bims-carter Biomed News
on CAR-T Therapies
Issue of 2025–05–11
eighteen papers selected by
Luca Bolliger, lxBio
  1. The Mechanisms and Countermeasures for CAR-T cell Expansion and Persistence Deficiency.
  2. European survey on CAR T-Cell analytical methods from apheresis to post-infusion immunomonitoring.
  3. Checkpoint Inhibitors, CAR T Cells, and the Hemostatic System: What Do We Know So Far?
  4. Endosialin-directed CAR-T cell therapy: A promising approach for targeting triple-negative breast cancer.
  5. Surveying local CAR T-cell manufacturing processes to facilitate standardization and expand accessibility.
  6. Bridging the Gap Between Bone Marrow Transplantation and CAR-T Cell Therapy in Hematological Cancers.
  7. Implementation of a CAR-T cell therapy program in India.
  8. A Novel Therapeutic Strategy for Central Nervous System Lymphoma: Integrating Chimeric Antigen Receptor T-Cell Therapy and Gamma Knife Radiation.
  9. Mechanistic insights into resistance mechanisms to T cell engagers.
  10. FDA Experience on CAR T Cell Pharmacokinetics/Pharmacodynamics and Model-Based Assessments.
  11. Optimization of hypo-alloimmunogenic multispecific CAR-T and SARS-CoV-2-specific T cells for off-the-shelf adoptive cell therapy.
  12. Generating potent and persistent antitumor immunity via affinity-tuned CAR-T cells targeting mesothelin.
  13. Enhanced CAR T-Cell Therapy for Lymphoma after Previous Failure.
  14. Quadruple adenine base-edited allogeneic CAR T cells outperform CRISPR/Cas9 nuclease-engineered T cells.
  15. Transition from manual to automated processes for autologous T cell therapy manufacturing using bioreactor with expandable culture area.
  16. Concept CARs are picking up speed.
  17. The Tale of Pediatric Hematopoietic Stem Cell Transplantation in Iran: An Uphill Battle.
  18. The information overload, immunology and their relationship to world health.
  1. Cancer Lett. 2025 May 02. pii: S0304-3835(25)00337-4. [Epub ahead of print] 217771
    The Mechanisms and Countermeasures for CAR-T cell Expansion and Persistence Deficiency.
    Yu-Tong Bao, Meng Lv, Xiao-Jun Huang, Xiang-Yu Zhao.
      Chimeric antigen receptor (CAR) T cell therapy has emerged as a groundbreaking treatment for hematological malignancies, particularly B-cell malignancies. However, its high risk of relapse and low efficacy in malignancies such as chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) have limited its clinical utility. The expansion, infiltration and persistence of CAR-T cells are key determinants of their efficacy. It has been recognized that limited expansion and lack of persistence are major contributors to non-remission and early relapse, highlighting the need to elucidate their mechanisms and countermeasures. In this review, we described features of CAR-T cell expansion and persistence in various hematogenic malignancies and solid tumors. Then, current knowledge on the mechanisms underlying deficiency in CAR-T cell expansion and persistence is presented, focusing on the intrinsic deficiency of CAR-T cells as well as their interaction with the systemic and local immune environment. Finally, we summarize approaches to enhance CAR-T cell expansion and persistence by improving CAR-T cell quality and overcoming the immunosuppressive environment.
    DOI:  https://doi.org/10.1016/j.canlet.2025.217771
  2. Front Immunol. 2025 ;16 1567582
    European survey on CAR T-Cell analytical methods from apheresis to post-infusion immunomonitoring.
    Biagio De Angelis, Maria Luisa D'Amore, Pacôme Lecot, Kerstin Neininger, Margot Lorrain, Laetitia Gambotti, Caroline Dreuillet, Elise Courcault, Sampurna Chatterjee, Julio Delgado, Anne Galy, Paul Franz, Juan Roberto Rodriguez-Madoz, Yolanda Cabrerizo, Anne Richter, Charis Girvalaki, Maddalena Noviello, Elena Tassi, Carmen Sanges, Maik Luu, Michael Hudecek, Andreas Kremer, Franco Locatelli, Helene Negre, Concetta Quintarelli.
       Background: Chimeric Antigen Receptor (CAR) T-cell therapy has emerged as a revolutionary approach to cancer treatment. Given the rapid expansion of new indications addressed by newly developed CAR T-cell products, it is essential to standardize analytical methods for the characterization/monitoring of apheresis materials, drug products, and post-infusion patient samples.
    Methods: The T2Evolve Consortium, part of the European Union's Innovative Medicines Initiative (IMI), conducted an extensive anonymous online survey between February and June 2022. Comprising 36 questions, the survey targeted a wide range of stakeholders involved in engineered T-cell therapies, including researchers, manufacturers, and clinicians. Its goal was to address the current variability within the CAR T-cell field, focusing on analytical assays for quality control of apheresis materials, drug products, and post-infusion immunomonitoring. Another objective was to identify gaps and needs in the field.
    Results: A total of 53 respondents from 13 european countries completed the survey, providing insights into the most commonly used assays for apheresis material and drug product characterization, alongside safety and efficacy tests required by the Pharmacopeia. Notably, a minority of respondents conducted phenotypical characterization of T-cell subsets in the drug product and assessed activation/exhaustion T cell profiles.
    Conclusion: The survey underscored the necessity to standardize CAR T-cell functional potency assays and identify predictive biomarkers for response, relapse, and toxicity. Additionally, responses indicated significant variability in CAR T-cell monitoring during short-term patient follow-up across clinical centers. This European survey represents the first initiative to report current approaches in different stages of CAR T-cell therapies via a survey, from drug product quality controls to post-infusion immunomonitoring. Based on these findings, and with input from T2EVOLVE experts, the next step will be to address harmonization in the identified areas. These efforts are anticipated to significantly enhance cancer patients' access to engineered T cell therapy safely and effectively throughout Europe.
    Keywords:  CAR T-cells; European survey; T2Evolve; immunomonitoring; leukapheresis; lymphodepleting chemotherapy
    DOI:  https://doi.org/10.3389/fimmu.2025.1567582
  3. Hamostaseologie. 2025 Apr;45(2): 175-187
    Checkpoint Inhibitors, CAR T Cells, and the Hemostatic System: What Do We Know So Far?
    Christina C Rolling, Samuel Lewirt, Antonia Beitzen-Heineke, Lennart Beckmann, Carsten Bokemeyer, Winfried Alsdorf, Minna Voigtlaender, Florian Langer.
      Immune checkpoint inhibitors (ICIs) and chimeric antigen receptor (CAR) T cells are novel therapeutic strategies that enhance anticancer immunity by activating or engineering cancer-targeting T cells. The resulting hyperinflammation carries several side effects, ranging from autoimmune-like symptoms to cytokine release syndrome (CRS), with potentially severe consequences. Recent findings indicate that ICIs increase the risk of venous and arterial thromboembolic adverse events. Patients with prior VTE might be at higher risk of developing new events under ICI while other risk factors vary across studies. So far, data on CAR T-linked coagulopathies are limited. Hypofibrinogenemia in the presence of CRS is the most commonly observed dysregulation of hemostatic parameters. A rare but particularly severe adverse event is the development of disseminated intravascular coagulation activation, which can occur in the setting of CRS and may be linked to immune effector cell-associated hemophagocytic lymphohistiocytosis. While the increasing number of studies on thromboembolic complications and coagulation alterations under ICIs and CAR T therapies are concerning, these results might be influenced by the retrospective study design and the heterogeneous patient populations. Importantly, numerous promising new T cell-based immunotherapies are currently under investigation for various cancers and are expected to become very prominent therapy options in the near future. Therefore, coagulopathies and thrombosis under T cell-directed immuno- and anti-cancer therapies is important. Our review provides an overview of the current understanding of ICI- and CAR T-associated thromboembolism. We discuss pathogenic mechanisms of inflammation-associated coagulation activation and explore potential biomarkers for VTE.
    DOI:  https://doi.org/10.1055/a-2528-5071
  4. Biochim Biophys Acta Mol Basis Dis. 2025 May 01. pii: S0925-4439(25)00197-8. [Epub ahead of print] 167852
    Endosialin-directed CAR-T cell therapy: A promising approach for targeting triple-negative breast cancer.
    Adil Farooq Wali, Sirajunisa Talath, Sathvik B Sridhar, Mohamed El-Tanani, Imran Rashid Rangraze.
      In triple-negative breast cancer, this review article explores into the utilization of Chimeric antigen receptor T-cell (CAR-T) cell therapy to target cells expressing endosialin. Even with all the new treatments available, breast cancer still kills more women than any other disease. Drug resistance and ineffective cancer cell targeting are two major problems with targeted medications, chemotherapy, and surgery. Among cancer treatments, CAR-T cell therapy stands out. To identify endosialin as a therapeutic target, it is essential to understand its molecular structure and its involvement in tumor angiogenesis and progression. An effective target for CAR-T cells is breast cancer, which overexpresses endosialin. The development of CARs that are specific to endosialin and the results of early trials are covered in relation to CAR-T cell therapy that targets endosialin. Perhaps the most effective cancer treatment is endosialin targeting, since it is expressed only in tumors and plays a crucial role in the course of cancer. This article reviews endosialin-directed CAR-T cell breast cancer treatments' safety and efficacy from current and completed clinical trials. Despite promising results, these trials reveal that clinical translation must overcome significant challenges. The report suggests further research and combination tactics to improve endosialin-targeted CAR-T cell treatment.
    Keywords:  Angiogenesis; CAR-T cells; Chemotherapy; Endosialin; Tumor; cancer
    DOI:  https://doi.org/10.1016/j.bbadis.2025.167852
  5. J Transl Med. 2025 May 06. 23(1): 507
    Surveying local CAR T-cell manufacturing processes to facilitate standardization and expand accessibility.
    Deven Gupta, Beth Shaz.
       BACKGROUND: Chimeric antigen receptor T-cell (CAR T-cell) therapies have shown significant promise in treating cancers and other diseases. However, the manufacturing processes for CAR T-cell therapies exhibit considerable variability, which can affect treatment consistency and patient outcomes. While centralized manufacturing models dominate, local decentralized approaches, including point-of-care production, are being explored to address logistical and access challenges. This study aims to evaluate the current landscape of local CAR T-cell manufacturing at academic institutions.
    METHODS: A comprehensive, cross-sectional survey was distributed to 130 FACT and/or JACIE accredited academic institutions globally. The survey, developed from semi-structured interviews with CAR T-cell manufacturing experts, assessed practices in cell modification methods, equipment protocols, and regulatory challenges. Data were analyzed using descriptive statistics, comparing responses across institutions and regions.
    RESULTS: 45 of the 130 institutions (35 from the United States and 10 internationally, from the European Union, the United Kingdom, and Australia) responded to the survey (35% response rate). Of the 45 responding institutions, 40 were actively engaged or planning to engage in CAR T-cell production, while five had no plans to initiate manufacturing. Within the 40 institutions engaged in CAR T-cell production, 63% (25/40) reported active manufacturing, while 37% (15/40) were in the process of developing manufacturing capabilities. The most commonly reported barriers to local manufacturing were cost constraints (70%, 28/40), regulatory complexities (70%, 28/40), and facility requirements (57%, 17/40). Variability in product quality was cited by 73% (29/40) of institutions. Equipment costs and the need for specialized training emerged as major challenges, particularly for international institutions. Institutions also highlighted the need for automated platforms, with 60% (24/40) using the Miltenyi CliniMACS Prodigy and 50% (20/40) using the Lonza Cocoon.
    CONCLUSIONS: This study highlights the widespread adoption of local CAR T-cell manufacturing and the significant variability in production processes across institutions. The findings emphasize the importance of establishing quality control benchmarks and data reporting frameworks to improve product consistency and access to CAR T-cell therapies. Addressing barriers such as cost, infrastructure, and regulatory challenges through standardization efforts and international collaboration could enhance the reproducibility, scalability, and accessibility of CAR T-cell therapies globally.
    Keywords:  CAR T-cell; Cancer immunology; Decentralized manufacturing; GMP Manufacturing; Point-of-care manufacturing; T cell engineering
    DOI:  https://doi.org/10.1186/s12967-025-06400-x
  6. Adv Exp Med Biol. 2025 May 07.
    Bridging the Gap Between Bone Marrow Transplantation and CAR-T Cell Therapy in Hematological Cancers.
    Babak Arjmand, Fatemeh Shahrahmani, Alieh Mirzaei, Sepideh Alavi-Moghadam, Rasta Arjmand, Mostafa Rezaei-Tavirani, Seyed Mohammadamin Nejati-Niyaki, Bagher Larijani, Ghasem Janbabaei, Seied Asadollah Mousavi, Abbas Hajifathali.
      Bone marrow transplantation and chimeric antigen receptor T cell therapy have become two important treatment modalities for hematological malignancies, each having different mechanisms of action and therapeutic roles. This chapter focuses on the chronological development and obstacles of bone marrow transplantation, the paradigm-shifting impact of chimeric antigen receptor T cell therapy, and further integrative approaches. The complementary roles of these modalities are emphasized given their optimal timing, selection of patients, and the development of novel strategies to improve therapeutic outcomes. Challenges such as cytokine release syndrome, graft-versus-host disease, and immune suppression are critically scrutinized. The future perspectives highlight the development of synergistic approaches, refining patient-centered treatments, and addressing long-term quality-of-life concerns. It is with this aim that the discussion below might help bridge these modalities through interdisciplinary efforts toward more effective, personalized, and sustainable treatments for cancer.
    Keywords:  Advanced cancer immunotherapy; Bone marrow transplantation; Chimeric antigen receptor T cell therapy; Hematological cancers; Integrative cancer treatment
    DOI:  https://doi.org/10.1007/5584_2025_862
  7. Expert Rev Anticancer Ther. 2025 May 08. 1-10
    Implementation of a CAR-T cell therapy program in India.
    Hema Hotchandani, Manju Sengar, Alok Shetty, Anupa John, Atharva Karulkar, Devanshi Kalra, Smrithi Ravikumar, Anjali Jaiswal, Yuktam Yadav, Sugandha Parkar, Anuradha Walawalkar, Sonali Kadam, Bhausaheb Bagal, Lingaraj Nayak, Rahul Purwar, Hasmukh Jain.
       INTRODUCTION: CAR-T cell therapy has changed the treatment paradigm for hematological malignancies, offering a curative potential for patients with relapsed or refractory disease. India, with its significant burden of hematological malignancies, faces unique challenges in implementing this therapy. The development of indigenous CAR-T cells has reduced costs substantially, but barriers remain, including limited manufacturing capacity, relatively high costs, and logistical constraints.
    AREAS COVERED: This article emphasizes the importance of optimized patient selection and triaging of apheresis slots to maximize the benefits of CAR-T cell therapy. The use of efficient bridging therapies and antibody-based approaches are being explored to improve outcomes, particularly in aggressive lymphomas and leukemias. Opportunities lie in leveraging India's growing biotechnology sector for cost-efficient production and in evaluating novel combination therapies to enhance CAR-T cell efficacy. This article also explores the technical and socioeconomic challenges of CAR-T cell development in India and suggests strategies to enhance accessibility, affordability, and implementation.
    EXPERT OPINION: Ongoing advancements and research may help tailor CAR-T cell protocols to the local population. Future integration of NK cell therapy, TCR-based approaches, and multi-antigen targeting holds promise for enhancing therapeutic efficacy.
    Keywords:  CAR-T cell; acute lymphoblastic leukemia; challenges; chimeric antigen receptor; hematological malignancies; immunotherapy; non-Hodgkin’s lymphoma; opportunities
    DOI:  https://doi.org/10.1080/14737140.2025.2501744
  8. J Hematol. 2025 Apr;14(2): 100-104
    A Novel Therapeutic Strategy for Central Nervous System Lymphoma: Integrating Chimeric Antigen Receptor T-Cell Therapy and Gamma Knife Radiation.
    Katherine Hickmann, Rachel DiLeo, Kathleen Faringer, Chelsea Peterson, Rodney Wegner, Zachary Horne, Yazan Samhouri.
      Central nervous system lymphoma (CNSL) is an aggressive disease with limited well-studied options for treatment, especially refractory treatment. First-line treatment usually includes high-dose methotrexate (HD-MTX) for induction and either autologous stem cell transplantation or whole-brain radiation therapy (WBRT) as consolidation. However, WBRT can result in significant neurotoxicity, so the use of focal radiation (i.e., gamma knife-stereotactic radiosurgery (GK-SRS)) of varying doses and fractions has been proposed. In the case of refractory disease, chimeric antigen receptor (CAR) T-cell therapy has begun to be used clinically, but patients with CNS involvement were left out of key approval trials. Here, we present a case of a 62-year-old patient with refractory secondary CNSL (SCNSL) previously treated with WBRT who was successfully treated with a combination of CAR T-cell therapy and GK-SRS.
    Keywords:  CAR T-cell; CNSL; GK-SRS
    DOI:  https://doi.org/10.14740/jh2029
  9. Front Immunol. 2025 ;16 1583044
    Mechanistic insights into resistance mechanisms to T cell engagers.
    Linlin Cao, Gabrielle Leclercq-Cohen, Christian Klein, Antonio Sorrentino, Marina Bacac.
      T cell engagers (TCEs) represent a groundbreaking advancement in the treatment of B and plasma cell malignancies and are emerging as a promising therapeutic approach for the treatment of solid tumors. These molecules harness T cells to bind to and eliminate cancer cells, effectively bypassing the need for antigen-specific T cell recognition. Despite their established clinical efficacy, a subset of patients is either refractory to TCE treatment (e.g. primary resistance) or develops resistance during the course of TCE therapy (e.g. acquired or treatment-induced resistance). In this review we comprehensively describe the resistance mechanisms to TCEs, occurring in both preclinical models and clinical trials with a particular emphasis on cellular and molecular pathways underlying the resistance process. We classify these mechanisms into tumor intrinsic and tumor extrinsic ones. Tumor intrinsic mechanisms encompass changes within tumor cells that impact the T cell-mediated cytotoxicity, including tumor antigen loss, the expression of immune checkpoint inhibitory ligands and intracellular pathways that render tumor cells resistant to killing. Tumor extrinsic mechanisms involve factors external to tumor cells, including the presence of an immunosuppressive tumor microenvironment (TME) and reduced T cell functionality. We further propose actionable strategies to overcome resistance offering potential avenues for enhancing TCE efficacy in the clinic.
    Keywords:  T cell engager; T cell function; intrinsic mechanism; resistance mechanism; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1583044
  10. Clin Pharmacol Ther. 2025 May 04.
    FDA Experience on CAR T Cell Pharmacokinetics/Pharmacodynamics and Model-Based Assessments.
    Million A Tegenge, Xiaofei Wang, Jiang Liu, Hao Zhu, Lola A Fashoyin-Aje.
      Chimeric antigen receptor T cell (CAR T) therapies are genetically modified T cells that are engineered to recognize specific cell surface antigens (e.g., CD19 or B cell maturation antigen (BCMA), expressed on B cells). The objective of this review is to describe FDA experience with assessing the pharmacokinetics (PK), pharmacodynamics (PD) and conducting model-based analyses of FDA-approved CAR T cell products. The seven currently approved CAR T cell products target CD19 or BCMA and have both flat dose and body-weight-based intravenous dosing. The PK (e.g., expansion and persistence) and PD (e.g., B-cell aplasia, cytokine levels, and chemokine levels) data were an integral component of CAR T cell clinical pharmacology assessments. Model-based assessments, including population PK and exposure-response analysis, were conducted to understand PK variability and identify intrinsic/extrinsic factors impacting safety and efficacy outcomes. Continued use of clinical pharmacology tools such as model-based assessment to inform dose selection, dose optimization, and therapeutic individualization is integral to characterizing the effects of CAR T products.
    DOI:  https://doi.org/10.1002/cpt.3703
  11. Mol Ther Methods Clin Dev. 2025 Jun 12. 33(2): 101462
    Optimization of hypo-alloimmunogenic multispecific CAR-T and SARS-CoV-2-specific T cells for off-the-shelf adoptive cell therapy.
    King Pan Ng, Michaela Su-Fern Seng, Wing Leung.
      Despite promising results with chimeric antigen receptor modified T(CAR-T) cells and virus-specific T(VST) cells, both forms of therapy are limited by timely availability, affordability, in vivo persistency, and antigen escape. To overcome these barriers, we developed multitargeting hypo-alloimmunogenic CAR-T and VST for off-the-shelf administration. We generated bi-specific CAR-T against CD19 and CD22 and tri-specific VST against S, M, and N proteins of SARS-CoV-2 for real patient use. Portions of these clinical-grade products were collected for proof-of-concept laboratory studies mimicking off-the-shelf settings. By electroporation delivery of Cas9 nuclease/guide RNA (gRNA) ribonucleoprotein, we developed a single-step approach to knockout B2M, achieving efficient (>80% of cells) B2M null on both bi-specific CAR-T and tri-specific VST, leading to marked reduction of allo-immunogenicity with intact potency, antigen specificity, phenotypes, and proliferative potential. Using newly designed paired Cas9 nickases-AAV6 B2M site-specific knockin system, we further refined the approach to re-express HLA-E in B2M null bi-specific CAR-T cells (>50% of cells), offering protection from natural killer cytotoxicity. The editing was highly specific with minimal off-target effects. Our approach enables expedient production of clinical-grade, off-the-shelf, hypo-alloimmunogenic, multi-specific CAR-T and VST, with improved potential for long-term in vivo persistence, primary disease control, genome-safety, immediate availability, product homogeneity, and reduced cost.
    Keywords:  AAV; B2M; CD19/CD22; CRISPR-Cas9; HLA-E; SARS-CoV-2-specific T cells; adoptive T cell therapy; chimeric antigen receptor; knockin; paired Cas9 nickase
    DOI:  https://doi.org/10.1016/j.omtm.2025.101462
  12. Acta Pharmacol Sin. 2025 May 08.
    Generating potent and persistent antitumor immunity via affinity-tuned CAR-T cells targeting mesothelin.
    Ya-Li Yue, Jun-Jun Liu, Hang Ma, Zhi-di Pan, Lei Wang, Jia-Wei Zhang, Shu-Sheng Wang, Yue-Qing Xie, Hua Jiang, Yan-Lin Bian, Ming-Yuan Wu, Yun-Sheng Yuan, Bao-Hong Zhang, Xiao-Dong Xiao, Jian-Wei Zhu.
      Chimeric antigen receptor (CAR)-T cell therapy for solid tumors faces challenges of insufficient efficacy and a high recurrence rate. Mesothelin (MSLN) is a membrane glycoprotein highly expressed in various solid tumors that has restricted low expression in normal tissues such as the pleura, peritoneum, and pericardium. We previously performed affinity maturation based on the parental antibody M912, and constructed the phage display library. In this study we identified four novel human anti-MSLN antibodies (LP12, HP4-11, HP4-41/LP6, and HP4-44/LP2) with varying degrees of enhanced affinity. These third-generation CARs targeting MSLN were packaged into lentiviral vectors to generate stable CAR-T cells. The CAR-T variants induced robust cytolytic activity, significant cytokine production, and activation-induced clonal proliferation against various MSLN-positive tumors in vitro, and effectively cleared disseminated tumors in mice. A single administration of the CAR-T variant LP12 potently eradicated various types of MSLN-positive solid tumors, achieved long-term persistence in vivo, effectively prevented tumor recurrence, and exhibited no non-specific toxicity. Therefore, optimizing the affinity of antigen-binding domain in CAR represents a promising strategy for advancing the development of safe and effective CAR-T cell therapies. The LP12 CAR-T cells developed in this study have potential applications in patients with MSLN-positive solid tumors. Schematic illustration of the generation and antitumor mechanism of affinity-tuned MSLN-targeted CAR-T cells. The expression plasmids carrying different anti-MSLN CAR genes were packaged into lentiviral vectors. Lentiviral transduction of human CD3+ T cells was performed to generate CAR-T cells, which were then expanded. After injection of moderately affinity-tuned MSLN-targeted CAR-T cells into mice, they enter the bloodstream, recognize, and infiltrate the solid tumors. They specifically recognize and bind to MSLN on the surface of tumor cells, and upon activation, release IFN-γ, IL-2, and TNF-α to exert cytolytic activity. Subsequently, they undergo clonal proliferation and primarily differentiate into effector memory CAR-T cells, maintaining long-term antitumor immunity and effectively preventing recurrence.
    Keywords:  LP12 CAR-T cells; affinity-tuned; chimeric antigen receptor; mesothelin; solid tumors; tumor recurrence
    DOI:  https://doi.org/10.1038/s41401-025-01572-0
  13. N Engl J Med. 2025 May 08. 392(18): 1824-1835
    Enhanced CAR T-Cell Therapy for Lymphoma after Previous Failure.
    Jakub Svoboda, Daniel J Landsburg, James Gerson, Sunita D Nasta, Stefan K Barta, Elise A Chong, Michael Cook, Noelle V Frey, Joanne Shea, Amanda Cervini, Amy Marshall, Megan Four, Megan M Davis, Julie K Jadlowsky, Anne Chew, Edward Pequignot, Vanessa Gonzalez, Julia Han Noll, Luca Paruzzo, Juliana Rojas-Levine, Gabriela Plesa, John Scholler, Donald L Siegel, Bruce L Levine, David L Porter, Saba Ghassemi, Marco Ruella, Andrew Rech, Rachel M Leskowitz, Joseph A Fraietta, Wei-Ting Hwang, Elizabeth Hexner, Stephen J Schuster, Carl H June.
       BACKGROUND: Chimeric antigen receptor (CAR) T cells targeting CD19 have transformed the treatment of B-cell cancers, but many patients do not have long-term remission. We designed an anti-CD19 enhanced (armored) CAR T-cell product (huCART19-IL18) that secretes interleukin-18 to enhance antitumor activity.
    METHODS: In this study, we assessed the safety, feasibility, and preliminary efficacy of huCART19-IL18 in patients with relapsed or refractory lymphoma after previous anti-CD19 CAR T-cell therapy. Using a 3-day manufacturing process, we administered huCART19-IL18-positive cells in doses ranging from 3×106 to 3×108.
    RESULTS: A total of 21 patients received huCART19-IL18. Cytokine release syndrome occurred in 62% of the patients (47% with grade 1 or 2), and immune effector-cell-associated neurotoxicity syndrome occurred in 14% (all grade 1 or 2). No unexpected adverse events were observed. Robust CAR T-cell expansion was detected across all dose levels. At 3 months after infusion, a complete or partial response was seen in 81% of the patients (90% confidence interval [CI], 62 to 93) and a complete response in 52% (90% CI, 33 to 71). With a median follow-up of 17.5 months (range, 3 to 34), the median duration of response was 9.6 months (90% CI, 5.5 to not reached).
    CONCLUSIONS: In this small study, huCART19-IL18 had a safety profile consistent with other CAR T-cell treatments and showed promising efficacy at low cell doses in patients with lymphoma after the failure of previous anti-CD19 CAR T-cell therapy. (ClinicalTrials.gov number, NCT04684563.).
    DOI:  https://doi.org/10.1056/NEJMoa2408771
  14. Proc Natl Acad Sci U S A. 2025 May 20. 122(20): e2427216122
    Quadruple adenine base-edited allogeneic CAR T cells outperform CRISPR/Cas9 nuclease-engineered T cells.
    Nils W Engel, Israel Steinfeld, Daniel Ryan, Kusala Anupindi, Samuel Kim, Nils Wellhausen, Linhui Chen, Katherine Wilkins, Daniel J Baker, Philipp C Rommel, Danuta Jarocha, Mercy Gohil, Qian Zhang, Michael C Milone, Joseph A Fraietta, Megan Davis, Regina M Young, Carl H June.
      Genome-editing technologies have enabled the clinical development of allogeneic cellular therapies, yet the optimal gene-editing modality for multiplex editing of therapeutic T cell product manufacturing remains elusive. In this study, we conducted a comprehensive comparison of CRISPR/Cas9 nuclease and adenine base editor (ABE) technologies in generating allogeneic chimeric antigen receptor (CAR) T cells, utilizing extensive in vitro and in vivo analyses. Both methods achieved high editing efficiencies across four target genes, critical for mitigating graft-versus-host disease and allograft rejection: TRAC or CD3E, B2M, CIITA, and PVR. Notably, ABE demonstrated higher manufacturing yields and distinct off-target profiles compared to Cas9, with translocations observed exclusively in Cas9-edited products. Functionally, ABE-edited CAR T cells exhibited superior in vitro effector functions under continuous antigen stimulation, including enhanced proliferative capacity and increased surface CAR expression. Transcriptomic analysis revealed that ABE editing resulted in reduced activation of p53 and DNA damage response pathways at baseline, along with sustained activation of metabolic pathways during antigen stress. Consistently, Assay for Transposase-Accessible Chromatin using sequencing data indicated that Cas9-edited, but not ABE-edited, CAR T cells showed enrichment of chromatin accessibility peaks associated with double-strand break repair and DNA damage response pathways. In a preclinical leukemia model, ABE-edited CAR T cells demonstrated improved tumor control and extended overall survival compared to their Cas9-edited counterparts. Collectively, these findings position ABE as superior to Cas9 nucleases for multiplex gene editing of therapeutic T cells.
    Keywords:  CRISPR/Cas9; adenine base editor; chimeric antigen receptor
    DOI:  https://doi.org/10.1073/pnas.2427216122
  15. Sci Rep. 2025 May 06. 15(1): 15819
    Transition from manual to automated processes for autologous T cell therapy manufacturing using bioreactor with expandable culture area.
    Jia Sheng Zach Lee, Akshaya V Prabhu, Ying Ying Wu, Ahmad Amirul Bin Abdul Rahim, Sixun Chen, May Win Naing, Dan Liu.
      Transition from the manual processes that are performed during the initial research and development (R&D) stage to automated processes for later and commercial stage cell therapy manufacturing can be challenging. It often requires significant effort, time, and costs - which hinders the therapy's access to the clinic. To ease this transition, we have developed a novel and flexible manufacturing platform, Bioreactor with Expandable Culture Area (BECA), that aims to support both R&D and manufacturing to accelerate cell therapies from bench to bedside. This report introduces two models in this manufacturing platform: BECA-S for manual small-scale operation at R&D phase and BECA-Auto for functionally closed and automated scaled-out operation at manufacturing phase. We employed these two models to streamline transition of the T cell culture process from manual to automated and reported insignificant differences in the culture outcome between the two. Our work represents the first detailed development and demonstration of a standalone cell manufacturing platform that facilitates a seamless transition between manual and automated processing for autologous T cell therapy manufacturing.
    Keywords:  Automation; Bioreactor; Cell expansion; Cell manufacturing; Process transfer; T cell therapy
    DOI:  https://doi.org/10.1038/s41598-025-00015-4
  16. Mol Ther. 2025 May 08. pii: S1525-0016(25)00378-8. [Epub ahead of print]
    Concept CARs are picking up speed.
    Jorge Mansilla-Soto, Michael C Milone.
      The field of adoptive T cell immunotherapy has been dominated by a CAR design that combines antigen recognition through antibody-derived domains and signaling into a single polypeptide. This conventional design redirects the immense cytotoxic potential of T cells towards tumors, and it is the core of several commercially marketed CAR T cell products. Recent research in the field has been focused on developing more effective CAR designs especially for solid tumors. Although most approaches have layered on top of the conventional CAR design, recent studies have taken a step back and redesigned the basic CAR to retain more of the natural structure of immunoreceptors such as the TCR or killer immunoglobulin-like receptors. These redesigned CARs promote enhanced function in preclinical models compared with conventional CAR designs, including in the more challenging solid tumor setting, and several have entered the clinic with emerging data on their activity. These observations highlight the importance of considering CAR design and looking beyond conventional CARs when developing new T cell immunotherapy approaches.
    DOI:  https://doi.org/10.1016/j.ymthe.2025.05.008
  17. J Pediatr Hematol Oncol. 2025 May 08.
    The Tale of Pediatric Hematopoietic Stem Cell Transplantation in Iran: An Uphill Battle.
    Maryam Behfar, Pouya Mahdavi Sharif, Amir Ali Hamidieh.
      Hematopoietic stem cell transplantation (HSCT) has revolutionized the treatment of hematologic malignancies, immunodeficiencies, and storage disorders. While this transformative therapy is widely adopted globally, its introduction in Iran faced significant challenges due to geopolitical and economic hardships. In 2007, the first pediatric HSCT department in Iran was established at Tehran University of Medical Sciences. Over the past 18 years, this department has made substantial contributions to the field, including pioneering various HSCT modalities and establishing the first HLA registry in the region, facilitating access to matched unrelated donors. Despite significant challenges, including economic constraints and limited access to advanced therapies, the department and its affiliated research center have persevered in their mission to provide care to pediatric patients and advance in cutting-edge research, including immune cell therapies and gene therapies. With constantly aggravating economic hurdles and geopolitical issues, these milestones could not be achieved without the financial support of health care philanthropies and the sacrifices of dedicated physicians, researchers, and nurses. However, no health system, no matter how resilient, is immune to debacle under perpetuated hurdles, underscoring the need for global collaborations. This letter highlights the journey of pediatric HSCT in Iran and the importance of public advocacy in overcoming obstacles.
    Keywords:  adoptive cellular therapy; hematopoietic stem cell transplantation; pediatric
    DOI:  https://doi.org/10.1097/MPH.0000000000003050
  18. Open Biol. 2025 Jan;15(5): 240392
    The information overload, immunology and their relationship to world health.
    Peter A Bretscher.
      Essential to much medical progress (for example, preventing AIDS, tuberculosis and cancer) is understanding how the class of immunity is controlled. Most envisage that pathogen- or danger-associated signals are critical. Many classical observations, particularly on the variables of immunization affecting the class of immunity generated, are paradoxical under this dominant view, and are therefore neglected. Among these is the role of antigen dose. Plausible strategies to prevent and treat AIDS, cancer and tuberculosis are based on such neglected observations. Many suggest that the information overload stultifies the canon, inhibiting progress. I illustrate here that seeking and resolving paradoxes can provide a different perspective from that of the dominant canon, opening vistas that address major issues pertinent to world health.
    Keywords:  AIDS; cancer; information overload; tuberculosis; vaccination; world health
    DOI:  https://doi.org/10.1098/rsob.240392
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