bims-carter 2025-04-27 papers

bims-carter

Biomed News

on CAR-T Therapies

Issue of 2025–04–27
seventeen papers selected by
Luca Bolliger, lxBio

The potential of chimeric antigen receptor -T cell therapy for endocrine cancer.
HHV-6 and HHV-7 reactivation in allogeneic CAR-T cell therapy.
CAR T-cell therapy in renal cell carcinoma: opportunities, challenges, and new strategies to overcome.
Application and prospect analysis of chimeric antigen receptor T-cell therapy in hepatocellular carcinoma treatment: a systematic review and meta-analysis.
A novel approach to refractory idiopathic inflammatory myopathy: CD19 CAR T-cell therapy-case report and literature review.
Changing lanes: extending CAR T-cell therapy to high-risk plasma cell dyscrasias.
CAR-NK cell therapy: promise and challenges in solid tumors.
A Systematic Literature Review of the Economic and Healthcare Resource Utilization Burden of Relapsed/Refractory Follicular Lymphoma.
A Cost-Effectiveness Analysis of Mosunetuzumab vs Tisagenlecleucel for Treatment of Third- or Higher-Line (3L+) Relapsed or Refractory (R/R) Follicular Lymphoma (FL) in Italy.
Immune mediated inflammatory diseases: moving from targeted biologic therapy, stem cell therapy to targeted cell therapy.
Case Report: Successful use of emapalumab in adult B-cell acute lymphoblastic leukemia experiencing severe neurotoxicity and hemophagocytic lymphohistiocytosis-like features after CAR-T cell therapy.
Perspectives on the use and availability of chimeric antigen receptor T cells (CAR-T) and cell therapies: A worldwide cross-sectional survey by the worldwide network for blood and marrow transplantation (WBMT).
Association of CAR-T approval on outcomes in patients with diffuse large B-cell lymphoma at the population level in the United States.
CAR T-cells for acute leukemias in children: current status, challenges, and future directions.
MARC, a novel modular chimeric antigen receptor, improves T cell-based cancer immunotherapies by preventing early T cell exhaustion and enhancing persistence.
State of the art in CAR-based therapy: In vivo CAR production as a revolution in cell-based cancer treatment.
Overcoming antigen loss in CAR T therapy with Vγ9Vδ2 CAR T-cells.

World J Surg Oncol. 2025 Apr 22. 23(1): 153

The potential of chimeric antigen receptor -T cell therapy for endocrine cancer.

Ruonan Yu, Xiaoyu Ji, Ping Zhang, Hao Zhang, Huiling Qu, Wenwu Dong.

  Endocrine cancer, a relatively rare and heterogeneous tumor with diverse clinical features. The facile synthesis of hormones further complicates endocrine cancer treatment. Thus, the development of safe and effective systemic treatment approaches, such as chimeric antigen receptor (CAR) T cell therapy, is imperative to enhance the prognosis of patients with endocrine cancer. Although this therapy has achieved good results in the treatment of hematological malignancies, it encounters diverse complications and challenges in the context of endocrine cancer. This review delineates the generation of CAR-T cells, examines the potential of CAR-T cell therapy for endocrine cancer, enumerates pivotal antigens linked to endocrine cancer, encapsulates the challenges confronted with CAR-T cell therapy for endocrine cancer, and expounds upon strategies to overcome these limitations. The primary objective is to provide insightful perspectives that can contribute to the advancement of CAR-T cell therapy in the field of endocrine cancer.

Keywords:  Antigen targets; CAR-T cell; Endocrine cancer; Immunotherapy; Thyroid

DOI:  https://doi.org/10.1186/s12957-025-03745-x
Trends Biotechnol. 2025 Apr 22. pii: S0167-7799(25)00124-6. [Epub ahead of print]

HHV-6 and HHV-7 reactivation in allogeneic CAR-T cell therapy.

Hiu Tung Chow, Wenjing Li, Bin Yang, Friedrich von Wintzingerode, Qi Chen.

  Autologous chimeric antigen receptor (CAR)-T cell therapy has revolutionized cancer treatment and allogeneic CAR-T cell therapy is poised to advance this revolution. CAR-T cell therapy faces some concerns regarding adventitious agents, which can threaten the safety of patients. Human herpesviruses 6 and 7 (HHV-6 and HHV-7) have become increasingly notable in this context, as they carry a risk with severe health consequences. This review explores these virus reactivations in CAR-T cell therapy and discusses mitigation strategies during allogeneic CAR-T cell manufacturing. We provide an overview of prevention and testing strategies, genetic engineering applications, and chemical substances with potential for interventions. This review aims to enhance understanding of HHV reactivation and improve the safety of allogeneic CAR-T cell therapies.

Keywords:  CAR-T; HHV-6; HHV-7; cell therapy manufacturing; virus reactivation; virus safety

DOI:  https://doi.org/10.1016/j.tibtech.2025.03.017
Med Oncol. 2025 Apr 24. 42(6): 179

CAR T-cell therapy in renal cell carcinoma: opportunities, challenges, and new strategies to overcome.

Mahan Mohammadi, Houshang Najafi, Pantea Mohammadi.

  Immunotherapy is a biological treatment for cancer that utilizes substances sourced from live organisms. Immunotherapy encompasses several modalities, including monoclonal antibodies, therapeutic vaccinations, immune system modulators, T-cell transfer treatment, and immune checkpoint inhibitors (ICIs). It may treat kidney cancer by modifying the immune system's reaction to cancerous cells. These medicines are delivered as ICIs or cytokines. Immunotherapy may sometimes be used with targeted therapies, such as CAR T-cell therapy, to improve outcomes in advanced cancer. Chimeric Antigen Receptor (CAR) T-cell therapy is a kind of cancer immunotherapy using genetically engineered T cells to augment their capacity to eradicate cancer cells. Although CAR T-cell therapy has achieved success, it continues to have substantial limitations that necessitate further investigation. Antigen escape, inhibition and resistance in B-cell malignancies, and life-threatening CAR T-cell-associated toxicities, such as cytokine release syndrome, neurologic toxicities, and sustained cytopenias, are among their limitations. Renal cell carcinoma RCC is the most common type of kidney cancer in adults. The surgical excision of a portion or the entire kidney is a common treatment for RCC. This procedure has the potential to cause agony, as well as organ and blood vessel injury. This study has examined the benefits of T cell therapy in the treatment of RCC, as well as the challenges and issues associated with this treatment method. It has also examined effective strategies for reducing the side effects, in light of the importance and incidence rate of this type of cancer.

Keywords:  Chimeric Antigen Receptor T cell; Cytokine release syndrome; Exosome; Immunotherapy; Renal cell carcinoma

DOI:  https://doi.org/10.1007/s12032-025-02735-z
Front Immunol. 2025 ;16 1566976

Application and prospect analysis of chimeric antigen receptor T-cell therapy in hepatocellular carcinoma treatment: a systematic review and meta-analysis.

Sichang Wu, Xinli Gan, Shuxin Huang, Yujun Zhong, Jialin Wu, Haojie Yang, Bangde Xiang.

   Introduction: Hepatocellular carcinoma (HCC), accounting for 90% of primary liver cancers, is a high-mortality malignancy and the third leading cause of cancer-related deaths globally, with major risk factors like hepatitis B/C, aflatoxin exposure, and obesity. Most patients are diagnosed at advanced stages, with a 5-year survival rate below 10%. Therefore, HCC treatment and research still face significant challenges, and more effective treatments need to be further explored.
Methods: We searched PubMed, Scopus, Web of Science and Embase from the time of repository construction to March 1, 2025, preliminary included studies involving animal experiments on the therapeutic effects of Chimeric Antigen Receptor T-cell (CAR-T cell) therapy on HCC. After exclusion and evaluation of literature, the random/fixed effects model was employed to perform meta-analysis and obtain Weighted Mean Difference (WMD) and 95% confidence interval (CI) of tumor volume and mass. We then verify the robustness of the results through subgroup analysis and sensitivity analysis. Use Q-test to evaluate heterogeneity and quantify it based on I² value.
Results: We included a total of 16 studies. Multiple independent sets of data were extracted from the experiments of these studies, of which 25 were used for volume-based meta-analysis and 16 were used for mass-based meta-analysis. Regarding volume, The combined mean CAR-T treatment group/control group resulted in an WMD of -515.77 (95% CI: -634.78 to -396.76; I² =90.8%). Meanwhile, based on mass, the combined mean CAR-T treatment group/control group resulted in an WMD of -0.30 (95% CI: -0.38 to -0.22; I² = 94.4%). The results of the bias analysis further validated the reliability of the research conclusions.
Conclusions: Based on the dual-index meta-analysis, the CAR-T therapy have been proved to possess significant therapeutic effect in HCC. However, the funnel plot of tumor mass and the Egger's regression suggest the potential presence of publication bias. Thus, it warrants further research to evaluate the potential of CAR-T therapy alone or as an adjuvant for HCC treatment.

Keywords:  CAR-T therapy; hepatocellular carcinoma; immunotherapy; meta-analysis; systematic review

DOI:  https://doi.org/10.3389/fimmu.2025.1566976
Rheumatology (Oxford). 2025 Apr 23. pii: keaf190. [Epub ahead of print]

A novel approach to refractory idiopathic inflammatory myopathy: CD19 CAR T-cell therapy-case report and literature review.

Isabell Haase, Johanna Richter, Marie-Therese Holzer, Boris Fehse, Nikolas Ruffer, Johan Seibel, Susanna C Berger, Nico Gagelmann, Dominic Borie, Francis Ayuk, Ina Kötter, Martin Krusche, Nicolaus Kröger.

   OBJECTIVES: To explore efficacy and safety of CD19-directed Chimeric Antigen Receptor (CAR) T cell therapy in a patient with Jo1-Antisynthetase-syndrome (ASyS) refractory to multiple immunosuppressants, including anti-CD38 therapy, and review published cases on CAR T cell therapy in idiopathic inflammatory myopathies (IIM).
METHODS: Following lymphodepletion, the patient received a single infusion of autologous CD19-directed CAR T cells. Clinical, serologic, and safety outcomes were monitored over 6 months. A literature review analysed prior cases for patient characteristics, outcomes, and adverse events.
RESULTS: CAR T cell therapy was well tolerated, with only low-grade cytokine release syndrome (CRS) and no neurotoxicity. Clinical assessments demonstrated significant and rapid improvement in muscle strength, arthritis, and pulmonary function, alongside normalization of muscle enzymes and inflammatory markers. Autoantibody levels remained unchanged. Transient skin alterations resolved with low-dose glucocorticoids. CAR T cells persisted for 3 months, followed by B cell reconstitution without disease relapse. The patient remains in remission on low-dose prednisolone at 6 months.Eight previously published cases of CAR T cell therapy in IIM consistently report significant improvement, with most patients stable off immunosuppressive therapy. Hypogammaglobulinemia was frequent, but no high-grade CRS, ICANS or serious infections were reported.
CONCLUSION: CD19-directed CAR T cell therapy shows promise in refractory IIM, offering sustained clinical improvement and a favourable safety profile. The nine reported cases collectively highlight the potential of CAR T cell therapy even in patients with insufficient response to B cell/plasma-cell depleting therapies. Larger studies are needed to evaluate long-term efficacy, safety, and underlying mechanisms of CAR T cell therapy in refractory IIM.

Keywords:  Antisynthetase-syndrome; B-cell depletion; CAR T-cell therapy; anti-Jo1; idiopathic inflammatory myopathy

DOI:  https://doi.org/10.1093/rheumatology/keaf190
Front Immunol. 2025 ;16 1558275

Changing lanes: extending CAR T-cell therapy to high-risk plasma cell dyscrasias.

Heather T Morgan, Benjamin A Derman, Hong Ma, Shaji K Kumar.

  Chimeric antigen receptor (CAR) cellular therapies have advanced outcomes in challenging hematologic malignancies like leukemia, lymphoma, and multiple myeloma. Plasma cell-directed CAR T-cell therapies have been particularly beneficial in multiple myeloma, suggesting that these agents may have a role in other challenging plasma cell disorders such as systemic AL amyloidosis and plasma cell leukemia. AL amyloidosis is a monoclonal plasma cell disorder resulting in the deposition of protein fibrils that compromise end-organ function. Delays in diagnosis can result in end-organ dysfunction and organ failure, making designing and completing treatment difficult. Plasma cell leukemia (PCL) is a rare and highly challenging malignancy with dismal survival outcomes despite aggressive therapy. Both diagnoses are currently treated with regimens borrowed from myeloma: a combination of novel agents and chemotherapy induction, then autologous stem cell transplantation (ASCT), with the current practice trending towards consolidation and maintenance. Unfortunately, only 20% of AL amyloidosis patients are transplant-eligible at diagnosis. Those transplant-ineligible (TIE) patients are treated with combination induction chemotherapy, which may be limited by worsening disease-related end-organ dysfunction. Plasma cell leukemia patients are still very likely to relapse after this intensive and prolonged therapy. Despite the promise of a shorter course of therapy, CAR T-cell therapies directed against plasma cells have not been rigorously investigated in patients with AL amyloidosis or PCL; most trials of MM have excluded these patients. Herein, we describe current treatment paradigms for AL amyloidosis and PCL and review the evidence for CAR T-cell therapies in these challenging plasma cell disorders. Further investigation into CAR T-cell therapies for plasma cell disorders other than multiple myeloma is warranted.

Keywords:  AL amyloidosis; CAR T-cell; immunotherapy; multiple myeloma; plasma cell dyscrasia; plasma cell leukemia; systemic light chain amyloidosis

DOI:  https://doi.org/10.3389/fimmu.2025.1558275
Front Immunol. 2025 ;16 1574742

CAR-NK cell therapy: promise and challenges in solid tumors.

Sahar Balkhi, Gaia Zuccolotto, Anna Di Spirito, Antonio Rosato, Lorenzo Mortara.

  Over the past few years, cellular immunotherapy has emerged as a promising treatment for certain hematologic cancers, with various CAR-T therapies now widely used in clinical settings. However, challenges related to the production of autologous cell products and the management of CAR-T cell toxicity highlight the need for new cell therapy options that are universal, safe, and effective. Natural killer (NK) cells, which are part of the innate immune system, offer unique advantages, including the potential for off-the-shelf therapy. A recent first-in-human trial of CD19-CAR-NK infusion in patients with relapsed/refractory lymphoid malignancies demonstrated safety and promising clinical activity. Building on these positive clinical outcomes, current research focuses on enhancing CAR-NK cell potency by increasing their in vivo persistence and addressing functional exhaustion. There is also growing interest in applying the successes seen in hematologic malignancies to solid tumors. This review discusses current trends and emerging concepts in the engineering of next-generation CAR- NK therapies. It will cover the process of constructing CAR-NK cells, potential targets for their manufacturing, and their role in various solid tumors. Additionally, it will examine the mechanisms of action and the research status of CAR-NK therapies in the treatment of solid tumors, along with their advantages, limitations, and future challenges. The insights provided may guide future investigations aimed at optimizing CAR-NK therapy for a broader range of malignancies.

Keywords:  CAR-NK therapies; CAR-T therapies; CD19-CAR-NK; cellular immunotherapy; natural killer (NK) cells

DOI:  https://doi.org/10.3389/fimmu.2025.1574742
Pharmacoecon Open. 2025 Apr 22.

A Systematic Literature Review of the Economic and Healthcare Resource Utilization Burden of Relapsed/Refractory Follicular Lymphoma.

Bijal Shah, Mei Xue, Wesley Furnback, Erlene K Seymour, Jin Kim, Po-Ya Chuang, Madeline Dec, Keri Yang.

OBJECTIVE: To quantify the economic or healthcare resource utilization (HCRU) burden and examine the value of interventions for relapsed or refractory (R/R) follicular lymphoma (FL).
METHODS: The PubMed and Embase databases were searched for full-text studies and conference abstracts published between 1 January 2019 and 31 December 2023 that reported either the economic or HCRU burden of R/R FL or reported the results of health economic models assessing interventions for R/R FL. A supplemental manual search was also undertaken to identify conference abstracts that may not have been indexed in the primary databases. A data extraction sheet was used to develop evidence tables.
RESULTS: A total of 30 records were included spanning 11 retrospective or prospective studies, 11 cost-effectiveness evaluations, and 8 other economic models. Costs and HCRU generally tended to increase as the line of therapy increased, reaching over US$400,000 annually in later lines. Costs associated with recently approved chimeric antigen receptor T-cell therapy (CAR-T) ranged from US$450,000 to over US$700,000 per patient. Economic models evaluating novel therapies, such as CAR-T, tazemetostat, and mosunetuzumab, estimated they would generally be cost-effective and have minimal budget impact or cost-savings. However, these models noted considerable assumptions regarding treatment duration and discontinuation. Real-world costs and resource use for newly approved therapies including CAR-Ts and bispecifics were limited.
CONCLUSIONS: The burden of R/R FL is substantial and increases as patients progress. Considerable gaps exist for the real-world impact of novel therapies, including CAR-Ts and bispecifics, on the economic burden and will need to be studied to properly assess their value.

DOI: https://doi.org/10.1007/s41669-025-00577-z
Clinicoecon Outcomes Res. 2025 ;17 335-348

A Cost-Effectiveness Analysis of Mosunetuzumab vs Tisagenlecleucel for Treatment of Third- or Higher-Line (3L+) Relapsed or Refractory (R/R) Follicular Lymphoma (FL) in Italy.

Stefano Luminari, Antonio Pinto, Benedetta Puccini, Alessandro D'Arpino, Emanuela Omodeo Salè, Marco Bellone, Lorenzo Pradelli, Alice Sabinot.

   Purpose: To compare the cost-effectiveness of mosunetuzumab with tisagenlecleucel for treating patients with relapsed or refractory follicular lymphoma (R/R FL 3L+) from the perspective of the Italian National Health Service (NHS).
Patients and Methods: The analysis employs a weekly cycle partitioned survival model (PSM) with a lifetime horizon. The PSM model tracks patient outcomes based on time-to-event data, including progression-free survival (PFS) and post-progression survival (PPS). A matching-adjusted indirect treatment comparison (MAIC) approach was used to account for differences in trial population characteristics on the relative efficacy of mosunetuzumab to tisagenlecleucel. PFS and overall survival (OS) were extrapolated beyond the trial period by applying the hazard ratios from the MAIC to mosunetuzumab's parametric survival curves. Utility values and patient data are retrieved from the GO29781 trial. Economic inputs, from the perspective of the Italian NHS, include direct medical costs such as drugs, administration, monitoring, adverse event (AE) management, therapy following FL progression. Discontinuation and terminal care costs were also considered. Probabilistic sensitivity (PSA) and scenario analyses were conducted.
Results: Mosunetuzumab was found to be dominant compared to tisagenlecleucel, resulting in an increase of 0.98 life years (LYs) and 0.70 quality-adjusted life years (QALYs), while also being associated with lower overall costs. The sensitivity analysis consistently favored mosunetuzumab, with 94% of simulations demonstrating its cost-effectiveness based on the Italian WTP threshold of €40,000/QALY. Even in a scenario where tisagenlecleucel maintained a PFS advantage with assumed equivalence in OS, mosunetuzumab still showed a favorable cost-saving profile due to its lower incremental costs.
Conclusion: In the Italian setting, mosunetuzumab is a cost-effective treatment option compared to tisagenlecleucel for adult patients with R/R 3L+ FL, presenting favourable outcomes from the perspective of the NHS. Future research and data collection efforts are crucial to validate these findings and reduce uncertainties regarding long-term clinical and economic implications.

Keywords:  economic evaluation; hospital cost; oncology; social cost

DOI:  https://doi.org/10.2147/CEOR.S509907
Front Immunol. 2025 ;16 1520063

Immune mediated inflammatory diseases: moving from targeted biologic therapy, stem cell therapy to targeted cell therapy.

Zhenguo Liang, Hui Xie, Dongze Wu.

  Despite the advancements in targeted biologic therapy for immune-mediated inflammatory diseases (IMIDs), significant challenges persist, including challenges in drug maintenance, primary and secondary non-responses, and adverse effects. Recent data have strengthened the evidence supporting stem cell therapy as an experimental salvage therapy into a standard treatment option. Recent preclinical and clinical studies suggested that chimeric antigen receptor T cell (CAR-T) therapy, which depleting tissue and bone marrow B cells, may lead to improvement, even inducing long-lasting remissions for patients with IMIDs. In this review, we address the unmet needs of targeted biologic therapy, delineate the critical differences between stem cell transplantation and CAR-T therapy, evaluate the current status of CAR-T therapy for IMIDs and explore its potential and existing limitations.

Keywords:  CAR-T; biologic therapy; cell therapy; immune mediated inflammatory disease; stem cell therapy

DOI:  https://doi.org/10.3389/fimmu.2025.1520063
Front Immunol. 2025 ;16 1563736

Case Report: Successful use of emapalumab in adult B-cell acute lymphoblastic leukemia experiencing severe neurotoxicity and hemophagocytic lymphohistiocytosis-like features after CAR-T cell therapy.

Beatrice Manghisi, Giulia Cotilli, Marilena Fedele, Paola Perfetti, Elisabetta Terruzzi, Luisa Verga, Lorenza Maria Borin, Andrea Carrer, Monica Fumagalli, Maria Beatrice Ferrari, Alex Moretti, Roberto Rona, Annalisa Benini, Beatrice Vergnano, Giovanni Palumbo, Alessandra Zincone, Oscar Maglia, Chiara Scollo, Carolina Steidl, Lorenzo Iovino, Adriana Balduzzi, Rocco Piazza, Carlo Gambacorti-Passerini, Matteo Parma, Andrea Aroldi.

  Chimeric antigen receptor (CAR)-T cell therapy is a powerful adoptive immunotherapy associated with significant toxicity, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). As CAR-T usage expands, hyperinflammatory toxicities resembling hemophagocytic lymphohistiocytosis (HLH) syndrome are increasingly recognized. Immune effector cell-associated HLH-like syndrome (IEC-HS) describes HLH-like symptoms attributable to CAR-T cell therapy, often presenting as CRS resolves. Treatments for IEC-HS are adapted from primary HLH, including corticosteroids, the recombinant human interleukin (IL)-1 receptor antagonist anakinra and the Janus Kinase inhibitor ruxolitinib. Emapalumab, an anti-IFN-γ antibody, is promising but underexplored in adult IEC-HS cases. We report an adult B-cell acute lymphoblastic leukemia (B-ALL) patient treated with brexucabtagene autoleucel (brexu-cel). The patient developed CRS, refractory neurotoxicity, and IEC-HS with worsening multiorgan failure and hyperinflammatory markers. Treatment included tocilizumab, high-dose corticosteroids, anakinra, siltuximab, and ruxolitinib. Despite aggressive management, hyperinflammation and neurotoxicity persisted. Emapalumab was initiated on day +11, resulting in normalization of the biochemical parameters and full neurological recovery by day +21. The patient recovered from IEC-HS and underwent allogeneic stem cell transplantation. This case highlights the role of emapalumab in managing refractory IEC-HS and persistent neurotoxicity in adults, underscoring the need for targeted interventions in severe CAR-T complications.

Keywords:  CAR-T cell therapy; CRS; HLH; ICANS; IEC-HS; emapalumab; leukemia

DOI:  https://doi.org/10.3389/fimmu.2025.1563736
Curr Res Transl Med. 2025 Apr 15. pii: S2452-3186(25)00024-8. [Epub ahead of print]73(2): 103515

Perspectives on the use and availability of chimeric antigen receptor T cells (CAR-T) and cell therapies: A worldwide cross-sectional survey by the worldwide network for blood and marrow transplantation (WBMT).

Eddie Hp Tan, Mahmoud Aljurf, Fazal Hussain, Christian Chabannon, Nina Worel, Daniel Weisdorf, Ibrahim Yakoub-Agha, Sebastian Galeano, Fermin Sanchez-Guijo, Laurent Garderet, Yoshiko Atsuta, Annalisa Ruggeri, Nada Hamad, Sharukh Hashmi, Cristobal Frutos, Yoshihisa Kodera, Adriana Seber, Carmem Bonfim, Dietger Niederwieser, Damiano Rondelli, Hildegard Greinix, Mickey Bc Koh.

  Chimeric antigen receptor T cell therapy (CAR-T) cells represent a new generation of autologous, allogeneic and personalised cell-based therapies that have revolutionised the treatment of B cell haematological malignancies. Despite their significant effectiveness in treating challenging relapsed and refractory diseases, access to this cutting-edge treatment remains a critical issue globally, even in high income countries. To gain insights into these challenges, the Worldwide Network for Blood & Marrow Transplantation (WBMT) initiated a survey focused on the state of CAR-T and cellular therapy availability worldwide. The survey aimed to identify the accessibility, manufacturing capabilities, apheresis, accreditation, reimbursement, presence of regulatory frameworks and legal oversight of these cell-based therapies. The survey included questions on demographics, the respondent's centre, CAR-T availability, details about haematopoietic stem cell transplant programs, supply and indications for CAR-T, quality assurance, and information about other cell and gene therapy products beside CAR-T. Conducted online over three months in 2023, the survey garnered 181 complete responses from various geographical regions, from North America, Asia, Europe, South and Central America, Australia and New Zealand, and Africa. Our findings suggested a promising level of awareness and interest in CAR-T therapy globally, even in lower-income regions. However, survey respondents cited cost as the primary barrier to access, alongside infrastructure and governmental support issues. The survey also highlighted the varying reimbursement strategies across regions, with costs in Europe and North America being relatively similar while Asia showed more variability. There was also variability in the regulatory and accreditation frameworks associated with delivery of these novel therapies As CAR-T therapy continues to grow, innovative solutions such as global partnerships, in-house production, and the establishment of cellular therapy centres in developing countries are essential. Addressing the challenges of access requires a comprehensive approach that combines efforts to lower costs, enhance healthcare infrastructure, and foster international collaborations, ensuring that CAR-T therapy becomes available to all who need it.

Keywords:  CAR-T; Cellular therapy; Chimeric antigen T cells; HSCT; Haematopoietic stem cell transplant

DOI:  https://doi.org/10.1016/j.retram.2025.103515
Biomark Res. 2025 Apr 24. 13(1): 64

Association of CAR-T approval on outcomes in patients with diffuse large B-cell lymphoma at the population level in the United States.

John L Vaughn, Angela Ramdhanny, Malak Munir, Sravani Rimmalapudi, Narendranath Epperla.

  While the advent of chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of relapsed or refractory DLBCL, it is unclear how survival has changed at the population level following its approval. Herein, we performed a population-based cohort study using the SEER-17 database. The primary exposure was a period of diagnosis (2014-2017 vs. 2018-2021), and these periods were selected based on the first FDA-approval of CAR-T in 2017. Study outcomes were relative survival (RS), overall survival (OS), lymphoma-specific survival (LSS), and the cumulative incidence of death from lymphoma (CIF). A total of 51,584 patients with DLBCL were included in the study with 24,861 patients diagnosed in time period-1 (2014-2017) and 26,723 patients diagnosed in time period-2 (2018-2021). The median age at diagnosis was 68 years (interquartile range, 57-77) and most patients were White (n = 42,190, 82%) with advanced stage at diagnosis (n = 28,203, 55%). In unadjusted analysis, the 5-year RS (95% CI) increased from 64% from 2014 to 2017 to 66% from 2018 to 2021, while 5-year OS increased from 54 to 55%, and 5-year LSS increased from 64 to 66%. On competing risks analysis, the 5-year probability of death from lymphoma decreased from 34 to 31%. The improvements in survival were observed across age, disease stage, and racial groups, and remained significant when adjusting for age, sex, race, stage, B symptoms and documented receipt of chemotherapy in multivariable survival models (adjusted OS HR = 0.97, 95%CI = 0.94-1.00, p = 0.04; adjusted LSS HR = 0.93, 95%CI = 0.90-0.96, p < 0.001). We found improved survival for patients with DLBCL diagnosed between 2018 and 2021 when compared to those diagnosed between 2014 and 2017. These findings will serve as the benchmark for future studies evaluating the impact of CAR-T administered earlier in their disease course.

Keywords:  CAR-T; DLBCL; Diffuse large B-cell lymphoma; Outcomes; Survival

DOI:  https://doi.org/10.1186/s40364-025-00780-4
Cancer Metastasis Rev. 2025 Apr 23. 44(2): 47

CAR T-cells for acute leukemias in children: current status, challenges, and future directions.

Marie Emilie Dourthe, André Baruchel.

  CAR T-cells therapy is seen as one of the most promising immunotherapies for leukemias, since targeting CD19 has revolutionized the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) in children, adolescents, and young adults. Early phase clinical trials have shown a very high initial response rate confirmed by follow up and real-world studies. However, almost half of patients relapse with the available commercial product currently suggesting the need of a consolidative treatment after CAR T-cell infusion in well-defined cases, according to several pre- and post-CAR clinical and biological factors. This finding highlights that numerous challenges exist before the extension of CAR T-cell indications (first relapse and high-risk first line) in the field of B-ALL: to enhance persistence of CAR T-cells to avoid CD19-positive relapse and to avoid CD19-negative relapse by reducing tumor burden pre-CAR-T infusion and/or by multitargeting. Promising approaches with exciting early clinical data are emerging in the field of T-cell ALL. The use of CAR T-cells for acute myeloid leukemias remains challenging due to the lack of leukemia-specific antigens and to the immunosuppressive microenvironment.

Keywords:  Acute lymphoblastic leukemia; Acute myeloid leukemia; CAR T-cells; Children; Immunotherapy

DOI:  https://doi.org/10.1007/s10555-025-10261-7
J Immunother Cancer. 2025 Apr 20. pii: e011829. [Epub ahead of print]13(4):

MARC, a novel modular chimeric antigen receptor, improves T cell-based cancer immunotherapies by preventing early T cell exhaustion and enhancing persistence.

Margaux Tual, Angélique Bellemare-Pelletier, Susan Moore, Delphine Guipouy, Negar Farzam-Kia, Leila Jafarzadeh, Jordan Quenneville, Benoit Barrette, Marc K Saba-El-Leil, Jean-Sebastien Delisle, Etienne Gagnon.

   BACKGROUND: Chimeric antigen receptor T cell (CAR-T)-based immunotherapies have reshaped the therapeutic landscape of cancer treatment, in particular for patients afflicted with leukemia. However, defects in CAR behaviors and clinical complications have hindered their widespread application across diverse cancer types. Chief among these defects is high tonic signaling, absent in native activating immune receptors, which accelerates T cell exhaustion and undermines treatment efficacy. We hypothesized that these limitations arise because current CAR architectures fail to replicate the modular design of native activating immune receptors, which integrate distinct receptor and signaling modules. This modular assembly is crucial for maintaining proper receptor regulation and function.
METHODS: Therefore, we set forth to develop a modular chimeric antigen receptor leveraging the same assembly principles found in native activating immune receptors to reestablish the intrinsic safeguards in receptor expression and signaling.
RESULTS: The resulting Modular Actuation Receptor Complex (MARC) displayed surface expression levels akin to its native immune receptor counterpart, the NK cell receptor KIR2DS3, while eliminating tonic signaling. In a clinically relevant mouse leukemia model, MARC-T cells exhibited remarkable long-term persistence and a less exhausted phenotype compared with conventional CAR-T cells.
CONCLUSIONS: With its modular architecture, the MARC offers unparalleled opportunities for optimization and broad applicability across different cell types, paving the way for transformative advancements in cell-based therapies. This innovation holds immense promise as a next-generation therapeutic tool in clinical settings.

Keywords:  Antigen receptor design; Chimeric antigen receptor - CAR; Immunotherapy; Leukemia; T cell

DOI:  https://doi.org/10.1136/jitc-2025-011829
Cell Oncol (Dordr). 2025 Apr 22.

State of the art in CAR-based therapy: In vivo CAR production as a revolution in cell-based cancer treatment.

Abdolreza Esmaeilzadeh, Kaveh Hadiloo, Sara Yaghoubi, Masoud Hassanzadeh Makoui, Parsa Mostanadi.

  Chimeric antigen receptor (CAR) therapy has successfully treated relapsed/refractory hematological cancers. This strategy can effectively target tumor cells. However, despite positive outcomes in clinical applications, challenges remain to overcome. These hurdles pertain to the production of the drugs, solid tumor resistance, and side effects related to the treatment. Some cases have been missed during the drug preparation due to manufacturing issues, prolonged production times, and high costs. These challenges mainly arise from the in vitro manufacturing process, so reevaluating this process could minimize the number of missed patients. The immune cells are traditionally collected and sent to the laboratory; after several steps, the cells are modified to express the CAR gene before being injected back into the patient's body. During the in vivo method, the CAR gene is introduced to the immune cells inside the body. This allows for treatment to begin sooner, avoiding potential failures in drug preparation and the associated high costs. In this review, we will elaborate on the production and treatment process using in vivo CAR, examine the benefits and challenges of this approach, and ultimately present the available solutions for incorporating this treatment into clinical practice.

Keywords:  Adoptive cellular immunotherapies; Antineoplastic protocols; Chimeric antigen receptor; Clinical setting; In vivo gene delivery

DOI:  https://doi.org/10.1007/s13402-025-01056-7
Immunooncol Technol. 2025 Jun;26 101053

Overcoming antigen loss in CAR T therapy with Vγ9Vδ2 CAR T-cells.

M Velasco Santiago, P Aehnlich, T M Hulen, K M Jensen, G Holmen Olofsson, Ö Met, P Thor Straten.

   Background: Vγ9Vδ2 T-cells demonstrate potent antitumor activity in vitro but, despite successful safety studies, the clinical benefit of Vγ9Vδ2 in adoptive cell therapy has been limited. One approach to enhance the therapeutic potential of Vγ9Vδ2 T-cells while maintaining their safety profile is genetic engineering to express a chimeric antigen receptor (CAR). Vγ9Vδ2 CAR T-cells retain the ability to target tumor cells even after target antigen loss, a major cause of CAR treatment relapse.
Methods: Vγ9Vδ2 T-cells were expanded from peripheral blood mononuclear cells in the presence of high levels of interleukin 2 (IL-2) or IL-2 in combination with IL-15. Cells were then virally transduced with a CD19-directed CAR and underwent antigen-specific stimulation to enrich CAR-expressing cells.
Results: Vγ9Vδ2 CAR T-cells showed similar cytotoxic activity to conventional αβ-CAR T-cells against CD19-positive tumor cells. They demonstrated superior responses against CD19-negative tumor cells, however, particularly when IL-15 was included during expansion. This enhanced function was further confirmed in co-culture assays with mixed CD19-positive and CD19-negative tumor populations, simulating antigen loss.
Conclusions: Vγ9Vδ2 CAR T-cell therapy presents a promising strategy for B-cell malignancies, offering sustained antitumor activity even after antigen loss. This approach may help overcome a major limitation of conventional CAR T-cell therapy, potentially improving clinical outcomes.

Keywords:  B-cell malignancies; CAR T-cells; Vγ9Vδ2 T-cells; antigen loss

DOI:  https://doi.org/10.1016/j.iotech.2025.101053