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Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of hematologic malignancies, yet it carries significant risks, including acute kidney injury (AKI). In this study, we investigated the risk factors and clinical impact of AKI in patients undergoing CAR-T cell therapy. This retrospective study involved hematologic patients treated with CAR-T therapy. Clinical and laboratory data were collected, and clinical outcomes were monitored during follow-up after CAR-T infusion. AKI was defined according to KDIGO criteria. The outcome measures included early mortality, overall survival (OS), and disease-free survival (DFS). Among the 48 patients analyzed, 14 (29%) developed AKI, with a mean onset of 6 days after CAR-T infusion. The risk of AKI was associated with baseline performance status (OR 8.65, IC95% 6.2-12, p = 0.032) and the development of severe cytokine release syndrome post-therapy (OR 16.4 95%CI 1.9-138.5, p = 0.01). Patients with AKI more frequently required intensive care. Furthermore, severe AKI was independently associated with worse clinical outcomes, including reduced OS and DFS (HR 18.2, 95%CI 2.6-27.3, p = 0.003). Additionally, patients who developed AKI post-CAR-T therapy were more likely to progress to chronic kidney disease during follow-up. In conclusion, frail patients undergoing CAR-T therapy are at an increased risk of developing AKI, which can significantly affect both short- and long-term outcomes. Preventive strategies and early recognition of AKI are essential in these patients., (© 2024. The Author(s).)

Chimeric antigen receptor T-cell (CAR T-cell) therapies have emerged as a promising treatment modality for several malignancies, particularly haematological malignancies, by inducing robust antitumour responses. However, CAR T-cell therapies are associated with a spectrum of adverse events, including neurological complications. We here provide a review of neurological adverse events observed in patients undergoing CAR T-cell therapy, focusing on their incidence, clinical manifestations, underlying mechanisms and potential management strategies., (Copyright © 2024. Published by Elsevier Masson SAS.)

Recent years have witnessed the success of αβ T cells engineered to express chimeric antigen receptors (CARs) in treating haematological cancers. CARs combine the tumour antigen binding capability of antibodies with the signalling functions of the T-cell receptor (TCR) ζ chain and co-stimulatory receptors. Despite the success, αβ CAR T cells face limitations. Possible solutions would be the use of γδ T cells and new chimeric receptors, such as TCR fusion constructs (TRuCs). Notably, γδ CAR T cells are gaining traction in pre-clinical and clinical studies, demonstrating a promising safety profile in several pilot studies. This review delves into the current understanding of γδ CAR and TCR fusion construct T cells, exploring the opportunities and challenges they present for cancer treatment., (© 2024 The Author(s). European Journal of Immunology published by Wiley‐VCH GmbH.)

Chimeric antigen receptor (CAR) T cells are in standard clinical use to treat relapsed or refractory hematologic malignancies, such as non-Hodgkin lymphoma, multiple myeloma and acute lymphoblastic leukemia. Owing to the rapidly progressing field of CAR T-cell therapy and the lack of generally accepted treatment guidelines, we hypothesized significant differences between European centers in prevention, diagnosis and management of short- and long-term complications. To capture the current CAR T-cell management among European Society for Blood and Marrow Transplantation (EBMT) centers and to determine the medical need and specific areas for future clinical research the EBMT Transplant Complications Working Party performed a survey among 227 EBMT CAR T-cell centers. We received complete servey answers from 106 centers (47%) addressing questions in the areas of product selection, CAR T-cell logistics, management of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome as well as management in later phases including prolonged cytopenias. We identified common patterns in complication management, but also significant variety in clinical management of the centers in important aspects. Our results demonstrate a high medical need for treatment harmonization and future clinical research in the following areas: treatment of steroid-refractory and very severe cytokine release syndrome/neurotoxicity, treatment of cytopenia, early discharge and outpatient management, as well as immunoglobulin substitution.

Few studies evaluated patient-reported outcomes (PROs) for patients with hematologic malignancies receiving with Chimeric Antigen Receptor T (CAR-T) cell therapy. We performed a systematic review and meta-analysis to evaluate the benefits of CAR-T cell therapies focused on PROs. A systematic literature searched from PubMed, Cochrane, and the Web of Science from inception to September 2023. Study selection and data extraction were conducted independently by two reviewers based on pre-specified criteria. The COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) Risk of Bias checklist was used to evaluate the methodological quality of the included studies. The random-effects model was employed to calculate the combined effect and 95% Confidence intervals. This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline and the protocol was registered with PROSPERO (CRD42024586706). We identified 20,110 studies. Of those, 15 studies with 16 different PRO measures (PROMs) were included in the meta-analysis. CAR-T cell therapy improved PROs in the six domains of general health status, pain, fatigue, depression, social function, and cognitive function: from the general health status (SMD: 0.57, 95% CI: 0.34 to 0.81) to cognitive function (SMD: 0.25, 95% CI: 0.14 to 0.37). The current meta-analysis shows that CAR-T cell therapy produces clinically meaningful differences in PROs. These results suggest that the professional perspective and patient values and preferences should be weighed equally when considering CAR-T cell therapy for hematologic malignancies., (© 2024. The Author(s).)

In recent years, following the groundbreaking achievements of chimeric antigen receptor (CAR) T cell therapy in hematological cancers, and advancements in cell engineering technologies, the exploration of other immune cells has garnered significant attention. CAR-Therapy extended beyond T cells to include CAR natural killer (NK) cells and CAR-macrophages, which are firmly established in the clinical trial landscape. Less conventional immune cells are also making their way into the scene, such as CAR mucosal-associated invariant T (MAIT) cells. This progress is advancing precision medicine and facilitating the development of ready-to-use biological treatments. However, in view of the unique features of natural killer cells, adoptive NK cell immunotherapy has emerged as a universal, allogenic, "off-the shelf" therapeutic strategy. CAR-NK cytotoxic cells present targeted tumor specificity but seem to be devoid of the side effects associated with CAR-T cells. CAR-NK cells appear to be potentially promising candidates for cancer immunotherapy. However, their application is hindered by significant challenges, particularly the limited persistence of CAR-NK cells in the body, which poses a hurdle to their sustained effectiveness in treating cancer. Based upon the foregoing, this review discusses the current status and applications of both CAR-T cells and CAR-NK cells in hematological cancers, and provides a comparative analysis of the structure, genetics, and clinical outcomes between these two types of genetically modified immune cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Andrea, Chiron, Sarrabayrouse, Bessoles and Hacein-Bey-Abina.)

Importance: The frequency and clinical phenotypes of cardiotoxic events in chimeric antigen receptor (CAR) T-cell recipients remain poorly understood given that landmark approval trials typically exclude patients with high-risk cardiovascular profiles and data from nontrial settings are scarce., Objective: To summarize the prevalence of adverse cardiovascular events among adults receiving CAR T-cell therapies for advanced hematologic malignant neoplasms., Data Sources: MEDLINE, Embase, Cochrane Library, and Google Scholar were systematically searched from database inception until February 26, 2024., Study Selection: Observational studies were included if they comprised adult CAR T-cell recipients with advanced hematologic malignant neoplasms and if they systematically evaluated cardiovascular complications., Data Extraction and Synthesis: Extraction of prespecified parameters related to the patient population, study design, and clinical events was performed at the study level by 2 independent reviewers in accordance with the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) reporting guideline. Meta-analysis of single proportions was conducted using random-effect models with Freeman-Tukey double arcsine transformations to calculate pooled prevalence estimates. Sensitivity analysis was performed using generalized linear mixed models with logit transformations., Main Outcomes and Measures: Ventricular and supraventricular arrhythmias, heart failure events, reduction in left ventricular ejection fraction, myocardial infarction, and cardiovascular and all-cause mortality., Results: Thirteen studies comprising 1528 CAR T-cell recipients (median [IQR] age, 61 [58.7-63.0] years; 1016 males [66%]; 80% patients with lymphoma) were included. The median (IQR) duration of follow-up was 487 (294-530) days. On random-effects meta-analysis, we observed a pooled prevalence of 0.66% (95% CI, 0.00%-2.28%) for ventricular arrhythmia, 7.79% (95% CI, 4.87%-11.27%) for supraventricular arrhythmia, 8.68% (95% CI, 2.26%-17.97%) for left ventricular dysfunction, 3.87% (95% CI, 1.77%-6.62%) for heart failure events, 0.62% (95% CI, 0.02%-1.74%) for myocardial infarction, and 0.63% (95% CI, 0.13%-1.38%) for cardiovascular death. The pooled prevalence of all-cause mortality was 30.01% (95% CI, 19.49%-41.68%). Sensitivity analyses generated similar findings., Conclusions and Relevance: This meta-analysis found a low prevalence of ventricular arrhythmia, myocardial infarction, and cardiovascular death among CAR T-cell recipients over a short-term to midterm follow-up. Left ventricular dysfunction and supraventricular arrhythmia were the most commonly reported cardiovascular complications, suggesting that cardiovascular surveillance strategies should focus on decreases in ejection fraction and supraventricular arrhythmia.

Chimeric antigen receptor (CAR) T-cell therapy is associated with potentially severe toxicities that create a substantial burden for patients. Patient-reported outcomes (PROs) offer valuable insights into symptoms, functioning, and other complex constructs of interest. In this Review, we aimed to identify symptom and impact concepts important to patients receiving CAR T-cell therapy, construct a conceptual framework for an electronic patient-reported outcome (ePRO) system, and identify timepoints to capture PRO data for CAR T-cell therapies. We searched MEDLINE (OVID) and Web of Science (Clarivate) for articles in English published from Aug 30, 2017, to March 2, 2023. No restrictions on study design were applied. 178 symptoms or constructs were extracted from 44 articles reporting PRO collection in adults with haematological malignancies receiving CAR T-cell therapy. Six health-care professionals and 11 patients and caregiver partners verified construct relevance to clinical management and lived experience, respectively. 109 constructs were sorted according to the four domains of conceptual framework: symptom burden, impact of disease and treatment, tolerability, and health-related quality of life. The identification of concepts beyond symptom burden underscores the importance of PRO measurement for long-term monitoring, to align outcomes with patient concerns. The framework will facilitate PRO measure selection for systematic gathering of PROs from individuals with haematological malignancies receiving CAR T-cell therapies., Competing Interests: Declaration of interests MC is Director of the Birmingham Health Partners Centre for Regulatory Science and Innovation, Director of the Centre for the Centre for Patient Reported Outcomes Research, and is a National Institute for Health and Care Research (NIHR) Senior Investigator. MC receives funding from the NIHR, UK Research and Innovation (UKRI), NIHR Birmingham Biomedical Research Centre (BRC), NIHR Applied Research Collaboration West Midlands, European Regional Development Fund – Demand Hub and Health Data Research UK at the University of Birmingham and University Hospitals Birmingham NHS Foundation Trust, Innovate UK (part of UKRI), Macmillan Cancer Support, UCB Pharma, Janssen, GSK, and Gilead. MC has received personal fees from Astellas, Aparito Ltd, CIS Oncology, Takeda, Merck, Daiichi Sankyo, Glaukos, GSK, Halfloop, Pfizer, the Patient-Centered Outcomes Research Institute, and Vertex outside the submitted work. In addition, a family member owns shares in GSK. OLA receives funding from the NIHR Birmingham BRC, the NIHR Blood and Transplant Research Unit (BTRU) in Precision Transplant and Cellular Therapeutics, NIHR Applied Research Collaboration (ARC) West Midlands, UKRI, Health Foundation, Merck, Gilead, Anthony Nolan, Sarcoma UK, and GSK. He declares personal fees from Gilead Sciences Ltd, Merck, and GSK outside the submitted work. CM receives funding from the NIHR Birmingham BRC, the NIHR BTRU in Precision Transplant and Cellular Therapeutics, Office of Veterans Affairs at The Cabinet Office (UK), and Anthony Nolan. She declares personal fees from Aparito Ltd. FKh receives funding from the NIHR BTRU in Precision Transplant and Cellular Therapeutics and the NIHR Birmingham BRC. SEH receives funding from the NIHR, NIHR ARC West Midlands, UKRI, UK SPINE, Rochester Institute of Technology, Anthony Nolan, and the NIHR BTRU in Precision and Cellular Therapeutics at the University of Birmingham. She declares personal fees from Cochlear, Pfizer, CIS Oncology, AstraZeneca, Rinri Therapeutics, and Aparito outside the submitted work. FKi receives research funding from Gilead, and personal fees from Therakos, Sanofi, and Vertex outside the submitted work. KLS receives funding from the NIHR Blood BTRU in Precision Cellular Therapeutics. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Chimeric antigen receptor T-cell (CAR-T) therapy has heralded a new era in the treatment of various hematological malignancies, increasingly being utilized in earlier lines of therapy. Moreover, cellular therapies are currently under investigation for their potential in treating solid malignancies and autoimmune disorders. As the scope of indications for CAR-T therapy continues to expand, along with the associated reductions in costs and hospital admissions, many medical centers are transitioning towards outpatient CAR-T models. Moreover, ongoing efforts to mitigate complications such as cytokine release syndrome (CRS) or neurotoxicity include the development of premedication strategies, prompt management of adverse events, and the advancement of newer, safer CAR-T cell therapies. However, despite these advancements, the inherent risk of these life-threatening complications remains a critical concern in CAR-T therapy. Institutions must diligently anticipate and effectively manage these complications to ensure the safety and well-being of patients undergoing CAR-T therapy. This includes establishing robust protocols for timely identification and intervention of adverse events, and seamless pathways for transitioning patients to a higher level of care if necessary. This review provides an overview of the current landscape of outpatient CAR-T therapy and offers essential insights into the key clinical and operational considerations needed to implement a successful outpatient CAR-T program., Competing Interests: Declaration of competing interest JW: Consultant: Instrumental Laboratories. KN: None. LL: Honorarium: MJH Lifesciences, CAHON, Medscape. TS: Research funding: Bristol Myers Squibb. Advisory boards: AbbVie, BeiGene, Bristol Myers Squibb, AstraZeneca, Gilead. Data safety monitoring board: BeiGene. Speakers’ bureaus: Bristol Myers Squibb, AstraZeneca, and BeiGene. Steering committee: Bristol Myers Squibb. AK: Speakers’ bureaus: Bristol Myers Squibb. Consultant: Sanofi, Pfizer, GSK, Regeneron, Janssen, Bristol Myers Squibb, Astra Zeneca. Stock: Bristol Myers Squibb. AB: Honorarium: Prime Education. Consultant: Janssen., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Chimeric antigen receptor T-cell (CAR-T) has revolutionized the treatment of hematologic malignancies. There are several approvals in lymphomas, leukemias and myeloma. Randomized clinical trials have shown that CAR-T cell therapy improves survival over standard of care in diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM), changing dramatically the current treatment paradigm. Current efforts are directed in improving outcomes in the frontline setting and confirmatory randomized trials are ongoing., Competing Interests: Declaration of competing interest OCP: Consultancy: Legend Biotech, BMS; JCC: Consultancy: BMS, AbbVie, GenMAb, ADC Therapeutics, MorphoSys, Kite/Gilead, Novartis, Karyopharm, Bayer; AstraZeneca, Allogene, AdiCet., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Chimeric antigen receptor T-cell (CAR-T) therapy has significantly impacted treatment algorithms and clinical outcomes for a variety of patients with hematologic malignancies over the past decade. The field of cellular immunotherapy is currently experiencing a rapid expansion of the number of patients eligible for CAR-T therapies as approvals are being seen in earlier lines of therapy. With the expanded patients eligible for these therapies, more treatment centers will be necessary to keep up with demand. Building a cellular therapy program can be a daunting task, and therefore, we present our experience with building a clinical cellular therapy program., Competing Interests: Declaration of competing interest The authors report no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Chimeric antigen receptor (CAR) T-cell therapy is rapidly advancing, offering promising treatments for patients with hematological malignancy. However, associated infectious complications remain a significant concern because of their contribution to patient morbidity and non-relapse mortality. Recent epidemiological insights shed light on risk factors for infections after CAR T-cell therapy. However, the available evidence is predominantly retrospective, highlighting a need for further prospective studies. Institutions are challenged with managing infections after CAR T-cell therapy but variations in the approaches taken underscore the importance of standardizing infection prevention and management protocols across different healthcare settings. Therefore, the Infectious Diseases Special Interest Group of the American Society of Transplantation and Cellular Therapy assembled an expert panel to develop best practice considerations. The aim was to guide healthcare professionals in optimizing infection prevention and management for CAR T-cell therapy recipients and advocates for early consultation of Infectious Diseases during treatment planning phases given the complexities involved. By synthesizing current evidence and expert opinion these best practice considerations provide the basis for understanding infection risk after CAR T-cell therapies and propose risk-mitigating strategies in children, adolescents, and adults. Continued research and collaboration will be essential to refining and effectively implementing these recommendations., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Chimeric antigen receptor (CAR) T-cell therapy is an innovative treatment approach that has shown remarkable efficacy against several hematologic malignancies. However, its use can be associated with unique and sometimes severe toxicities that require admission to intensive care unit in 30% of patients, and intensivists should be aware of immune-mediated toxicities of CAR T-cell therapy and management of adverse events. We will review available literature on current diagnostic criteria and therapeutic strategies for mitigating these most common toxicities associated with CAR T-cell therapy including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) in the post-infusion period. The authors will also review other toxicities associated with CAR T-cell therapy including cytopenias, acquired immunocompromised states, and infections, and discuss the available literature on best supportive care and prophylaxis recommendations. Critical care medicine specialists play a crucial role in the management of patients undergoing CAR T-cell therapies. With the expanding use of these products in increasing numbers of treating centers, intensivists' roles as part of the multidisciplinary team caring for these patients will have an outsized impact on the continued success of these promising therapies., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Chimeric antigen receptor T (CAR-T) cell therapy has been a milestone breakthrough in the treatment of hematological malignancies, offering an effective therapeutic option for multi-line therapy-refractory patients. So far, abundant CAR-T products have been approved by the United States Food and Drug Administration or China National Medical Products Administration to treat relapsed or refractory hematological malignancies and exhibited unprecedented clinical efficiency. However, there were still several significant unmet needs to be progressed, such as the life-threatening toxicities, the high cost, the labor-intensive manufacturing process and the poor long-term therapeutic efficacy. According to the demands, many researches, relating to notable technical progress and the replenishment of alternative targets or cells, have been performed with promising results. In this review, we will summarize the current research progress in CAR-T eras from the "targets" to "alternative cells", to "combinational drugs" in preclinical studies and clinical trials., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhou, Yang, Jing and Zhu.)

CAR-T cell therapy is a revolutionary new treatment for hematological malignancies, but it can also result in significant adverse effects, with cytokine release syndrome (CRS) being the most common and potentially life-threatening. The identification of biomarkers to predict the severity of CRS is crucial to ensure the safety and efficacy of CAR-T therapy. To achieve this goal, we characterized the expression profiles of seven cytokines, four conventional biochemical markers, and five hematological markers prior to and following CAR-T cell infusion. Our results revealed that IL-2, IFN-γ, IL-6, and IL-10 are the key cytokines for predicting severe CRS (sCRS). Notably, IL-2 levels rise at an earlier stage of sCRS and have the potential to serve as the most effective cytokine for promptly detecting the condition's onset. Furthermore, combining these cytokine biomarkers with hematological factors such as lymphocyte counts can further enhance their predictive performance. Finally, a predictive tree model including lymphocyte counts, IL-2, and IL-6 achieved an accuracy of 85.11% (95% CI = 0.763-0.916) for early prediction of sCRS. The model was validated in an independent cohort and achieved an accuracy of 74.47% (95% CI = 0.597-0.861). This new prediction model has the potential to become an effective tool for assessing the risk of CRS in clinical practice., Competing Interests: LC, LX, AF, RJ and JL are employees of bioMérieux. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Su, Chen, Xie, Fleurie, Jonquieres, Cao, Li, Liang and Tang.)

Abstract: We report a first-in-human clinical trial using chimeric antigen receptor (CAR) T cells targeting CD37, an antigen highly expressed in B- and T-cell malignancies. Five patients with relapsed or refractory CD37+ lymphoid malignancies were enrolled and infused with autologous CAR-37 T cells. CAR-37 T cells expanded in the peripheral blood of all patients and, at peak, comprised >94% of the total lymphocytes in 4 of 5 patients. Tumor responses were observed in 4 of 5 patients with 3 complete responses, 1 mixed response, and 1 patient whose disease progressed rapidly and with relative loss of CD37 expression. Three patients experienced prolonged and severe pancytopenia, and in 2 of these patients, efforts to ablate CAR-37 T cells, which were engineered to coexpress truncated epidermal growth factor receptor, with cetuximab were unsuccessful. Hematopoiesis was restored in these 2 patients after allogeneic hematopoietic stem cell transplantation. No other severe, nonhematopoietic toxicities occurred. We investigated the mechanisms of profound pancytopenia and did not observe activation of CAR-37 T cells in response to hematopoietic stem cells in vitro or hematotoxicity in humanized models. Patients with pancytopenia had sustained high levels of interleukin-18 (IL-18) with low levels of IL-18 binding protein in their peripheral blood. IL-18 levels were significantly higher in CAR-37-treated patients than in both cytopenic and noncytopenic cohorts of CAR-19-treated patients. In conclusion, CAR-37 T cells exhibited antitumor activity, with significant CAR expansion and cytokine production. CAR-37 T cells may be an effective therapy in hematologic malignancies as a bridge to hematopoietic stem cell transplant. This trial was registered at www.ClinicalTrials.gov as #NCT04136275., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

T cell-redirecting therapies (TCRTs), such as chimeric antigen receptor (CAR) or T cell receptor (TCR) T cells and T cell engagers, have emerged as a highly effective treatment modality, particularly in the B and plasma cell-malignancy setting. However, many patients fail to achieve deep and durable responses; while the lack of truly unique tumor antigens, and concurrent on-target/off-tumor toxicities, have hindered the development of TCRTs for many other cancers. In this review, we discuss the recent developments in TCRT targets for hematological malignancies, as well as novel targeting strategies that aim to address these, and other, challenges., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Chimeric antigen receptor (CAR) T-cell therapies have revolutionised the field of haematological malignancies by achieving impressive remission rates in patients with highly refractory haematological malignancies, improving overall survival. To date, six commercial anti-CD19 and anti-BCMA CAR T-cell products have been approved by the Food and Drug Administration (FDA) for the treatment of relapsed/refractory B-cell haematological malignancies and multiple myeloma. The indications for CAR T-cell therapies are gradually expanding, with these therapies being investigated in a variety of diseases, including non-malignant ones. Despite the great success, there are several challenges surrounding CAR T-cell therapies, such as non-durable responses and high-grade toxicities. In addition, a new safety concern was added by the FDA on 28 November 2023 following reports of T-cell malignancies in patients previously treated with either anti-CD19 or anti-BCMA autologous CAR T-cell therapies both in clinical trials and in the real-world setting. Since then, several reports have been published presenting the incidence and analysing the risks of other secondary malignancies after CAR T-cell therapies. In this opinion article, the current landscape of secondary malignancies after CAR T-cell therapies is presented, along with a proposed strategy for future research aiming at potentially diminishing or abrogating the risk of developing secondary malignancies after CAR T-cell therapies.

Introduction: In recent years, chimeric antigen receptor T (CAR-T) cell therapy has resulted in a breakthrough in the treatment of patients with refractory or relapsed hematological malignancies. However, the identification of patients suitable for CAR-T cell therapy needs to be improved., Areas Covered: CAR-T cell therapy has demonstrated excellent efficacy in hematological malignancies; however, views on determining when to apply CAR-T cells in terms of the evaluation of patient characteristics remain controversial., Expert Opinion: We reviewed the current feasibility and challenges of CAR-T cell therapy in the most common hematological malignancies and classified them according to the disease type and treatment priority, to guide clinicians and researchers in applying and investigating CAR-T cells furtherly.

Introduction: In recent years, chimeric antigen receptor T (CAR-T) cell therapy has resulted in a breakthrough in the treatment of patients with refractory or relapsed hematological malignancies. However, the identification of patients suitable for CAR-T cell therapy needs to be improved., Areascovered: CAR-T cell therapy has demonstrated excellent efficacy in hematological malignancies; however, views on determining when to apply CAR-T cells in terms of the evaluation of patient characteristics remain controversial., Expert Opinion: We reviewed the current feasibility and challenges of CAR-T cell therapy in the most common hematological malignancies and classified them according to disease type and treatment priority, to guide clinicians and researchers in applying and investigating CAR-T cells further.

Introduction: The bone marrow microenvironment (BME) is critical for healthy hematopoiesis and is often disrupted in hematologic malignancies. Tumor-associated macrophages (TAMs) are a major cell type in the tumor microenvironment (TME) and play a significant role in tumor growth and progression. Targeting TAMs and modulating their polarization is a promising strategy for cancer therapy., Areas Covered: In this review, we discuss the importance of TME and different multiple possible targets to modulate immunosuppressive TAMs such as: CD123, Sphingosine 1-Phosphate Receptors, CD19/CD1d, CCR4/CCL22, CSF1R (CD115), CD24, CD40, B7 family proteins, MARCO, CD47, CD163, CD204, CD206 and folate receptors., Expert Opinion: Innovative approaches to combat the immunosuppressive milieu of the tumor microenvironment in hematologic malignancies are of high clinical significance and may lead to increased survival, improved quality of life, and decreased toxicity of cancer therapies. Standard procedures will likely involve a combination of CAR T/NK-cell therapies with other treatments, leading to more comprehensive cancer care.

Chimeric antigen receptor (CAR) T-cell therapy is a human gene therapy product where T cells from a patient are genetically modified to enable them to recognize desired target antigen(s) more effectively. In recent years, promising antitumor activity has been seen with autologous CAR T cells. Since 2017, six CAR T-cell therapies for the treatment of hematological malignancies have been approved by the Food and Drug Administration (FDA). Despite the rapid progress of CAR T-cell therapies, considerable statistical challenges still exist for this category of products across all phases of clinical development that need to be addressed. These include (but not limited to) dose finding strategy, implementation of the estimand framework, use of real-world data in contextualizing single-arm CAR T trials, analysis of safety data and long-term follow-up studies. This paper is the first step in summarizing and addressing these statistical hurdles based on the development of the six approved CAR T-cell products., (© 2024. The Author(s), under exclusive licence to The Drug Information Association, Inc.)

Chimeric antigen receptor (CAR) T-cell therapy causes serious side effects including cytokine release syndrome (CRS). CRS-related coagulopathy is associated with hypofibrinogenemia that has up to now been considered the result of disseminated intravascular coagulation (DIC) and liver dysfunction. We investigated the incidence and risk factors for hypofibrinogenemia in 41 consecutive adult patients with hematologic malignancies (median age 69 years, range 38-83 years) receiving CAR T-cell therapy between January 2020 and May 2023 at the University Medical Center Regensburg. CRS occurred in 93% of patients and was accompanied by hypofibrinogenemia already from CRS grade 1. Yet DIC and liver dysfunction mainly occurred in severe CRS (≥ grade 3). After an initial increase during CRS, fibrinogen levels dropped after administration of tocilizumab in a dose-dependent manner (r = -0.44, P=0.004). In contrast, patients who did not receive tocilizumab had increased fibrinogen levels. Logistic regression analysis identified tocilizumab as an independent risk factor for hypofibrinogenemia (odds ratio = 486, P<0.001). We thus hypothesize that fibrinogen synthesis in CRS is up-regulated in an interleukin-6-dependent acute phase reaction compensating for CRS-induced consumption of coagulation factors. Tocilizumab inhibits fibrinogen upregulation resulting in prolonged hypofibrinogenemia. These observations provide novel insights into the pathophysiology of hypofibrinogenemia following CAR T-cell therapy, and emphasize the need for close fibrinogen monitoring after tocilizumab treatment of CRS.

The use of chimeric antigen receptor T (CAR-T) cells is a significant therapeutic improvement increasing the prognosis for patients with a variety of hematological malignancies. However, this therapy has also sometimes life-threatening, complications. Therefore, knowledge of the treatment and management of these complications, especially in treatment centers and intensive care units, respectively, is of outstanding importance. This review provides recommendations for the diagnosis, management, and treatment of CAR-T cell-associated complications such as cytokine release syndrome, immune effector cell associated neurotoxicity syndrome, hematotoxicity, hypogammaglobulinemia, and CAR-T cell-induced pseudo-progression amongst others for physicians treating patients with CAR-T cell-associated complications and intensivists., (© 2024. The Author(s).)

Chimeric antigen receptor T cell (CAR-T) therapy is a promising treatment for hematologic tumors, and adverse events of acute kidney injury (AKI) have been reported. However, its incidence, clinical characteristics, and prognosis remained unclear. We searched PubMed, EMBASE, and Web of Science for study about AKI after CAR-T therapy, a total of 15 studies, comprising 694 patients, were included. Among the 694 patients, 154 (22%) developed AKI, of which 89 (57.8%) were in stage 1, 59 (38.3%) were in stage 2 or 3, and 6 (3.9%) were not reported. Cytokine release syndrome is considered to be the most common cause of AKI. Of the 154 AKI patients, only 16 (10.4%) received renal replacement therapy, most AKI recovered renal function after symptomatic treatment. Although the occurrence of AKI after CAR-T therapy is rare and mostly mild, active knowledge of its pathogenesis, timely diagnosis and treatment are necessary for clinicians., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2023. Published by Elsevier Inc.)

COVID-19 has been associated with high mortality in patients treated with Chimeric Antigen Receptor (CAR) T-cell therapy for hematologic malignancies. Here, we investigated whether the outcome has improved over time with the primary objective of assessing COVID-19-attributable mortality in the Omicron period of 2022 compared to previous years. Data for this multicenter study were collected using the MED-A and COVID-19 report forms developed by the EBMT. One-hundred-eighty patients were included in the analysis, 39 diagnosed in 2020, 35 in 2021 and 106 in 2022. The median age was 58.9 years (min-max: 5.2-78.4). There was a successive decrease in COVID-19-related mortality over time (2020: 43.6%, 2021: 22.9%, 2022: 7.5%) and in multivariate analysis year of infection was the strongest predictor of survival (p = 0.0001). Comparing 2022 with 2020-2021, significantly fewer patients had lower respiratory symptoms (21.7% vs 37.8%, p = 0.01), needed oxygen support (25.5% vs 43.2%, p = 0.01), or were admitted to ICU (5.7% vs 33.8%, p = 0.0001). Although COVID-19-related mortality has decreased over time, CAR T-cell recipients remain at higher risk for complications than the general population. Consequently, vigilant monitoring for COVID-19 in patients undergoing B-cell-targeting CAR T-cell treatment is continuously recommended ensuring optimal prevention of infection and advanced state-of-the art treatment when needed., (© 2024. The Author(s).)

CAR-T cell therapy has established itself as a highly effective treatment for hematological malignancies. There are currently six commercial CAR-T products that have been FDA approved for diseases such as B-ALL, LBCL, MCL, FL, MM, and CLL/SLL. "Real-world" studies allow us to evaluate outcomes from the general population to determine their efficacy and safety compared to those who were included in the original trials. Based on several well conducted "Real-world" studies that represent diverse populations, we report that outcomes from the original trials that led to the approval of these therapies are comparable to those in practice.

Recently, CAR-T cell therapy in hematological malignancies has received extensive attention. The objective of this study is to gain a comprehensive understanding of the current research status, development trends, research hotspots, and emerging topics pertaining to CAR-T cells in the treatment of hematological malignancies. Articles pertaining to CAR-T cell therapy for hematological malignancies from the years 2012 to 2023 were obtained and assessed from the Web of Science Core Collection (WoSCC). A bibliometric approach was employed to conduct a scientific, comprehensive, and objective quantitative analysis, as well as a visual analysis, of this particular research domain. A comprehensive analysis was conducted on a corpus of 3643 articles, which were collaboratively authored by 72 countries and various research institutions. CAR-T cell research in treating hematological malignancies shows an increasing trend each year. Notably, the study identified the countries and institutions displaying the highest level of activity, the journals with the most citations and output, as well as the authors who garnered the highest frequency of citations and co-citations. Furthermore, the analysis successfully identified the research hotspots and highlighted six emerging topics within this domain. This study conducted a comprehensive exploration and analysis of the research status, development trends, research hotspots, and emerging topics about CAR-T cells in the treatment of hematological malignancies from 2012 to 2023. The findings of this study will serve as a valuable reference and guide for researchers seeking to delve deeper into this field and determine the future direction of their research.

The promising results seen in the treatment of refractory hematologic malignancies with tisagenlecleucel (Kymriah), the pioneering Chimeric Antigen Receptor (CAR) T-cell immunotherapy, has stimulated a fast growth in research and clinical testing of novel CAR-T constructs, targets, and various generations of CAR T-cells. Pharmacists may receive inquiries about active clinical trials or may be contributing to the care of patients participating in these studies. This briefing discusses the on-going clinical trials that explore novel CAR T-cell immunotherapies in pediatric refractory malignancies of hematologic and solid organ origins. It can be valuable in assisting practitioners in navigating the rapidly evolving field of CAR T-cell immunotherapies., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Chimeric antigen receptor T-cell (CAR-T) therapy has shown promise in treating hematologic malignancies, yet its potential cardiotoxic effects require thorough investigation., Objectives: We aim to conduct a systematic review and meta-analysis to examine the cardiotoxic effects of CAR-T therapy in adults with hematologic malignancies., Methods: We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials for studies reporting cardiovascular outcomes, such as arrhythmias, heart failure, and reduced left ventricle ejection fraction (LVEF)., Results: Our analysis of 20 studies involving 4789 patients revealed a 19.68% incidence rate of cardiovascular events, with arrhythmias (7.70%), heart failure (5.73%), and reduced LVEF (3.86%) being the most prevalent. Troponin elevation was observed in 23.61% of patients, while NT-Pro-BNP elevation was observed in 9.4. Subgroup analysis showed higher risks in patients with pre-existing conditions, such as atrial arrhythmia (OR 3.12; p < .001), hypertension (OR 1.85; p = .002), previous heart failure (OR 3.38; p = .003), and coronary artery disease (OR 2.80; p = .003)., Conclusion: Vigilant cardiovascular monitoring is crucial for patients undergoing CAR-T therapy to enhance safety and treatment efficacy.Novelty Statements., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Abstract: Recent studies demonstrating the feasibility of outpatient chimeric antigen receptor (CAR)-modified T-cell therapy administration are either restricted to CARs with 41BB costimulatory domains or use intensive at-home monitoring. We report outcomes of outpatient administration of all commercially available CD19- and B-cell maturation antigen (BCMA)-directed CAR T-cell therapy using a strategy of no remote at-home monitoring and an early cytokine release syndrome (CRS) intervention strategy. Patients with hematologic malignancies who received CAR T-cell therapy in the outpatient setting during 2022 to 2023 were included. Patients were seen daily in the cancer center day hospital for the first 7 to 10 days and then twice weekly through day 30. The primary end point was to determine 3-, 7-, and 30-day post-CAR T-cell infusion hospitalizations. Early CRS intervention involved administering tocilizumab as an outpatient for grade ≥1 CRS. Fifty-eight patients received outpatient CAR T-cell infusion (33 myeloma, 24 lymphoma, and 1 acute lymphoblastic leukemia). Of these, 17 (41%), 16 (38%), and 9 patients (21%) were admitted between days 0 to 3, 4 to 7, and 8 to 30 after CAR T-cell infusion, respectively. The most common reason for admission was CAR T-cell-related toxicities (33/42). Hospitalization was prevented in 15 of 35 patients who received tocilizumab for CRS as an outpatient. The nonrelapse mortality rates were 1.7% at 1 month and 3.4% at 6 months. In conclusion, we demonstrate that the administration of commercial CAR T-cell therapies in an outpatient setting is safe and feasible without intensive remote monitoring using an early CRS intervention strategy., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Malignant tumors of the hematologic system have a high degree of malignancy and high mortality rates. Chimeric antigen receptor T cell (CAR-T) therapy has become an important option for patients with relapsed/refractory tumors, showing astonishing therapeutic effects and thus, it has brought new hope to the treatment of malignant tumors of the hematologic system. Despite the significant therapeutic effects of CAR-T, its toxic reactions, such as Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), cannot be ignored since they can cause damage to multiple systems, including the cardiovascular system. We summarize biomarkers related to prediction, diagnosis, therapeutic efficacy, and prognosis, further exploring potential monitoring indicators for toxicity prevention. This review aims to summarize the effects of CAR-T therapy on the cardiovascular, hematologic, and nervous systems, as well as potential biomarkers, and to explore potential monitoring indicators for preventing toxicity, thereby providing references for clinical regulation and assessment of therapeutic effects., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Chen, Xu, Hu, Li and Chang.)

Over the past decade, chimeric antigen receptor T cells have emerged as a breakthrough cancer therapy in selected hematologic malignancies. Translating the success of this therapy to solid tumors is challenging. In this issue, we discuss strategies potentially useful to increase the chimeric antigen receptor T-cell efficacy in this clinical indication. See related article by Fischer-Riepe et al., p. 3564., (©2024 American Association for Cancer Research.)

Abstract: Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising immunotherapeutic strategy for eradicating human cancers. Their therapeutic success and durability of clinical responses hinges, in large part, on their functional capacity, including the ability of these engineered cells to simultaneously expand and persist after infusion into patients. CD19 CAR T-cell polyfunctionality, assessing the simultaneous functions of cytokine production, proliferation, and cytotoxicity has been reported to correlate with clinical outcomes. Assay optimization is potentially limited by the heterogeneous nature of CAR T-cell infusion products and target specificity. We optimized a single-cell platform for polyfunctionality using CAR T-cell products manufactured from healthy donors, engineered against a novel target, B-cell-activating factor receptor (BAFF-R) and validated the protocol using CD19 CAR T cells. We observed distinct qualitative differences between BAFF-R and CD19 CAR T cells relative to the proportions of stimulatory vs effector cytokines, based on target antigen density, and, generally, CD19 CAR T cells exhibited lower indices of polyfunctionality. Finally, we applied our assay to the autologous BAFF-R CAR T-cell product generated from the first patient with non-Hodgkin lymphoma treated in an ongoing clinical trial who had progressed after prior CD19 CAR T-cell therapy. We observed robust indicators of polyfunctionality, which correlated with successful CAR T-cell expansion after infusion and achievement of durable complete remission ongoing after 18 months. The precise identification of factors determining the role of BAFF-R CAR T-cell fitness in toxicity and clinical outcome will require the application of this robust assay in the analysis of additional treated patients. This trial was registered at www.ClinicalTrials.gov as #NCT05370430., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

In recent years, the therapeutic landscape for hematological malignancies has markedly advanced, particularly since the inaugural approval of autologous chimeric antigen receptor T cell (CAR-T) therapy in 2017 for relapsed/refractory acute lymphoblastic leukemia (ALL). Autologous CAR-T therapy involves the genetic modification of a patient's T cells to specifically identify and attack cancer cells, while bispecific antibodies (BsAbs) function by binding to both cancer cells and immune cells simultaneously, thereby triggering an immune response against the tumor. The subsequent approval of various CAR-T therapies and BsAbs have revolutionized the treatment of multiple hematological malignancies, highlighting high response rates and a subset of patients achieving prolonged disease control. This review explores the mechanisms underlying autologous CAR-T therapies and BsAbs, focusing on their clinical application in multiple myeloma, ALL, and non-Hodgkin lymphoma. We provide comprehensive insights into their individual efficacy, limitations concerning broad application, and the potential of combination therapies. These upcoming strategies aim to propel the field forward, paving the way for safer and more effective therapeutic interventions in hematological malignancies., Competing Interests: Declaration of interests S.A.H. reports receiving consulting fees from Jansen, Pfizer, Sanofi, and Galapagos, and research funding from the International Myeloma Society and Alexion. H.E.H. has equity in Allovir and Marker Therapeutics, has served on advisory boards for Tessa Therapeutics, March Biosciences, GSK, Kiadis, and Fresh Wind Biotechnologies, and received research support from Tessa Therapeutics and Kuur Therapeutics. M.K.B. has equity in Allovir, Marker Therapeutics, March Biosciences, and Tessa Therapeutics, has served on advisory boards for Walking Fish Therapeutics, CellGenix GmbH, Marker Therapeutics, Tessa Therapeutics, Abintus, Allogene, Bellicum Pharmaceuticals, Bluebird Bio, Athenex, Memgen, Turnstone Biologics, Coya Therapeutics, TScan Therapeutics, Onkimmune, Poseida Therapeutics, Allovir, Triumvira, MEMGEN, Adaptimmune, and AstraZeneca, and received research support from Tessa Therapeutics. M.S. was a scientific consultant for Tessa Therapeutics and received research support from Tessa Therapeutics and AstraZeneca. Disclosure of outside interests for CAGT investigators: BCM (https://www.bcm.edu/academic-centers/cell-and-gene-therapy/research/disclosure-of-outside-interests)., (Copyright © 2024 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

The application of chimeric antigen receptor T cell (CAR-T) immunotherapy has ushered in a new era in cancer therapy, especially in the treatment of many kinds of refractory malignant tumors. The curative effect is significant for refractory/recurrent hematologic malignancies, such as acute leukemia, lymphoma, and multiple myeloma (MM). Tumor microenvironment (TME) is closely related to the efficacy and adverse reactions of CAR-T therapy. TME not only affects the activity of CAR-T cells, reduces their anti-tumor ability, but also directly involved in the occurrence and development of CAR-T cell therapy-related adverse reactions, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Therefore, a deeper understanding of the role of blood TME in the process of CAR-T immunotherapy and the occurrence and development of adverse reactions is helpful for the application of CAR-T therapy in hematological malignancies. In this review, the influence of blood TME on the efficacy and adverse reactions of CAR-T immunotherapy was briefly summarized, aiming to provide evidence-based support for the clinical optimization of therapeutic regimen of refractory/recurrent hematologic malignancies.

There have been several clinical studies using chimeric antigen receptor (CAR)-T cell therapy for different hematological malignancies. It has transformed the therapy landscape for hematologic malignancies dramatically. Nonetheless, in acute myeloid leukemia (AML) and T cell malignancies, it still has a dismal prognosis. Even in the most promising locations, recurrence with CAR-T treatment remains a big concern. Oncolytic viruses (OVs) can directly lyse tumor cells or cause immune responses, and they can be manipulated to create therapeutic proteins, increasing anticancer efficacy. Oncolytic viruses have been proven in a rising number of studies to be beneficial in hematological malignancies. There are limitations that cannot be avoided by using either treatment alone, and the combination of CAR-T cell therapy and oncolytic virus therapy may complement the disadvantages of individual application, enhance the advantages of their respective treatment methods and improve the treatment effect. The alternatives for combining two therapies in hematological malignancies are discussed in this article., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Despite Peng and colleagues providing an extensive review of the clinical and laboratory aspects of CAR-T-associated coagulopathy, the current literature often lacks specificity in nomenclature and gradings, and the clinical implications of coagulopathy may remain unclear. Clear recommendations on stratification and prophylaxis are still required to standardize the clinical approach to this topic. Commentary on: Peng et al. Coagulation abnormalities associated with CAR-T therapy in hematological malignancies: A review. Br J Haematol 2024;205:420-428., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Chimeric antigen receptor (CAR)-T-cell therapy has demonstrated considerable efficacy and safety in the treatment of patients with relapsed/refractory haematological malignancies. Owing to significant advances, CAR-T-cell therapeutic modality has undergone substantial shifts in its clinical application. Coagulation abnormalities, which are prevalent complications in CAR-T-cell therapy, can range in severity from simple abnormalities in coagulation parameters to serious haemorrhage or disseminated intravascular coagulation associated with life-threatening multiorgan dysfunction. Nonetheless, there is a lack of a comprehensive overview concerning the coagulation abnormalities associated with CAR-T-cell therapy. With an aim to attract heightened clinical focus and to enhance the safety of CAR-T-cell therapy, this review presents the characteristics of the coagulation abnormalities associated with CAR-T-cell therapy, including clinical manifestations, coagulation parameters, pathogenesis, risk factors and their influence on treatment efficacy in patients receiving CAR-T-cell infusion. Due to limited data, these conclusions may undergo changes as more experience accumulates., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Objectives: This study aimed to systematically review evidence on the cost-effectiveness of chimeric antigen receptor T-cell (CAR-T) therapies for patients with cancer., Methods: Electronic databases were searched in October 2022 and updated in September 2023. Systematic reviews, health technology assessments, and economic evaluations that compared costs and effects of CAR-T therapy in patients with cancer were included. Two reviewers independently screened studies, extracted data, synthesized results, and critically appraised studies using the Philips checklist. Cost data were presented in 2022 US dollars., Results: Our search yielded 1809 records, 47 of which were included. Most of included studies were cost-utility analysis, published between 2018 and 2023, and conducted in the United States. Tisagenlecleucel, axicabtagene ciloleucel, idecabtagene vicleucel, ciltacabtagene autoleucel, lisocabtagene maraleucel, brexucabtagene autoleucel, and relmacabtagene autoleucel were compared with various standard of care chemotherapies. The incremental cost-effectiveness ratio (ICER) for CAR-T therapies ranged from $9424 to $4 124 105 per quality-adjusted life-year (QALY) in adults and from $20 784 to $243 177 per QALY in pediatric patients. Incremental cost-effectiveness ratios were found to improve over longer time horizons or when an earlier cure point was assumed. Most studies failed to meet the Philips checklist due to a lack of head-to-head comparisons and uncertainty surrounding CAR-T costs and curative effects., Conclusions: CAR-T therapies were more expensive and generated more QALYs than comparators, but their cost-effectiveness was uncertain and dependent on patient population, cancer type, and model assumptions. This highlights the need for more nuanced economic evaluations and continued research to better understand the value of CAR-T therapies in diverse patient populations., Competing Interests: Author Disclosures Author disclosure forms can be accessed below in the Supplemental Material section., (Copyright © 2024. Published by Elsevier Inc.)

Chimeric antigen receptor (CAR) T-cell therapy has transformed the care of patients with relapsed/refractory B-cell-derived hematologic malignancies. To date, six CAR T-cell therapies, targeting either CD19 or B-cell maturation antigen, have received regulatory approval. Along with the promising survival benefit, CAR T-cell therapy is associated with potentially life-threatening adverse events, including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. While clinical trials evaluating CAR T-cell therapy consistently report the incidence of these adverse events, most trials do not collect health-related quality of life (HRQoL) data. As such, the impact of the CAR T-cell therapy process and related adverse events on the physical and psychological well-being of patients remains uncertain. HRQoL and other patient-reported outcome (PRO) assessments in patients with relapsed or refractory hematologic malignancies are of utmost importance, as individuals may have unmet needs and a high demand for tolerable therapy if a cure is not obtained. In addition, it is important to standardize methods of data collection to better assess the impact of CAR T-cell therapy on quality of life, optimize patients' care and costs, and enable comparisons between different studies. We conducted a literature search up to June 2023 to identify the HRQoL tools used in clinical trials and in real-world studies investigating CAR T-cell therapy in patients with lymphomas or leukemias. In the present comprehensive review, we summarize the most commonly used CAR T-cell specific and non-specific HRQoL tools and discuss how the use of HRQoL and other PRO tools may be optimized.

Chimeric antigen receptor T-cell (CAR-T) therapy is a novel anticancer therapy using autologous or allogeneic T-cells. To date, six CAR-T therapies for specific B-cell acute lymphoblastic leukemia (B-ALL), non-Hodgkin lymphomas (NHL), and multiple myeloma (MM) have been approved by the Food and Drug Administration (FDA). Significant barriers to the effectiveness of CAR-T therapy include cytokine release syndrome (CRS), neurotoxicity in the case of Allogeneic Stem Cell Transplantation (Allo-SCT) graft-versus-host-disease (GVHD), antigen escape, modest antitumor activity, restricted trafficking, limited persistence, the immunosuppressive microenvironment, and senescence and exhaustion of CAR-Ts. Furthermore, cancer drug resistance remains a major problem in clinical practice. CAR-T therapy, in combination with checkpoint blockades and bispecific T-cell engagers (BiTEs) or other drugs, appears to be an appealing anticancer strategy. Many of these agents have shown impressive results, combining efficacy with tolerability. Biomarkers like extracellular vesicles (EVs), cell-free DNA (cfDNA), circulating tumor (ctDNA) and miRNAs may play an important role in toxicity, relapse assessment, and efficacy prediction, and can be implicated in clinical applications of CAR-T therapy and in establishing safe and efficacious personalized medicine. However, further research is required to fully comprehend the particular side effects of immunomodulation, to ascertain the best order and combination of this medication with conventional chemotherapy and targeted therapies, and to find reliable predictive biomarkers.

The introduction of immunotherapies has led to remarkable progress in the treatment of hematological malignancies, including B-cell malignancies such as B-cell lymphoma and multiple myeloma (MM). Although conventional therapeutic antibodies are effective as immunotherapy for newly diagnosed and relapsed/refractory B-cell lymphoma and MM, some cases are resistant. Chimeric antigen receptor (CAR) T-cell therapies targeting B-cell lymphoma and MM have progressed through several generations, and have improved treatment strategies for relapsed/refractory disease. In addition to conventional therapeutic antibodies, bispecific antibodies targeting both tumor cells and T cells have been developed for MM. Both CAR T-cell therapies and bispecific antibodies are effective for heavily treated patients with relapsed/refractory disease. However, most patients treated with these therapies relapse, and serious adverse events like cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are problematic. This Progress in Hematology, "Novel treatment strategies for hematological malignancies in the immunotherapy era," focuses on such limitations and the future outlook for CAR T-cell therapies and bispecific antibodies for B-cell malignancies. The role of NK cells in anti-tumor immunity for AML and various therapeutic strategies for NK-cell therapy in AML is also discussed., (© 2024. Japanese Society of Hematology.)

The rise of immuno-oncology, including the use of chimeric antigen receptor T-cell (CAR-T) therapy is bringing in a new wave of cancer treatments, particularly in hematologic malignancies. However, data on their adverse events, particularly of the eye, is under-reported. To assess the ocular adverse events associated with the six FDA-approved CAR-T cell therapies, a disproportionality analysis utilizing the FAERS database was conducted from the first quarter of 2017 to the third quarter of 2023, as well as a systematic review of case reports of ocular events following CAR-T cell therapy up to December 20, 2023. A total of 53 ocular adverse events were identified from the FDAs FAERS database. The adverse events most frequently observed were mydriasis and xerophthalmia with tisagenlecleucel (Kymriah). The systematic review resulted in 8 case reports encompassing 19 patients which included a total of 27 events. This study demonstrates the importance of anticipation of potential ocular adverse events by ophthalmologists and oncologists as they can greatly contribute to morbidity in patients with cancer., (© 2024 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of several haematological malignancies and is being investigated in patients with various solid tumours. Characteristic CAR T cell-associated toxicities such as cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are now well-recognized, and improved supportive care and management with immunosuppressive agents has made CAR T cell therapy safer and more feasible than it was when the first regulatory approvals of such treatments were granted in 2017. The increasing clinical experience with these therapies has also improved recognition of previously less well-defined toxicities, including movement disorders, immune effector cell-associated haematotoxicity (ICAHT) and immune effector cell-associated haemophagocytic lymphohistiocytosis-like syndrome (IEC-HS), as well as the substantial risk of infection in patients with persistent CAR T cell-induced B cell aplasia and hypogammaglobulinaemia. A more diverse selection of immunosuppressive and supportive-care pharmacotherapies is now being utilized for toxicity management, yet no universal algorithm for their application exists. As CAR T cell products targeting new antigens are developed, additional toxicities involving damage to non-malignant tissues expressing the target antigen are a potential hurdle. Continued prospective evaluation of toxicity management strategies and the design of less-toxic CAR T cell products are both crucial for ongoing success in this field. In this Review, we discuss the evolving understanding and clinical management of CAR T cell-associated toxicities., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Introduction: While CAR T-cell therapy has led to remarkable responses in relapsed B-cell hematologic malignancies, only 50% of patients ultimately have a complete, sustained response. Understanding the mechanisms of resistance and relapse after CAR T-cell therapy is crucial to future development and improving outcomes., Areas Covered: We review reasons for both primary resistance and relapse after CAR T-cell therapies. Reasons for primary failure include CAR T-cell manufacturing problems, suboptimal fitness of autologous T-cells themselves, and intrinsic features of the underlying cancer and tumor microenvironment. Relapse after initial response to CAR T-cell therapy may be antigen-positive, due to CAR T-cell exhaustion or limited persistence, or antigen-negative, due to antigen-modulation on the target cells. Finally, we discuss ongoing efforts to overcome resistance to CAR T-cell therapy with enhanced CAR constructs, manufacturing methods, alternate cell types, combinatorial strategies, and optimization of both pre-infusion conditioning regimens and post-infusion consolidative strategies., Expert Opinion: There is a continued need for novel approaches to CAR T-cell therapy for both hematologic and solid malignancies to obtain sustained remissions. Opportunities for improvement include development of new targets, optimally combining existing CAR T-cell therapies, and defining the role for adjunctive immune modulators and stem cell transplant in enhancing long-term survival.

Chimeric antigen receptor (CAR)-T cell therapy has shown promising results in patients with hematological malignancies. However, many patients still have poor prognoses or even fatal outcomes due to the life-threatening toxicities associated with the therapy. Moreover, even after improving the known influencing factors (such as number or type of CAR-T infusion) related to CAR-T cell infusion, the results remain unsatisfactory. In recent years, it has been found that endothelial cells (ECs), which are key components of the organization, play a crucial role in various aspects of immune system activation and inflammatory response. The levels of typical markers of endothelial activation positively correlated with the severity of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxic syndrome (ICANS), suggesting that ECs are important targets for intervention and toxicity prevention. This review focuses on the critical role of ECs in CRS and ICANS and the intervention strategies adopted., (© 2024. The Author(s).)