors and hematologic malignancies such as acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL) treated with TCE bispecific antibodies.
    STUDY DESIGN: A TCE dataset including clinical trials from 2014 to 2019 evaluating non-CAR-T TCE therapies was sourced from the Medidata Enterprise Data Store, an anonymized data repository from completed clinical trials. The outcome of interest was the first CRS grade ≥2 occurring within 10 days of TCE therapy. Risk factors for CRS grade ≥2 were identified from the literature and preliminary data analysis. Features were measured prior to or at the first TCE treatment. Patients were included in the analysis dataset if they had a data element fill rate of >70% for the key features. Features were pruned by assessing multicollinearity across features. Logistic regression and tree-based models were trained. Across 100 iterations with different train-test splits, the average area under the receiver-operator characteristic (AUROC) curve was calculated for each model type.
    RESULTS: A total of 715 patients (115 CRS grade ≥2 and 600 CRS grade <2) were included in the analysis; most patients had ALL (81%) and 19% had solid tumors or NHL. Patients who developed CRS grade ≥2 had a higher incidence of prior infections (38% versus 28%; P = 0.03) and a higher first dose of TCE therapy (P < 0.001). The best model to predict CRS grade ≥2 had a mean AUROC of 0.69 (95% confidence interval 0.66-0.72) on the test set. When patients were ranked based on their predicted probability of getting CRS grade ≥2 and divided into quartiles based on predicted CRS grade ≥2 risk (very low, low, high, very high), the very high-risk quartile developed CRS grade ≥2 at 5.9 times the rate (38.10% [interquartile range: 33.33-43.54]) compared to the very-low risk quartile (6.45% [3.44-8.82]; the sample average was 12.96% [9.25-24.07]). Compared to patients with very low CRS grade ≥2 risk, patients with very high CRS grade ≥2 risk had ALL as a disease type (99% versus 67%, P < 0.001), received a higher TCE dose (1.00 versus 0.61, P < 0.001), had a higher rate of prior infections (49% versus 12%, P < 0.001) and a higher serum creatinine (0.60 versus 0.32, P < 0.001).
    CONCLUSIONS: Using the CRS grade ≥2 risk model, it was possible to stratify patients by risk categories. CRS grade ≥2 risk stratification may facilitate patient selection for TCE therapy and tailored pretreatment and monitoring of CRS to maximize treatment efficacy and safety.
    Keywords:  T-cell engaging therapy; cytokine release syndrome; risk prediction
    DOI:  https://doi.org/10.1016/j.jcyt.2025.07.002
  22. Asian Pac J Cancer Prev. 2025 Aug 01. pii: 91818. [Epub ahead of print]26(8): 2741-2754
      Personalized cancer vaccines represent a promising advancement in cancer immunotherapy, designed to target tumor-specific mutations unique to individual patients. By stimulating a tailored immune response, these vaccines aim to enhance antitumor immunity while minimizing off-target effects. However, cancer is a complex disease, and single-modality treatments often face challenges such as immune evasion and tumor heterogeneity. To address these limitations, personalized cancer vaccines are increasingly being explored in combination with other therapeutic strategies, including immune checkpoint inhibitors, cytokine therapies, oncolytic viruses, and traditional chemotherapies. This review provides a comprehensive overview of the current status of personalized cancer vaccines, focusing on their development, clinical trials, and early outcomes. It also discusses the synergistic potential of combination therapies, offering insights into how these strategies could overcome immunosuppressive tumor microenvironments and improve patient outcomes. Finally, we explore future prospects, addressing challenges such as vaccine production, patient selection, and regulatory frameworks to outline the path forward for the successful integration of personalized vaccines into standard oncological care.
    Keywords:  Future Prospects; Therapeutics Prevention; cancer vaccine; current status; quality improvement
    DOI:  https://doi.org/10.31557/APJCP.2025.26.8.2741
  23. Cytotherapy. 2025 Jul 24. pii: S1465-3249(25)00787-X. [Epub ahead of print]
       BACKGROUND: Cell therapy using differentiated cells with less immune rejection of the patient's own cells can be realized by generating therapeutic cells from induced pluripotent stem cells (iPSCs). Current methods to produce iPSCs and differentiated cells in cell culture and processing facilities under GMP control typically involve 5-6 people working in one room. This process is suitable for large-scale production, but not for custom manufacturing of autologous iPSCs. A cell manufacturing process suitable for the production of autologous iPSCs can be implemented by simplifying aseptic operations, using small cell culture bags to enable small batch production, and providing a cell processing platform that integrates successive cell processing steps by building a connected loop of small cell culture bags.
    OBJECTIVE: We are developing a closed culture system to produce therapeutic cells using iPSCs derived from the patient's own cells. Cell Therapy Applications for Autologous iPSCs is a closed culture kit with 10 culture ports (small cell culture bags with many connecting tubes for cell processing) for each culture step.
    STUDY DESIGN: Cells are moved from one culture port to the next at each step of the process. We initially designed our own culture port, which is a cell culture site in the cell therapy kit. Manufacturing was outsourced to CellBios (India). The ports were designed according to a series of 10 linked steps as follows: vector infection (2 hours), vector dilution, iPSC establishment (14 days), iPSC proliferation 1 (7 days), iPSC proliferation 2 (7 days), differentiation inducing solution A (0-10 days), differentiation inducing solution B (0-10 days), differentiation inducing solution C (0-10 days) and final formulation process of the cell product.
    RESULTS: During iPSC derivation and differentiation induction, cells are attached to atelocollagen beads so that the cells and beads can move between culture processes without cell detachment. We conducted a pilot study to determine the effect of the beads on iPSC differentiation. In the pilot study, we first established iPSCs on atelocollagen beads using Peripheral Blood Mononuclear Cells (PBMCs) and induced the differentiation of different cells (cardiomyocytes, pancreatic progenitor cells, and dopaminergic neurons). Marker expression of the differentiated cells was evaluated.
    CONCLUSION: A series of processes were reproduced in a closed culture system to study cell characteristics.
    Keywords:  autologous; cell characteristics; closed culture system; differentiation; induced pluripotent stem cells(iPSCs); small-lot production
    DOI:  https://doi.org/10.1016/j.jcyt.2025.07.004
  24. Front Immunol. 2025 ;16 1626082
      Autoimmune diseases are a diverse group of chronic disorders characterized by inappropriate immune responses against self-antigens, resulting in persistent inflammation and tissue destruction. Affecting an estimated 7-10% of the global population, these conditions include both systemic and organ-specific entities such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), type 1 diabetes (T1D), and multiple sclerosis (MS). Despite their clinical heterogeneity, autoimmune diseases share a common etiologic framework involving the convergence of genetic predisposition, environmental exposures, and immune dysregulation. Genome-wide association studies (GWAS) have identified hundreds of risk loci, most notably within the major histocompatibility complex (MHC), and highlighted the role of non-HLA genes regulating cytokine signaling, antigen presentation, and T cell tolerance. The majority of disease-associated variants lie in non-coding regulatory elements, suggesting that transcriptional dysregulation plays a central role in disease susceptibility. Yet, genetics alone does not determine disease onset-environmental factors such as infections, diet, microbiome alterations, and hormonal influences critically shape immune responses and may trigger disease in genetically susceptible individuals. Additionally, epigenetic modifications further compound these effects, creating lasting changes in gene expression and immune cell function. At the core of autoimmune pathogenesis lies immune dysregulation, particularly failure of peripheral tolerance maintained by regulatory T cells (Tregs). While Treg frequencies may appear normal in patients, emerging data indicate intrinsic signaling defects-especially impaired IL-2 receptor (IL-2R) signal durability-compromise Treg suppressive function. This dysfunction is linked to aberrant degradation of key IL-2R second messengers, including phosphorylated JAK1 and DEPTOR, due to diminished expression of GRAIL, an E3 ligase that inhibits cullin RING ligase activation. This review integrates recent insights across genetic factors, environmental triggers, and immune dysregulation to build a comprehensive understanding of autoimmune disease pathogenesis. We propose a novel therapeutic strategy targeting IL-2R signaling using Neddylation Activating Enzyme inhibitors (NAEis) conjugated to IL-2 or anti-CD25 antibodies. This approach selectively restores Treg function and immune tolerance without inducing systemic immunosuppression. By focusing on immune restoration rather than suppression, This therapy could provide an off the shelf therapy for many different autoimmune diseases.
    Keywords:  Autoimmune disease; GRAIL; IL-2 receptor signaling; environmental triggers; genetic susceptibility; neddylation; phosphor-S6; regulatory T cells
    DOI:  https://doi.org/10.3389/fimmu.2025.1626082
  25. J Mark Access Health Policy. 2025 Sep;13(3): 38
      Patient involvement in health technology assessment (HTA) processes is increasingly recognized as pivotal for informed, equitable, and patient-relevant health care decision-making. With the implementation of Joint Scientific Consultations (JSCs) and Joint Clinical Assessments (JCAs) under Regulation (EU) 2021/2282, the European Union has a unique opportunity to design harmonized mechanisms that reflect best practices from established HTA systems. This article, drawing on the Acute Leukemia Advocates Network (ALAN)'s comparative analysis of HTA practices across seven countries (Canada, England, Scotland, France, Germany, Spain, and Italy), examines how current patient involvement processes can inform the JCA framework. It identifies opportunities to replicate effective practices and proposes strategies to embed patient voices meaningfully into the JCA process. By prioritizing robust and inclusive patient involvement, the EU can establish a global benchmark for impactful and consistent HTA processes. By leveraging lessons from international HTA systems and prioritizing clear frameworks, early involvement, and capacity building, the EU can set a global standard for meaningful patient participation in HTA processes. ALAN is an independent global network of patient organizations dedicated to improving outcomes for patients with acute leukemia.
    Keywords:  HTA; health technology assessments; joint clinical assessments; patient involvement
    DOI:  https://doi.org/10.3390/jmahp13030038
  26. Front Drug Deliv. 2024 ;4 1360302
      The delivery of therapeutics into the brain is highly limited by the blood-brain barrier (BBB). Although this is essential to protect the brain from potentially harmful material found in the blood, it poses a great challenge for the treatment of diseases affecting the central nervous system (CNS). Substances from the periphery that are required for the function of the brain must rely on active mechanisms of entry. One such physiological pathway is called receptor-mediated transcytosis (RMT). In this process, ligands bind to specific receptors expressed at the luminal membrane of endothelial cells composing the BBB leading to the internalization of the receptor-ligand complex into intracellular vesicles, their trafficking through various intracellular compartments and finally their fusion with the abluminal membrane to release the cargo into the brain. Targeting such RMT receptors for BBB crossing represents an emerging and clinically validated strategy to increase the brain permeability of biologicals. However, the choice of an appropriate receptor is critical to achieve the best selectivity and efficacy of the delivery method. Whereas the majority of work has been focused on transferrin (Tf) receptor (TfR), the search for novel receptors expressed in brain endothelial cells (BECs) that can deliver protein or viral vector cargos across the BBB has yielded several novel targets with diverse molecular/structural properties and biological functions, and mechanisms of transcytosis. In this review, we summarize well-studied RMT pathways, and explore mechanisms engaged in BBB transport by various RMT receptors. We then discuss key criteria that would be desired for an optimal RMT target, based on lessons-learned from studies on TfR and accumulating experimental evidence on emerging RMT receptors and their ligands.
    Keywords:  RMT receptors; blood-brain barrier; drug delivery; receptor-mediated transcytosis; trafficking
    DOI:  https://doi.org/10.3389/fddev.2024.1360302