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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. [ABSTRACT FROM AUTHOR]

Objective: Unusual clinical course Background: CRS (cytokine release syndrome) is a massive activation of the inflammatory system characterized by a supra- physiological rate of inflammatory cytokines. The interleukin 6 cytokine plays a central role in CRS. The main clinical sign of CRS is fever, but CRS can lead to multiple organ failure in severe cases. CRS is usually described in sepsis, more recently in SARS COV-2 infection, and in chimeric antigen receptor T-cell therapy. However, it can also be associated with immune checkpoint inhibitors (ICIs), which is infrequently described. ICI have growing indications and can lead to CRS by causing an uncontrolled activation of the immune system. There are currently no treatment guidelines for ICI-induced CRS. Case Report: We report a rare case of grade 3 CRS induced by nivolumab associated with 5-fluorouracil and oxaliplatin for gastric cancer. The patient was 65-year-old man with an adenocarcinoma of the cardia. CRS developed during the tenth course of treatment and was characterized by fever, hypotension requiring vasopressors, hypoxemia, acute kidney injury, and thrombopenia. The patient was transferred quickly to the Intensive Care Unit. He was treated for suspected sepsis, but it was ruled out after multiple laboratory examinations. There was rapid resolution after infusion of hydrocortisone. Conclusions: The use of ICIs is expanding. Nivolumab-induced CRS is rarely described but can be severe and lead to multiple organ dysfunction; therefore, intensive care practitioners should be informed about this adverse effect. More studies are needed to better understand this condition and establish treatment guidelines. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T-cell therapy (CART) can be administered outpatient yet requires management of potential side effects such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The pre-infusion tumor burden is associated with CRS, yet there is no data on the relevance of pre-infusion tumor growth rate (TGR). Our objective was to investigate TGR for the occurrence and severity of CRS and ICANS. Consecutive patients with available pre-baseline and baseline (BL) imaging before CART were included. TGR was determined as both absolute (abs) and percentage change (%) of Lugano criteria-based tumor burden in relation to days between exams. CRS and ICANS were graded according to ASTCT consensus criteria. Clinical metadata was collected including the international prognostic index (IPI), patient age, ECOG performance status, and LDH. Sixty-two patients were included (median age: 62 years, 40% female). The median pre-BL TGR [abs] and pre-BL TGR [%] was 7.5 mm2/d and 30.9%/d. Pre-BL TGR [abs] and pre-BL TGR [%] displayed a very weak positive correlation with the grade of CRS (r[abs] = 0.14 and r[%] = 0.13) and no correlation with ICANS (r[abs] = − 0.06 and r[%] = − 0.07). There was a weak positive correlation between grade of CRS and grade of ICANS (r = 0.35; p = 0.005) whereas there was no significant correlation of CRS or ICANS to any other of the examined parameters. The pre-infusion TGR before CART was weakly associated with the occurrence of CRS, but not the severity, whereas there were no significant differences in the prediction of ICANS. There was no added information when compared to pre-infusion tumor burden alone. Outpatient planning and toxicity management should not be influenced by the pre-infusion TGR. [ABSTRACT FROM AUTHOR]

The assessment of bioactivity for therapeutic antibody release assay poses challenges, particularly when targeting immune checkpoints. An in vitro bioassay platform was developed using the chimeric antigen receptor on Jurkat cells (Jurkat-CAR) to analyze antibodies targeting immune checkpoints, such as CD47/SIRPα, VEGF/VEGFR1, PD-1/PD-L1, and CD70/CD27. For CD47/SIRPα, the platform involved a Jurkat-CAR cell line expressing the chimeric SIRPα receptor (CarSIRPα). CarSIRPα was created by sequentially fusing the SIRPα extracellular region with the CD8α hinge region, the transmembrane (TM) and intracellular (IC) domains of CD28, and the intracellular signaling domain of CD3ζ. The resulting Jurkat-CarSIRPα cells can undergo "activation-induced cell death (AICD)" upon incubation with purified or cellular CD47, as evidenced by the upregulation of CD69, IL-2, and IFN-γ. Similar results also appeared in Jurkat CarVEGFR1, Jurkat CarPD1 and Jurkat CARCD27 cells. These cells are perfectly utilized for the bioactivity analysis of therapeutic antibody. Our study indicates that the established in vitro assay platform based on Jurkat-CAR has been confirmed repeatedly and has shown robust reproducibility; thus, this platform can be used for screening or for release assays of given antibody drugs targeting immune checkpoints., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Wenzhi Tian, and Song Li hold ownership interest in ImmuneOnco Biopharmaceuticals (Shanghai) Inc. Wenzhi Tian, Song Li and Dianze Chen are the owners of Jurkat-CD47(KO)-CarSIRPα patent (CN111303295A). If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

While targeted therapies such as Bruton's tyrosine kinase and BCL2 inhibitors have fundamentally changed the treatment of mantle cell lymphoma (MCL), not all patients respond to these therapies, and responses are finite and can be fleeting, especially with high-risk MCL. As patients progress through successive therapies, the clinical course is characterized by shortening response times,1 frequent disease acceleration, and limited survival outcomes. Recently, the sensitivity of MCL to novel immune-based therapies is being realized with favorable results, as chimeric antigen receptor-modified T cells and bispecific T-cell-engaging antibodies are being investigated and implemented into practice for patients. However, critical issues remain to understand the role of these agents in routine practice. In this review, we discuss the current landscape regarding these agents, examine our approach to incorporating them into practice, and consider unanswered questions that we must ultimately address to improve outcomes for patients., (Copyright © 2024 by The American Society of Hematology.)

Background: Given the growing acknowledgment of the detrimental effects of excessive myocardial fibrosis on pathological remodeling after myocardial ischemia-reperfusion injury (I/R), targeting the modulation of myocardial fibrosis may offer protective and therapeutic advantages. However, effective clinical interventions and therapies that target myocardial fibrosis remain limited. As a promising chimeric antigen receptor (CAR) cell therapy, whether CAR macrophages (CAR-Ms) can be used to treat I/R remains unclear., Methods: The expression of FAP (fibroblast activation protein) was studied in mouse hearts after I/R. FAP CAR-Ms were generated to target FAP-expressing cardiac fibroblasts in mouse hearts after I/R. The phagocytosis activity of FAP CAR-Ms was tested in vitro. The efficacy and safety of FAP CAR-Ms in treating I/R were evaluated in vivo., Results: FAP was significantly upregulated in activated cardiac fibroblasts as early as 3 days after I/R. Upon demonstrating their ability to engulf FAP-overexpressing fibroblasts, we intravenously administered FAP CAR-Ms to mice at 3 days after I/R and found that FAP CAR-Ms significantly improved cardiac function and reduced myocardial fibrosis in mice after I/R. No toxicities associated with FAP CAR-Ms were detected in the heart or other organs at 2 weeks after I/R. Finally, we found that FAP CAR-Ms conferred long-term cardioprotection against I/R., Conclusions: Our proof-of-concept study demonstrates the therapeutic potential of FAP CAR-Ms in alleviating myocardial I/R and potentially opens new avenues for the treatment of a range of heart diseases that include a fibrotic phenotype., Competing Interests: None.

Objective: Chimeric antigen-receptor T-cell therapy (CAR-T) is characterised by early phase data at the time of registration, high upfront cost and a complex manufacturing and administration process compared with standard therapies. Our objective was to compare the performance of different models to assess the cost effectiveness of CAR-T using a state-transition model (STM), partitioned survival model (PSM) and discrete event simulation (DES)., Methods: Individual data for tisagenlecleucel for the treatment of young patients with acute lymphoblastic leukaemia (ALL) were used to populate the models. Costs and benefits were measured over a lifetime to generate a cost per quality-adjusted life-year (QALY). Model performance was compared quantitatively on the outcomes generated and a checklist developed summarising the components captured by each model type relevant to assessing cost effectiveness of CAR-T., Results: Models generated similar results with base-case analyses ranging from an incremental cost per QALY of $96,074-$99,625. DES was the only model to specifically capture CAR-T wait time, demonstrating a substantial loss of benefit of CAR-T with increased wait time., Conclusion: Although model type did not meaningfully impact base-case results, the ability to incorporate an outcome-based payment arrangement (OBA) and wait time are important elements to consider when selecting a model for CAR-T. DES provided greater flexibility compared with STM and PSM approaches to deal with the complex manufacturing and administration process that can lead to extended wait times and substantially reduce the benefit of CAR-T. This is an important consideration when selecting a model type for CAR-T, so major drivers of uncertainty are considered in funding decisions., Competing Interests: Declarations Conflict of interest Amy Gye is an employee of Novartis Pharmaceuticals. Stephen Goodall and Richard De Abreu Lourenco have no conflicts to disclose. Author contributions Concept and design: Gye, Goodall, De Abreu Lourenco; acquisition of data: Gye; analysis and interpretation of data: Gye; drafting of the manuscript: Gye, Goodall, De Abreu Lourenco; critical revision of the paper for important intellectual content: Goodall, De Abreu Lourenco; supervision: Goodall, De Abreu Lourenco. Data availability statement Individual data used to support this study are not publicly available for ethical and legal reasons. All other sources used in this research are referenced and publicly available. Funding Open Access funding enabled and organized by CAUL and its Member Institutions. This research is part of an Industry Doctorate Program at the Centre for Health Economics Research and Evaluation, University of Technology Sydney in collaboration with Novartis Pharmaceuticals Australia. Novartis Pharmaceuticals Australia provided a Research Support Fee. Role of the Funder/Sponsor The funder had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; or preparation of the manuscript. The manuscript was reviewed by Novartis prior to submitting for publication. The views expressed are those of the authors and not necessarily those of Novartis Pharmaceuticals or the Centre for Health Economics Research and Evaluation (CHERE)., (© 2024. The Author(s).)

Background: Patients undergoing chimeric antigen receptor (CAR) T-cell therapy are vulnerable to infection and sepsis. Treatment course is frequently complicated by cytokine release syndrome which is often clinically and biochemically indistinguishable from sepsis. Procalcitonin (PCT) levels have been examined as a promising biomarker for infection in this cohort of patients., Methods: In this study, we measured daily PCT levels for patients for fourteen days (or hospital discharge) after receiving CAR T-cells to determine threshold PCT values specific for infection compared to those without infection., Results: We present preliminary results of our enrolled cohort to date (sixteen patients). Infection was present in only 12.5% of patients. However, those diagnosed with sepsis had elevated PCT levels with a peak mean of 2.6 µg/L observed on the seventh day post-treatment compared to those without infection remaining below 0.5 µg/L. Furthermore, we observed a trend for early and liberal antibiotic administration within our cohort., Conclusion: Our study highlights the challenges of antimicrobial stewardship in managing CAR T-cell therapy recipients. Our preliminary results underscore the utility of PCT in the risk-stratification and diagnosis of those patients at high risk for infectious complications after receiving CAR T-cell therapy and continue to advocate for a PCT threshold of 1.5 µg/L for diagnosing sepsis. Additionally, in the setting of CRS and lymphodepletion, where white cell count and CRP value are unreliable, a PCT value of < 0.5 µg/L may help exclude sepsis.

Background: B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor T-cell (CAR T-cell) therapy has exhibited remarkable efficacy in refractory or relapsed multiple myeloma (R/R MM), but recurrence and rapid progression of disease are still observed within a short time after treatment. Long-term pomalidomide therapy, which potentiates T-cell functionality, might enhance the efficacy of BCMA CAR T-cell therapy., Methods: We performed a single-center retrospective clinical study. Patients with relapsed or refractory multiple myeloma who received BCMA CAR T-cell infusion were enrolled in our study, and were followed by long-term pomalidomide treatment (4 mg/day) or not one month after infusion. The response and adverse events were assessed after infusion. The effect of pomalidomide on BCMA CAR T-cells was assessed in vitro., Results: The objective response rate (ORR) of BCMA-CART was 100%. Three months following CAR T-cell infusion, of the 8 patients receiving pomalidomide, except for 2 patients who stopped maintenance therapy and were lost to follow-up, all patients (6/6) achieved VGPR (very good partial response) or CR (complete response), while only 5 patients (5/8) who did not receive pomalidomide treatment achieved VGPR or better. At a median follow-up of 27 months, for the 8 patients who did not receive pomalidomide administration, the median TTP (time to progression) was 5.85 (1-14) months, while the OS (overall survival) was 10.7 (1.2-16) months. Of the 8 patients who received pomalidomide therapy after CAR T-cell infusion, the median TTP was 13 (7-13) months, while the OS was not reached. Moreover, neither long-term hematological toxicity nor drug-induced liver damage was observed during the follow-up period. Mechanistically, pomalidomide promotes antimyeloma efficacy of BCMA CAR T-cells by inhibiting cell apoptosis and enhancing cytoxicity., Conclusions: Our results confirmed that BCMA CAR T-cell therapy combined with long-term pomalidomide had a low recurrence rate and manageable therapy-related side effects, providing a promising option for treating R/R MM., Competing Interests: Declarations. Ethics approval and consent to participate: This study was performed in line with the principles of the Declaration of Helsinki. This study was approved by the Institutional Review Board of the Third Xiangya Hospital of Central South University. All patients included in this study provided written informed consent. Consent for publication: Informed consent was obtained from all individual participants included in the study. Competing interests: The authors declare that they have no competing interests., (© 2024. The Author(s).)

B-cell maturation antigen(BCMA)-directed chimeric antigen receptor (CAR)-T-cell therapy has significantly improved the treatment of relapsed or refractory multiple myeloma (MM). Nevertheless, the uncommon phenomenon of biphasic CAR-T cell expansion in vivo and its related severe toxicities have not been methodically described and studied. Herein, we report a case of patients with MM who experienced two CAR-T cell expansion peaks and subsequently developed multiple severe toxicities following BCMA CAR-T cell infusion. The first expansion peak occurred on Day 7, accompanied by grade 3 cytokine release syndrome. The second peak occurred on Day 28, associated with severe immune effector cell-associated hematotoxicity (ICAHT), immune effector-cell associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS), and polymicrobial infections. Both ICAHT and IEC-HS were refractory to our standard treatments; however, human umbilical cord mesenchymal stem cell infusion exhibited some efficacy in improving cytopenia. Despite the administration of a broad-spectrum anti-infective regimen, cytomegalovirus viremia remained uncontrollable, resulting in the development of central nervous system infection, neurological symptoms, and ultimately death. Additionally, we also employed high-dimensional 33-color spectral flow cytometry to describe the dynamic changes in immune cell components and functions between the two expansion peaks. Collectively, this case provides novel insights into the biphasic CAR-T expansion and related immune effector cell-associated toxicities., Competing Interests: Competing interests: No, there are no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Chimeric antigen receptor T-cell (CAR-T) immunotherapy has achieved remarkable success in treating chemotherapy-refractory hematological malignancies. However, its efficacy in solid and brain tumors remains limited due to challenges such as insufficient target antigens, poor T-cell adaptability, inefficient tumor site trafficking, and the immunosuppressive tumor microenvironment. To address these challenges, Shaw and colleagues proposed an innovative strategy targeting cancer-specific exons (CSEs) in pediatric solid and brain tumors. Using RNA sequencing data from 16 tumor types, the study identified 157 highly tumor-specific targets, including both known and novel proteins. The researchers validated several targets, including FN1 and COL11A1, demonstrating their therapeutic potential in in vitro and in vivo models. The study's approach of integrating exon-level analysis with a broad search for extracellular matrix proteins offers a new frontier for CAR-T therapy, providing valuable insights for improving immunotherapy in pediatric solid tumors. Although promising, the study also highlights the need for further evaluation of tumor recurrence and CAR-T cell exhaustion. The identification of novel pan-tumor targets may revolutionize CAR-T therapy design and expand its application in pediatric cancer treatment., Competing Interests: Declarations Ethics approval and consent to participate Not applicable. Consent for publication All authors have read and agreed to the published version of the manuscript. Competing interests The authors declare that they have no competing interests., (© 2024. The Author(s).)

Abstract: Hematologic toxicity is a common side effect of chimeric antigen receptor T-cell (CAR-T) therapies, being particularly severe among patients with relapsed or refractory multiple myeloma (MM). In this study, we characterized 48 patients treated with B-cell maturation antigen (BCMA) CAR-T cells to understand kinetics of cytopenia, identify predictive factors, and determine potential mechanisms underlying these toxicities. We observed that overall incidence of cytopenia was 95.7%, and grade >3 thrombocytopenia and neutropenia, 1 month after infusion, was observed in 57% and 53% of the patients, respectively, being still present after 1 year in 4 and 3 patients, respectively. Baseline cytopenia and high peak inflammatory markers were highly correlated with cytopenia that persisted up to 3 months. To determine potential mechanisms underlying cytopenias, we evaluated the paracrine effect of BCMA CAR-T cells on hematopoietic stem and progenitor cell (HSPC) differentiation using an ex vivo myeloid differentiation model. Phenotypic analysis showed that supernatants from activated CAR-T cells (spCAR) halted HSPC differentiation, promoting more immature phenotypes, which could be prevented with a combination of interferon γ, tumor necrosis factor α/β, transforming growth factor β, interleukin-6 (IL-6) and IL-17 inhibitors. Single-cell RNA sequencing demonstrated upregulation of transcription factors associated with early stages of hematopoietic differentiation in the presence of spCAR (GATA2, RUNX1, CEBPA) and a decrease in the activity of key regulons involved in neutrophil and monocytic maturation (ID2 and MAFB). These results suggest that CAR-T activation induces HSPC maturation arrest through paracrine effects and provides potential treatments to mitigate the severity of this toxicity., (© 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.)

Chimeric antigen receptor T-cell therapies (CAR-T therapies) are a type of advanced therapy medicinal product (ATMP) that belong to a new generation of personalised cancer immunotherapies. This paper compares the approval, availability and financing of CAR-T cell therapies in ten countries. It also examines the implementation of this type of ATMP within the health care system, describing the organizational elements of CAR-T therapy delivery and the challenges of ensuring equitable access to all those in need, taking a more systems-oriented view. It finds that the availability of CAR-T therapies varies across countries, reflecting the heterogeneity in the organization and financing of specialised care, particularly oncology care. Countries have been cautious in designing reimbursement models for CAR-T cell therapies, establishing limited managed entry arrangements under public payers, either based on outcomes or as an evidence development scheme to allow for the study of real-world therapeutic efficacy. The delivery model of CAR-T therapies is concentrated around existing experienced cancer centres and highlights the need for high networking and referral capacity. Some countries have transparent and systematic eligibility criteria to help ensure more equitable access to therapies. Overall, as with other pharmaceuticals, there is limited transparency in pricing, eligibility criteria and budgeting decisions in this therapeutic area., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

CAR T-cells is an innovative treatment for relapsed/refractory aggressive B cell lymphomas, initially proposed as third-line therapy and beyond, now allowed as soon as second-line treatment for patients with early relapse after first-line treatment. FDG PET/CT remains the modality of choice to evaluate response to this therapeutic strategy, to detect or confirm treatment failure, and allow for salvage therapy if needed. Correct classification of patients regarding response is thus of the utmost importance. In many cases, metabolic response follows classical known patterns, and Deauville score and Lugano criteria yield accurate characterization of patient status. However, given its specific mode of action, it can result in delayed response or atypical patterns of response. We report here a few examples of response from our experience to illustrate the existence of tricky cases. These atypical cases require multidisciplinary management, with clinical, biological, imaging, and pathological work-up., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Institute of Radiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

This study used COTA de-identified data (2010-2021) of patients in the US to explore outcomes of novel therapies in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) in real-world settings. Demographics, clinical characteristics, and clinical outcomes of patients with R/R DLBCL who received novel treatments including chimeric antigen receptor T-cell (CAR T) therapy and tafasitamab- or polatuzumab-based therapies were evaluated. Overall, 175 patients with R/R DLBCL were analyzed; 73, 69, and 27 received CAR T therapy, polatuzumab-based regimens, and tafasitamab-based regimens, respectively. In patients who had ≥1 prior lines of therapy (i.e. starting second-line or later therapy; 2 L+), CAR T, polatuzumab-based regimens, and tafasitamab-based regimens achieved a median overall survival of 26.5, 7.8, and 6.3 months, respectively. Outcomes were particularly poor for patients with relapse following CAR T, indicating that polatuzumab- and tafasitamab-based regimens in 2 L + R/R DLBCL have suboptimal outcomes in the real world. Additional treatment options are needed.

Recipients of cellular therapies, including hematopoietic cell transplant (HCT) and chimeric antigen receptor T-cell (CART) therapy, are at risk for poor outcomes from coronavirus disease 2019 (COVID-19). There are limited data describing outcomes among patients in the pre- and early post-cellular therapy period during the Omicron era when multiple antiviral therapeutics were widely available. The objective of this study is to describe COVID-19 treatment and outcomes in patients diagnosed with COVID-19 during the pre- or early post-cellular therapy period. This is a single-center retrospective cohort study of adult HCT and CART recipients diagnosed with COVID-19 in the pre- and early post-cellular therapy period who tested positive for COVID-19 at our cancer center between January 1, 2022 and March 1, 2023. Primary outcomes were 30-day COVID-19-related hospitalization and death. A secondary outcome was development of persistent COVID-19, defined by a positive SARS-CoV-2 polymerase chain reaction (PCR) 31 to 90 days after COVID-19 diagnosis. Among 65 patients included, 52 (80%) received at least one COVID-19 therapeutic. The most common treatment after initial COVID-19 diagnosis was nirmatrelvir/ritonavir (29%), followed by monoclonal antibody therapy (26%) and remdesivir (11%). Of the 64 patients with at least 30 days of follow-up, 8 (12%) had at least one COVID-19-related hospitalization and one patient died, though cause of death was not due to COVID-19. Of the 8 patients hospitalized for COVID-19, one had severe disease and 7 had mild or moderate infection. Persistent COVID-19 was observed in 13/65 (20%) patients, with 4 patients requiring additional antiviral therapy. Three pre-cellular therapy patients had delays in receiving cellular therapy due to persistent COVID-19. During the Omicron era, rates of 30-day COVID-19-related hospitalization and death were relatively low in this cohort of pre- and early post-HCT and CART recipients, the majority of whom received treatment with at least one antiviral agent. Persistent COVID-19 occurred in 1 in 5 patients in the peri-cellular therapy period and led to cellular therapy treatment delays in several patients, highlighting the need for new COVID-19 treatment strategies., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

We report two patients who displayed evidence of localized ocular inflammation after CAR T-cell infusion. To manage the resulting severe visual impairment, systemic corticosteroids were administered to both patients. This treatment led to a reduction in local inflammation and restored vision in one of the patients.

Objectives: The aim of the study was to examine the incidence, baseline characteristics, and outcomes of Chimeric Antigen Receptor T-cell (CAR-T) therapy admissions in individuals who developed acute respiratory failure (ARF). The study utilized the National Inpatient Sample (NIS) database for the years 2017 to 2020. Methods: The study identified CAR-T cell therapy hospitalizations through the International Classification of Diseases, Tenth Revision, Procedure Coding System (ICD-10-PCS) codes. Patients with acute respiratory failure (ARF) were further classified using specific International Classification of Disease, Tenth Revision, Clinical Modification (ICD-10-CM) codes. Descriptive statistics were performed to analyze baseline characteristics, comorbidities, complications, and outcomes. Results: Analysis of the NIS Database identified 5545 CAR-T therapy admissions between 2017 and 2020, revealing a rising trend over time. In our study, we found that hypertension (39%), dyslipidemia (21.7%), and venous thromboembolism (13%) were the most frequently observed comorbidities in CAR-T cell therapy admissions. Acute respiratory failure (ARF) was reported in 7.1% of admissions, and they had higher all-cause in-hospital mortality than CAR-T cell therapy admissions without ARF (32.9% vs 1.3%, P  < 0.001). ARF admissions that required invasive mechanical ventilation (IMV) also had higher all-cause in-hospital mortality compared to admissions not requiring IMV (48.9% vs 11.8%, P  = 0.001). There was no difference in the mortality rate among admissions with non-Hodgkin's Lymphoma, Multiple Myeloma, and Leukemia that utilized CAR-T therapy. Conclusions: In this largest study to date, we illuminate the incidence and outcomes of CAR-T cell therapy admissions with ARF. Higher mortality rates were observed in CAR-T cell therapy admissions with ARF. The study emphasizes the crucial role of interdisciplinary collaboration in CAR-T patient management and calls for additional research to clarify ARF's etiology and inform effective management strategies., Competing Interests: Declaration of Conflicting InterestsThe authors whose names are listed immediately below certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.

The one-year survival rate for patients experiencing a relapse of B-cell acute lymphocytic leukemia (B-ALL) following hematopoietic stem cell transplantation (HSCT) is approximately 30%. Patients experiencing a relapse after allogeneic HSCT frequently encounter difficulties in obtaining autologous CAR-T products. We conducted a study involving 14 patients who received donor-derived CAR-T therapy for relapsed B-ALL following HSCT between August 2019 and May 2023 in our center. The results revealed a CR/CRi rate of 78.6% (11/14), a GVHD rate of 21.4% (3/14), and a 1-year overall survival (OS) rate of 56%. Decreased bone marrow donor cell chimerism in 9 patients recovered after CAR-T therapy. The main causes of death were disease progression and infection. Further analysis showed that GVHD (HR 7.224, 95% CI 1.42-36.82, P = 0.017) and platelet recovery at 30 days (HR 6.807, 95% CI 1.61-28.83, P = 0.009) are significantly associated with OS after CAR-T therapy. Based on the findings, we conclude that donor-derived CAR-T cells are effective in treating relapsed B-ALL patients following HSCT. Additionally, GVHD and poor platelet recovery impact OS, but further verification with a larger sample size is needed., Competing Interests: Declaration of Competing Interest The authors of this manuscript declare that they have no conflicts of interest., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Abstract: Tafasitamab plus lenalidomide (TAFA-LEN) treatment relevance pre- or post-anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is debated. We analyzed patients with large B-cell lymphoma in the DESCAR-T registry treated with axi[1]cel or tisa-cel in ≥3rd line and TAFA-LEN before (n = 15, "TL-pre-CAR-T" set) or directly after (n = 52, "TL-post-CAR-T" set) CAR T-cell therapy. We compared TAFA-LEN v. other treatments using inverse probability weighting in the TL-post-CAR[1]T set. In the TL-post-CAR-T set, the median progression-free survival (mPFS), overall survival (mOS), and duration of response (mDOR) since the first treatment for progression (mPFS2/mOS2/mDOR2) were 3, 4.7, and 8.1 months, respectively. The best overall response rate (bORR) and best complete response rate (bCRR) after TAFA-LEN were 13.5% and 7.7%, respectively. Outcomes were better for patients who relapsed >6 months after CAR T-cell therapy (mPFS2: 5.6 vs 2 months, P = .0138; mOS2: not reached vs 3.8 months, P = .0034). The bORR and bCRR between TAFA-LEN and other treatments were 20.6% vs 24.9% and 11.6% vs 15.6%, respectively. Outcomes were similar between TAFA-LEN and other treatments (mPFS2: 2.9 vs 2.4 months, P = .91; mOS2: 3.3 vs 5.5 months, P = .06). In an exploratory analysis of the TL-pre-CAR-T set, the median TAFA-LEN treatment duration before CAR-T was 3.7 months with no patient becoming CD19 negative. The bORR, bCRR, 6- month PFS, and OS rates after CAR T-cell infusion were 45.5%, 36.4%, 20.1%, and 58.2%, respectively. Neither TAFA-LEN nor comparative salvage treatment improved outcomes for patients relapsing after CAR T-cell therapy., (© 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.)

Background: Chimeric antigen receptor (CAR) T-cell therapy has demonstrated significant benefits in the treatment of relapsed/refractory multiple myeloma (RRMM). However, these outcomes can be compromised by severe complications, including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome (ICANS) and immune effector cell-associated hematotoxicity (ICAHT), predisposing for life-threatening infections., Methods: This retrospective observational study examined a total of 129 patients with RRMM who had received idecabtagene vicleucel (ide-cel) at two major myeloma centers in Germany and one center in the USA to assess the Endothelial Activation and Stress Index (EASIX) as a risk marker for an unfavorable clinical course and outcome after CAR T-cell therapy. EASIX is calculated by lactate dehydrogenase (U/L) × creatinine (mg/dL) / platelets (10 9 cells/L) and was determined before lymphodepletion (baseline) and at the day of CAR T-cell infusion (day 0). The analysis was extended to EASIX derivatives and the CAR-HEMATOTOX score., Results: An elevated baseline EASIX (>median) was identified as a risk marker for severe late ICAHT, manifesting with an impaired hematopoietic reconstitution and pronounced cytopenias during the late post-CAR-T period. Patients with high EASIX levels (>upper quartile) were particularly at risk, as evidenced by an increased rate of an aplastic phenotype of neutrophil recovery, severe late-onset infections and ICANS. Finally, we found associations between baseline EASIX and an inferior progression-free and overall survival. Moreover, the EASIX at day 0 also demonstrated potential to serve as a risk marker for post-CAR-T complications and adverse outcomes., Conclusions: In conclusion, EASIX aids in risk stratification at clinically relevant time points prior to CAR T-cell therapy with ide-cel. Increased EASIX levels might help clinicians to identify vulnerable patients to adapt peri-CAR-T management at an early stage., Competing Interests: Competing interests: JF has received honoraria from BMS and Stemline and travel and congress participation grants from Janssen-Cilag. XZ declares advisory services for and has received travel support from SkylineDx. JK has received honoraria from AstraZeneca. EKM declares a consulting or advisory role for Amgen, BMS/Celgene, GlaxoSmithKline, Janssen-Cilag, Pfizer, Sanofi, Stemline and Takeda. He has received honoraria from Amgen, BMS/Celgene, GlaxoSmithKline, Janssen-Cilag, Pfizer, Sanofi, Stemline and Takeda, research funding from BMS/Celgene, GlaxoSmithKline, Janssen-Cilag, Sanofi and Takeda and travel support from BMS/Celgene, GlaxoSmithKline, Janssen-Cilag, Sanofi, Stemline and Takeda. MJF declares consulting activity for Pfizer and Kerna Ventures. CSM has received honoraria and travel support from Janssen-Cilag. IB has received honoraria from Oncopeptide and travel support from Janssen. ON reports receiving consulting fees from Janssen, BMS, Takeda, GPCR therapeutics, Sanofi and Pfizer. AS has received travel grants from Hexal and Jazz Pharmaceuticals and research grants from Therakos/Mallinckrodt. She is a consultant for Janssen-Cilag and BMS and co-founder of TolerogenixX Ltd. AS is part-time employee of TolerogenixX Ltd. MS declares an advisory role or expert testimony for MSD, Novartis, BMS and Pierre Fabre. He is co-founder and shareholder of TolerogenixX GmbH, Heidelberg. He has received financial support for research on biosimilars and travel grants from Hexal, financial support of educational activities and conference participation and travels grants from Kite and BMS, collaborative research grants from Novartis and funding for collaborative research from Apogenix. MT has received research funding from Kite, Regeneron and Roche. He is an advisory board member for AstraZeneca, BMS, Incyte, Janssen and Novartis. HE declares a consulting or advisory role for BMS/Celgene, Janssen, Amgen, Takeda, Sanofi, GSK, Novartis and Roche. He has received research funding from BMS/Celgene, Janssen, Amgen, GSK, Sanofi and Novartis, honoraria from BMS/Celgene, Janssen, Amgen, Takeda, Sanofi, GSK, Novartis and travel support from BMS/Celgene, Janssen and Amgen. PD reports consultancy for AbbVie, AstraZeneca, Beigene, BMS, Gilead, Miltenyi, Novartis and Riemser. He is member of the speakers’ bureau for AbbVie, AstraZeneca, BeiGene, BMS, Gilead, Novartis, Riemser and Roche and has received research support from Riemser (all to institution). NCM reports receiving personal fees from BMS, Janssen, Amgen, Takeda, OncoPep, AbbVie, Karyopharm, Novartis, Legend, Raqia, Adaptive Biotechnology, and Pfizer outside the submitted work. He has intellectual property licensed to OncoPep and held stocks in C4 Therapeutics. ASp reports receiving consulting fees from Novartis and Roche. LR consulted for Janssen, Amgen, GSK, Pfizer, BMS, Sanofi, and received honoraria from Janssen, GSK, Pfizer, BMS, Sanofi and received research funding from Skyline Dx and BMS. SS has received travel grants or honoraria for presentations from Celgene, BMS, Janssen, Takeda and Amgen. MSR declares a consulting or advisory role for BMS, Amgen, GSK, Janssen, Sanofi, Pfizer, AbbVie and Takeda. He has received research funding from BMS, Janssen, Sanofi and Heidelberg Pharma, travel support from BMS, Amgen and Janssen and honoraria from BMS, Janssen, AbbVie and Sanofi., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Backgrounds: The incidence of extramedullary diseases (EMDs) in patients diagnosed with acute myeloid leukemia (AML) is approximately 10-20%. These patients exhibit a significantly distinct etiology, therapeutic response, and prognosis compared to patients without EMDs. CLL1 CAR-T therapy has been demonstrated satisfactory efficacy and safety in the treatment of refractory and relapsed AML patients. However, concerns have been raised regarding the potential impact of extramedullary niduses on the effectiveness of CLL1 CAR-T therapy., Methods: A total of 47 patients were enrolled in this study, including 27 patients with isolated AML tumor bone marrow infiltration and 20 patients with both extramedullary and bone marrow infiltration of AML. CLL1 CAR-T cells were manufactured and subjected to rigorous quality control in the hematology laboratory of Tianjin First Central Hospital. The efficacy and adverse reactions were assessed following CAR-T cell infusion, while expansion of CAR-T cells, levels of cytokines releasing, and other indicators were closely monitored., Results: Among the 20 patients with EMDs and the 27 individuals without EMDs, complete remission in bone marrow was achieved by 65.00% and 81.48% of patients, respectively. Meanwhile, among the patients with EMDs, 55.00% achieved complete remission while 10.00% achieved partial remission when assessing the efficacy of CLL1 CAR-T cells against extramedullary niduses. Although the overall survival, progression-free survival, and duration of remission period appeared to be shorter for patients with EMDs compared to those without EMDs, this difference did not reach statistical significance. The incidence rates of complications were comparable between both groups. Meanwhile, there were no significant differences observed in the levels of CAR-T cell expansion and accompanying cytokines release between patients with and without EMDs., Conclusions: Our study findings have demonstrated the efficacy of CLL1 CAR-T therapy in the treatment of AML patients with EMDs, while also indicating manageable occurrence rates of complications within a tolerable range. The CLL1 CAR-T therapy, serving as an ideal strategy for AML patients irrespective of the presence of EMDs, effectively ameliorates the conditions of AML patients and provides them with an opportunity to undergo curative hematopoietic stem cell transplantation while significantly enhancing their prognosis., (© 2024. The Author(s).)

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 therapies have increased the patients with relapsed/refractory multiple myeloma (RRMM) in whom standard electrophoretic techniques fail to detect the M-protein. Quantitative immunoprecipitation mass spectrometry (QIP-MS) can accurately measure serum M-protein with high sensitivity, and identify interferences caused by therapeutic monoclonal antibodies. Here, we investigate the outcome of QIP-MS in 33 patients treated with the academic BCMA-directed CAR T-cell ARI0002h (Cesnicabtagene Autoleucel). QIP-MS offered more detailed insights than serum immunofixation (sIFE), identifying glycosylated M-proteins and minor additional peaks. Moreover, the potential interferences owing to daratumumab or tocilizumab treatments were successfully detected. When analysing different assay platforms during patient's monitoring after ARI0002h administration, we observed that QIP-MS showed a high global concordance (78.8%) with sIFE, whereas it was only moderate (55.6%) with bone marrow (BM)-based next-generation flow cytometry (NGF). Furthermore, QIP-MS consistently demonstrated the lowest negativity rate across the different timepoints (27.3% vs. 60.0% in months 1 and 12, respectively). Patients with QIP-MS(+)/BM-based NGF(-) showed a non-significant shorter median progression free survival than those with QIP-MS(-)/BM-based NGF(-). In summary, we show the first experience to our knowledge demonstrating that QIP-MS could be particularly useful as a non-invasive technique when evaluating response after CAR T-cell treatment in MM., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Purpose: Despite chimeric antigen receptor (CAR) T-cell therapy has achieved great advances in recent year, approximately 50% of relapsed/refractory B cell acute lymphoblastic leukemia (r/r B-ALL) patients treated with CAR-T experience relapse 6 months post CAR-T treatment. CD20 express on 30 to 50% of B-ALL, which makes CD20 Monoclonal Antibody as one of the potential therapy strategies to decrease the tumor burden and improve the efficacy of CAR-T therapy. Adding Rituximab to chemotherapy protocol had been demonstrated to improve the outcome for CD20-positive ALL. However, rare study explored the influence of Rituximab combined with CAR-T therapy., Methods: We retrospectively analyzed 20 r/r B-ALL patients who received CAR-T therapy, all of whom had failed multiple lines of therapy. Before CAR-T infusion, we administered Rituximab to 10 patients with high CD20 expression at a dose of 375 mg/m 2 for 1 day. Meanwhile, we selected 10 patients with the comparable features who underwent CAR-T treatment without Rituximab in the same period as the control group. In vitro, the surface molecule expression and killing of CAR-T post Rituximab-treated B-ALL cells co-incubated with CAR-T cells were detected by flow cytometry., Results: The median follow-up of Rituximab and Control groups were 29.27 and 9.83 months. We found that adding Rituximab may confer a favorable prognosis compared with Control group. The 2-year overall survival (OS) and leukemia-free survival (LFS) rates both were longer in the Rituximab group (90% vs. 26.7%, p = 0.0342; 41.7% vs. 25%, p = 0.308). In vitro, we observed that Rituximab-treated tumour cells are more sensitive to CAR-T killing and a broad range of cytokines and chemokines were produced when Rituximab-treated Nalm-6 cells co-cultured with 19-22CAR-T cells, such as interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2). To investigate whether Rituximab has an effect on CAR-T persistence, we stimulated CAR-T cells repeatedly in vitro with Rituximab-treated Nalm-6 to evaluate the changes in CAR-T surface exhaustion molecules at different times. We found that the expression of exhaustion molecules (LAG-3, PD-1, TIM-3) on CAR-T cells were significantly lower in the Rituximab group than in the Control group., Conclusion: Rituximab combined with CAR-T therapy is effective for improving the long-term prognosis of B-ALL patients who have failed multiple lines of therapy. In vitro, we observed that rituximab potentially improves CAR-T efficacy by sensitizing ALL to CART-mediated cytotoxicity and reducing CAR-T exhaustion., (© 2024. The Author(s).)

Chimeric antigen receptor T-cell (CAR-T) therapy, including axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel), has demonstrated significant efficacy in treating refractory or relapsed diffuse large B-cell lymphoma and B-cell acute lymphoblastic leukemia. Though adverse events such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are well characterized, the dermatologic adverse event (DAE) profile is less thoroughly described. This study aims to provide the first comprehensive analysis of DAEs associated with axi-cel and tisa-cel using real-world data from the FDA Adverse Event Reporting System (FAERS) database. FAERS database reports citing axi-cel or tisa-cel in patients aged 16 years or older were included, excluding duplicate reports and off-label indications. Disproportionality analysis by reporting odds ratio (ROR) was utilized to detect increased reporting of drug-adverse event combinations. Of the 11,256,845 reports in the FAERS database, 5559 identified CAR-T therapy as the primary suspected drug. After exclusions, 3,666 reports were analyzed (2,168 for axi-cel and 1,498 for tisa-cel). Among these, 2.7% of axi-cel and 5.1% of tisa-cel cases reported DAEs. There was a statistically significant increased reporting of 2 DAE groups associated with CAR-T therapy: severe cutaneous eruptions (ROR 5.18, 95% CI 1.29, 20.76) and vascular cutaneous (ROR 2.91, 95% CI 1.51, 5.60). The median time to DAE onset was 3 days after CAR T-cell infusion. Death was a reported outcome in 11.9% and 13.0% of axi-cel and tisa-cel DAE cases, respectively, and in 50% and 25% of severe cutaneous eruptions and vascular cutaneous cases, respectively. This study reveals a significantly increased reporting rate of severe cutaneous eruptions and vascular cutaneous DAEs associated with CAR-T therapy, with both event groups associated with high mortality. These results emphasize the importance of monitoring dermatologic toxicities in clinical practice to ensure timely identification and management of potentially severe adverse events., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

The evolving field of chimeric antigen receptor (CAR) T-cell therapy, though promising, necessitates more comprehensive imaging methods to enhance therapeutic effectiveness and track cell trafficking in patients and ex vivo. This review examines the application of PET imaging in CAR T-cell trafficking and optimizing their therapeutic impact. The application of PET imaging using various radiotracers is promising in providing evaluation of CAR T-cell interaction within the host, thereby facilitating strategies for improved patient outcomes. As this technology progresses, further innovative strategies to streamline assessments of immunotherapeutic effectiveness are anticipated., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Secondary primary malignancies (SPM) have been reported after anti-BCMA or anti-CD19 chimeric antigen receptor (CAR)-T-cell therapies. While the cytotoxic effect of antecedent therapies, including chemotherapy and radiotherapy, has been well established, few data are available on risk related to CAR-T immunotherapies. The study aimed to analyse the incidence of SPM in 651 patients enrolled in the Italian prospective observational CART-SIE study. SPMs were documented in 4.3% (28/651), and the most frequent SPMs were haematological malignancies. In conclusion, the frequency of SPMs in our cohort of heavily pretreated patients receiving CAR-T was relatively low and consistent with previous studies., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Richter transformation is still a serious risk in the era of innovative therapies, despite the fact that targeted therapy with Bruton's tyrosine kinase inhibitor has significantly improved the prognosis for chronic lymphocytic leukemia (CLL). We report a rare case of a 61-year-old male patient's CLL transforming into a synchronous clonal related plasmablastic lymphoma (PBL) after receiving ibrutinib. During COVID-19, the patient stopped taking ibrutinib, which caused the illness to worsen. Histology revealed that PBL was present in the right supraclavicular mass and that CLL had penetrated the bone marrow. Three cycles of CHP (cyclophosphamide, doxorubicin, and prednisone) were administered together with venetoclax and brentuximab vedotin. After receiving BCMA CAR-T cell treatment, the patient was in complete remission. For PBL transformation, a condition with a worse prognosis and few therapy choices, our results suggest the use of BCMA CAR-T and novel target agents., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The influence of chimeric antigen receptor T (CAR-T) cell therapy on platelet function in relapsed/refractory (R/R) multiple myeloma (MM) has not been thoroughly investigated. Our cohort comprised fifty MM patients treated with CAR-T cells. The mean platelet closure time (PCT) induced by collagen/adenosine diphosphate (CADP) in peripheral blood was significantly prolonged before lymphodepletion (195.24 ± 11.740 s) and notably reduced post-CAR-T cell therapy (128.02 ± 5.60 s), with a statistically significant improvement (67.22, 95% CI 46.91-87.53, P < 0.001). This post-treatment PCT was not significantly different from that of healthy controls (10.64, 95% CI 1.11-22.40, P > 0.05). Furthermore, a pronounced enhancement in PCT was observed in patients with a response greater than partial remission (PR) following CAR-T cell infusion compared to pre-treatment values (P < 0.001). An extended PCT was also associated with a less favorable remission status. In patients with cytokine release syndrome (CRS) grades 0-2, those with a PCT over 240.5 s exhibited a shorter progression-free survival (PFS), with median PFS times of 10.2 months for the PCT > 240.5 s group versus 22.0 months for the PCT ≤ 240.5 s group. Multivariate analysis revealed that a PCT value exceeding 240.5 s is an independent prognostic factor for overall survival (OS) in R/R MM patients after CAR-T cell therapy. The study demonstrates that CAR-T cell therapy enhances platelet function in R/R MM patients, and PCT emerges as a potential prognostic biomarker for the efficacy of CAR-T cell therapy., (© 2024. The Author(s).)

Background: High-risk double-expressor diffuse large B-cell lymphoma has an inferior prognosis following standard first-line therapy. After failure of second-line therapy, treatment options are limited if accompanied by localized compressive symptoms. Chimeric Antigen Receptor T cell (CAR-T) therapy preceded by bridging radiotherapy may be an effective emerging therapy., Case Presentation: We report a 66-year-old female patient diagnosed with stage IV double-expressor diffuse large B-cell lymphoma. The patient achieved progressive disease after two cycles of rituximab, cyclophosphamide, liposomal doxorubicin, vincristine, and prednisone and continued to develop cervical lymph node recurrence after second-line therapy. The patient was infused with CAR-T cells after receiving focal bridging radiotherapy and remained in complete response more than 9 months after treatment. In addition, the patients did not experience serious adverse reactions related to radiotherapy as well as CAR-T cell therapy., Conclusions: In this article, we describe a patient with double-expressor diffuse large B-cell lymphoma with localized compression symptoms after second-line treatment failure who benefited from CAR-T combined with focal bridging radiotherapy., 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 Yang, Wu, Yang, Sun, Xing, Liu, Xing and Yu.)

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.)

The current CAR-T cell therapy products have been hampered in their druggability due to the personalized preparation required, unclear pharmacokinetic characteristics, and unpredictable adverse reactions. Enabling standardized manufacturing and having clear efficacy and pharmacokinetic characteristics are prerequisites for ensuring the effective practicality of CAR-T cell therapy drugs. This review provides a broad overview of the different approaches for controlling behaviors of CAR-T cells in vivo. The utilization of genetically modified vectors enables in vivo production of CAR-T cells, thereby abbreviating or skipping the lengthy in vitro expansion process. By equipping CAR-T cells with intricately designed control elements, using molecule switches or small-molecule inhibitors, the control of CAR-T cell activity can be achieved. Moreover, the on-off control of CAR-T cell activity would yield potential gains in phenotypic remodeling. These methods provide beneficial references for the future development of safe, controllable, convenient, and suitable for standardized production of CAR-T cell therapy products., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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.

Background Aims: The production of commercial autologous cell therapies such as chimeric antigen receptor T cells requires complex manual manufacturing processes. Skilled labor costs and challenges in manufacturing scale-out have contributed to high prices for these products., Methods: We present a robotic system that uses industry-standard cell therapy manufacturing equipment to automate the steps involved in cell therapy manufacturing. The robotic cluster consists of a robotic arm and customized modules, allowing the robot to manipulate a variety of standard cell therapy instruments and materials such as incubators, bioreactors, and reagent bags. This system enables existing manual manufacturing processes to be rapidly adapted to robotic manufacturing, without having to adopt a completely new technology platform. Proof-of-concept for the robotic cluster's expansion module was demonstrated by expanding human CD8+ T cells., Results: The robotic cultures showed comparable cell yields, viability, and identity to those manually performed. In addition, the robotic system was able to maintain culture sterility., Conclusions: Such modular robotic solutions may support scale-up and scale-out of cell therapies that are developed using classical manual methods in academic laboratories and biotechnology companies. This approach offers a pathway for overcoming manufacturing challenges associated with manual processes, ultimately contributing to the broader accessibility and affordability for personalized immunotherapies., Competing Interests: Declaration of competing interest BS, ALJ, YA, AR, DC, ED, KP, KH, DS, US, VB, AS, NK, AH, MG and AT, wish to disclose that they are current employees of Multiply Labs, Inc. or were employed with the company at the time of this study's execution. They hold equity in the company; AM and FP wish to disclose that they are co-founders of Multiply Labs, Inc. and hold the position of Chief Scientific Officer and Chief Executive Officer, respectively; SC wishes to disclose that she is employed by Cytiva, which is a company active in the cell therapy manufacturing space; MH wishes to disclose that he is employed by Charles River Laboratories, which is a company active in the cell therapy manufacturing space; HA and XJ wishes to disclose that they are employed by Thermo Fisher Scientific, which is a company active in the cell therapy manufacturing space; BDR is a paid advisor to Multiply Labs, Inc. and holds equity in the company; JHE is a paid advisor to and receives sponsored research funding from Multiply Labs, Inc. He serves on its scientific advisory board and holds equity in the company. He receives sponsored research funding from Lonza, Inc. for the development of cellular therapy manufacturing devices., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

The hook effect is a well-described but clinically underappreciated immunoassay interference, where a falsely lowered result is caused by analyte excess. We describe a situation in which ferritin immunoassay results from a 27-year-old female with immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome were more than 1000 times lower at a reference laboratory than those determined in-house after dilution. This case underscores the importance for clinical care providers to be aware of the impact of the hook effect on ferritin measurements, and to promptly communicate with the laboratory when there are discrepancies between clinical symptoms and test results., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA.)

Background: Mucorales infections continue to cause significant morbidity and mortality in immunocompromised hosts despite the advent of new approaches for diagnosis and treatment of fungal infections. We aimed to evaluate risk factors and outcomes of Mucorales infection in solid organ transplant, hematopoietic cell transplant, and chimeric antigen receptor T-cell therapy recipients., Methods: This single-center retrospective study included solid organ transplant, hematopoietic cell transplant, and chimeric antigen receptor T-cell patients with cultures positive for Mucorales., Results: Forty-three patients were included for analysis; 34 solid organ transplant (79%) and 9 hematopoietic stem cell transplant or chimeric antigen receptor T-cell (21%). Infection with Mucorales occurred a median of 184 days after transplant. At the time of diagnosis, 36 patients were on antifungal prophylaxis with the majority receiving posaconazole (53%). Thirty-three had clinically significant disease; 30 received definitive anti-Mucorales therapy and 3 empiric antifungal therapy. Isavuconazole was the most common azole used for treatment in monotherapy recipients. All-cause mortality was 64% and, of these deaths, 18 (75%) were directly related to Mucormycosis. The highest mortality was seen in disseminated and intra-abdominal disease (100%), followed by pulmonary disease (50%). There was no significant association with mortality and transplant type or number of immunosuppressive agents., Conclusion: Mucormycosis is an important cause of morbidity and mortality in immunocompromised patients. Breakthrough infection was not uncommon in this study. Data regarding the incidence of infection at approximately 6 months after transplantation can inform prophylaxis and treatment regimens. The spectrum of antifungal regimens used reflects the lack of consensus on ideal regimens for these organisms and a need for more studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To estimate the comparative efficacy of ciltacabtagene autoleucel (cilta-cel) versus idecabtagene vicleucel (ide-cel) in patients with relapsed/refractory multiple myeloma (RRMM) treated with 2-4 prior lines of therapy., Methods: Matching adjusted indirect comparison (MAICs) were performed using individual patient-level data (IPD) for cilta-cel from CARTITUDE-1 and CARTITUDE-4 and published aggregated data for ide-cel from KarMMa-3. Cilta-cel patients who met inclusion criteria from KarMMa-3 were selected, and outcomes were compared against data for ide-cel using simulated IPD derived from aggregate-level data from KarMMa-3. Patient characteristics were adjusted by reweighting cilta-cel IPD to match the distribution of prognostic factors in KarMMa-3. Comparative efficacy was estimated for response outcomes using a weighted logistic regression analysis and for progression-free survival using a weighted Cox proportional hazards model., Results: Patients treated with cilta-cel were 1.2 times more likely to achieve overall response (relative response ratio [RR]: 1.18 [95% confidence interval: 1.03-1.34]; p  = 0.04), 1.3 times more likely to achieve very good partial response or better (RR: 1.34 [1.15-1.57]; p  = 0.003), and 1.9 times more likely to achieve complete response or better (RR: 1.91 [1.54-2.37]; p  < 0.0001) versus ide-cel patients from KarMMa-3. Cilta-cel was associated with a significant 49% reduction in risk of disease progression or death versus ide-cel (hazard ratio: 0.51 [95% confidence interval: 0.31, 0.84]; p  = 0.0078)., Conclusion: For patients with triple-class exposed RRMM treated with 2-4 prior lines of treatment, cilta-cel was found to provide superior clinical benefit over ide-cel in terms of response and progression-free survival.

Recent reports have raised concerns about the association of chimeric antigen receptor T cell (CAR-T) with non-negligible cardiotoxicity, particularly atrial arrhythmias. First, we conducted a pharmacovigilance study to assess the reporting of atrial arrhythmias following CD19-directed CAR-T. Subsequently, to determine the incidence, risk factors and outcomes of atrial arrhythmias post-CAR-T, we compiled a retrospective single-centre cohort of non-Hodgkin lymphoma patients. Only commercial CAR-T products were considered. Atrial arrhythmias were nearly fourfold more likely to be reported after CAR-T therapy compared to all other cancer patients in the FAERS (adjusted ROR = 3.76 [95% CI 2.67-5.29]). Of the 236 patients in our institutional cohort, 23 (10%) developed atrial arrhythmias post-CAR-T, including 12 de novo arrhythmias, with most (83%) requiring medical intervention. Atrial arrhythmias frequently co-occurred with cytokine release syndrome and were associated with higher post-CAR-T infusion peak levels of IL-10, TNF-alpha and LDH, and lower trough levels of fibrinogen. In a multivariable analysis, risk factors for atrial arrhythmia were history of atrial arrhythmia (OR = 6.80 [2.39-19.6]) and using CAR-T product with a CD28-costimulatory domain (OR = 5.17 [1.72-18.6]). Atrial arrhythmias following CD19-CAR-T therapy are prevalent and associated with elevated inflammatory biomarkers, a history of atrial arrhythmia and the use of a CAR-T product with a CD28 costimulatory domain., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Chimeric antigen receptor (CAR) T-cell therapy provides promising outcomes in relapsed/refractory B acute lymphoblastic leukemia (ALL), yet still carries high toxicity rates and relatively poor long-term survival. Efficacy has yet to be demonstrated in other diagnoses while toxicity and risk profiles remain formidable. To date, treatment-related symptom burden is gleaned from clinical trial toxicity reports; the patient perspective remains understudied., Methods: English- or Spanish-speaking patients (ages 8-25 years) undergoing CAR T-cell therapy for any malignancy and their primary caregivers were recruited from Seattle Children's Hospital (SCH), St. Jude Children's Research Hospital (SJCRH), and the Pediatric Oncology Branch of the National Cancer Institute (NCI). Both patient and caregiver completed semi-structured dyadic interviews 3 months post treatment. We used directed content analysis for codebook development and thematic network analysis for inductive qualitative analysis., Results: Twenty families completed interviews (13 patients, 15 parents). Patients were a median age 16.5 years, predominantly female (65%), White (75%), and diagnosed with ALL (75%). Global themes included "A clear decision," "Coping with symptoms," and "Unforeseen psychosocial challenges." When families were asked to describe the "most challenging part of treatment," most described "the unknown." Most reported "the symptoms really weren't that bad," even among patients hospitalized for severe toxicity events. Fatigue, pain, and nausea were the most prevalent symptoms. Importantly, only one family would have chosen a different therapy, if given another opportunity., Conclusions: Although physical symptoms were largely tolerable, recognizing supportive care opportunities remains imperative, particularly psychosocial concerns., (© 2024 Wiley Periodicals LLC.)

Objective: To analyze the incidence of cytokine release syndrome (CRS) and its impact on the prognosis of patients with relapsed and refractory multiple myeloma (RRMM) following treatment with chimeric antigen receptor T-cell (CAR-T) therapy. Methods: A retrospective collection was conducted of the clinical data of 91 patients with RRMM who underwent CAR-T therapy at the Affiliated Hospital of Xuzhou Medical University from January 2020 to October 2022. Before CAR-T cell infusion, the patient underwent pretreatment with the fludarabine plus cyclophosphamide (FC) regimen. On day 0 (d0), the patient received a dose of 1×10 6 cells/kg of CAR-T. The occurrence of CRS was recorded post-treatment and graded accordingly, with grades 1 to 2 indicating mild CRS and grade≥3 indicating severe CRS. The follow-up cut-off date was February 14, 2023, with a median follow-up time [ M ( Q 1, Q 3 )] of 14.1 (3.1, 37.7) months. Kaplan-Meier survival curve analysis assessed the progression-free survival (PFS) and overall survival (OS) of Grade 1 and Grade 2 CRS patients. Furthermore, univariate logistic regression analysis was conducted to identify factors associated with the development of severe CRS. Results: In a cohort of 91 patients diagnosed with RRMM, there were 51 male and 40 female individuals, with a median age [ M ( Q 1, Q 3 )] of 57 (31, 73) years. All 91 cases (100%) experienced CRS, with 82 cases (90%) classified as mild (grades 1-2) CRS and 9 cases (10%) classified as severe (grades 3-5) CRS. In a study involving 9 patients with severe CRS, 8 cases resulted in mortality. The Kaplan-Meier survival curve analysis revealed that among grade 1 CRS patients, neither the median PFS nor the median OS was achieved. For grade 2 CRS patients, the median PFS was 12 months (95% CI : 4-not achieved), and the median OS was 21 months (95% CI : 4-not achieved). The progression-free survival and overall survival rates of grade 2 CRS patients were both lower than those of grade 1 CRS patients (both P <0.05). Single-factor logistic regression analysis revealed that a high tumor burden ( OR =1.025, 95% CI : 1.002-1.049, P =0.031), a prolonged duration of CRS onset ( OR =0.809, 95% CI : 0.646-0.971, P =0.037) and persistence ( OR =1.758, 95% CI : 1.349-2.481, P =0.001) were identified as significant factors associated with severe CRS in patients with RRMM. Conclusions: Patients with RRMM who undergoes CAR-T therapy have a high incidence of CRS, with a higher mortality rate among those experiencing severe CRS. Furthermore, patients with grade 2 CRS exhibit lower rates of progression-free survival and overall survival compared to those with grade 1 CRS. Factors associated with the development of severe CRS in RRMM patients include high tumor burden and prolonged duration and onset of CRS.

Waldenström macroglobulinemia (WM) is characterized by lymphoplasmacytic lymphoma associated with large amounts of monoclonal immunoglobulin M (IgM) protein (Owen et al., 2003). Common signs and symptoms include fatigue due to anemia, lymph node enlargement, hepatosplenomegaly, thrombocytopenia, symptoms related to high viscosity, and peripheral neuropathy, among others. Despite significant advances in WM treatment, this type of indolent lymphoma remains incurable, with a wide array of patient outcomes (Ruan et al., 2020). In recent years, chimeric antigen receptor T (CAR-T) cell therapy targeting cluster of differentiation 19 (CD19) has shown unprecedented response rates and durability in the treatment of B-cell malignancies. In this report, we describe a challenging case of WM that involved multiple extramedullary sites, relapsed, and was refractory to chemotherapy, immunotherapy, and targeted therapy. After anti-CD19 CAR-T cell therapy, the tumor burden significantly decreased and the patient's condition remained stable at the writing of this report.

Abstract: B-cell maturation antigen (BCMA)-targeting chimeric antigen receptor T cells (CAR-Ts) used in multiple myeloma (MM) are rapidly becoming a mainstay in the treatment of relapsed/refractory (R/R) disease, and CAR-T expansion after infusion has been shown to inform depth and duration of response (DoR), but measuring this process remains investigational. This multicenter study describes the kinetics and prognostic impact of absolute lymphocyte count (ALC) in the first 15 days after CAR-T infusion in 156 patients with relapsed MM treated with the BCMA-targeting agents ciltacabtagene autoleucel and idecabtagene vicleucel. Patients with higher maximum ALC (ALCmax) had better depth of response, progression-free survival (PFS), and DoR. Patients with ALCmax >1.0 × 103/μL had a superior PFS (30.5 months vs 6 months; P < .001) compared with those with ≤1.0 × 103/μL, whereas patients with ALCmax ≤0.5 × 103/μL represent a high-risk group with early disease progression and short PFS (hazard ratio, 3.4; 95% confidence interval, 2-5.8; P < .001). In multivariate analysis, ALCmax >1.0 × 103/μL and nonparaskeletal extramedullary disease were the only independent predictors of PFS and DoR after accounting for international staging systemic staging, age, CAR-T product, high-risk cytogenetics, and the number of previous lines. Moreover, our flow cytometry data suggest that ALC is a surrogate for BCMA CAR-T expansion and can be used as an accessible prognostic marker. We report, to our knowledge, for the first time the association of ALC after BCMA CAR-T infusion with clinical outcomes and its utility in predicting response in patients with R/R MM., (© 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.)

Asthma poses a major public health burden. While existing asthma drugs manage symptoms for many, some patients remain resistant. The lack of a cure, especially for severe asthma, compels exploration of novel therapies. Cancer immunotherapy successes with CAR-T cells suggest its potential for asthma treatment. Researchers are exploring various approaches for allergic diseases including membrane-bound IgE, IL-5, PD-L2, and CTLA-4 for asthma, and Dectin-1 for fungal asthma. NK cells offer several advantages over T cells for CAR-based immunotherapy. They offer key benefits: (1) HLA compatibility, meaning they can be used in a wider range of patients without the need for matching tissue types. (2) Minimal side effects (CRS and GVHD) due to their limited persistence and cytokine profile. (3) Scalability for "off-the-shelf" production from various sources. Several strategies have been introduced that highlight the superiority and challenges of CAR-NK cell therapy for asthma treatment including IL-10, IFN-γ, ADCC, perforin-granzyme, FASL, KIR, NCRs (NKP46), DAP, DNAM-1, TGF-β, TNF-α, CCL, NKG2A, TF, and EGFR. Furthermore, we advocate for incorporating AI for CAR design optimization and CRISPR-Cas9 gene editing technology for precise gene manipulation to generate highly effective CAR constructs. This review will delve into the evolution and production of CAR designs, explore pre-clinical and clinical studies of CAR-based therapies in asthma, analyze strategies to optimize CAR-NK cell function, conduct a comparative analysis of CAR-T and CAR-NK cell therapy with their respective challenges, and finally present established novel CAR designs with promising potential for asthma treatment., (© 2024. The Author(s).)

Objectives: Our aim was to describe the frequency and severity of infectious complications after chimeric antigen receptor (CAR) T-cell therapy in patients with large B-cell lymphoma (LBCL)., Methods: We retrospectively reviewed clinical records of LBCL patients treated with CD19-targeted CAR T-cell therapy from July/2018 to December/2021 at our institution, and identified all infectious episodes from CAR T-cell infusion until disease progression, death or last follow-up., Results: Overall, 137 patients were included. Thirty six percent had received ≥3 previous lines of therapy and 26% an autologous hematopoietic cell transplantation (auto-HCT). Cytokine release syndrome occurred in 87 (64%) patients. Antibacterial prophylaxis was not used in any patient; only 38% received antifungal prophylaxis. Sixty three infectious events were observed in 41 (30%) patients. Fifty two (83%) of the infectious events had at least one pathogen identified (bacteria [n = 38], virus [n = 11], and fungi [n = 3]). Most of the infectious events occurred during hospitalization for CAR-T treatment. Infection-related mortality was observed in two patients. Independent risk factors for infection included male gender, previous auto-HCT, ≥3 lines of treatment and pre-lymphodepletion neutropenia., Conclusions: Infections after CAR T-cell therapy in patients with lymphoma are frequent but generally not severe. A conservative and tailored antimicrobial prophylaxis seems to be a safe approach., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)