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Chimeric antigen receptor (CAR) T-cell therapy is a novel immunotherapy approved for the treatment of hematologic malignancies. This therapy leads to a variety of immunologic deficits that could place patients at risk for invasive fungal disease (IFD). Studies assessing IFD in this setting are limited by inconsistent definitions and heterogeneity in prophylaxis use, although the incidence of IFD after CAR T-cell therapy, particularly for lymphoma and myeloma, appears to be low. This review evaluates the incidence of IFD after CAR T-cell therapy, and discusses optimal approaches to prevention, highlighting areas that require further study as well as future applications of cellular therapy that may impact IFD risk. As the use of CAR T-cell therapy continues to expand for hematologic malignancies, solid tumors, and most recently to include non-oncologic diseases, understanding the risk for IFD in this uniquely immunosuppressed population is imperative to prevent morbidity and mortality.

Cancer immunotherapy has emerged as a promising strategy for the treatment of cancer, with the tumor microenvironment (TME) playing a pivotal role in modulating the immune response. CD47, a cell surface protein, has been identified as a crucial regulator of the TME and a potential therapeutic target for cancer therapy. However, the precise functions and implications of CD47 in the TME during immunotherapy for cancer patients remain incompletely understood. This comprehensive review aims to provide an overview of CD47's multifaced role in TME regulation and immune evasion, elucidating its impact on various types of immunotherapy outcomes, including checkpoint inhibitors and CAR T-cell therapy. Notably, CD47-targeted therapies offer a promising avenue for improving cancer treatment outcomes, especially when combined with other immunotherapeutic approaches. The review also discusses current and potential CD47-targeted therapies being explored for cancer treatment and delves into the associated challenges and opportunities inherent in targeting CD47. Despite the demonstrated effectiveness of CD47-targeted therapies, there are potential problems, including unintended effects on healthy cells, hematological toxicities, and the development if resistance. Consequently, further research efforts are warranted to fully understand the underlying mechanisms of resistance and to optimize CD47-targeted therapies through innovative combination approaches, ultimately improving cancer treatment outcomes. Overall, this comprehensive review highlights the significance of CD47 as a promising target for cancer immunotherapy and provides valuable insight into the challenges and opportunities in developing effective CD47-targeted therapies for cancer treatment.

Aim: Novel treatment options for relapsed/refractory diffuse large B-cell lymphoma include T-cell targeting therapies. Practice efficiency and cost are important for informed treatment decisions. Materials/methods: An institutional decision-maker cost model was developed for 6-month, 1-year and median cycles of treatment time horizons comparing practice efficiency and costs of epcoritamab vs glofitamab and axicabtagene ciloleucel (axi-cel). Results: Overall, epcoritamab required the shortest personnel and chair time, except over 1 year (second shortest chair time). Across all time horizons, epcoritamab was cost-saving vs axi-cel and had similar costs to glofitamab on a per-month basis. Conclusion: Epcoritamab reduced personnel and chair time. Additionally, epcoritamab was cost-saving vs axi-cel and had similar costs to glofitamab on a per-month basis. Plain Language Summary There are new ways to treat diffuse large B-cell lymphoma, which is a type of cancer called lymphoma. When new treatments are available it is important to see if they take more or less time to give to patients and how much they cost versus other treatments. This study looked at three drugs used to treat diffuse large B-cell lymphoma, including epcoritamab, axi-cel and glofitamab. It estimated the time and cost with those treatments in patients who get them for 6 months, 1 year or for the most common length of time in the clinical trials. In most of the scenarios, epcoritamab had the least time needed for nurses or doctors and the least time needed for a patient to be in a chair in a clinic. When thinking about the cost per month, epcoritamab saved money versus axi-cel and was similar to glofitamab. Article highlights Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma in the USA and, despite aggressive treatment, approximately 35% of patients treated in the second-line setting will require third-line and subsequent treatment. In 2023, epcoritamab was the first bispecific antibody approved by the US FDA for the treatment of adult patients with relapsed/refractory (R/R) DLBCL; shortly thereafter, glofitamab was approved as the second bispecific antibody by the FDA for the same patient population. Despite the increased availability of R/R DLBCL treatment options, the ongoing healthcare capacity strain poses a significant obstacle to patients receiving timely care, as many of these treatments require inpatient administration and monitoring. Therefore, it is increasingly important for institutions to be informed on the impact of treatment choice on clinical practice efficiency and cost to make informed treatment decisions. A clinical efficiency analysis based on time-and-motion data along with a micro-costing analysis with a variable time horizon of up to 1 year (6 months, 1 year or median cycles received by patients of each comparator) was developed to compare practice efficiency and total costs of epcoritamab to glofitamab and axi-cel for the treatment of patients with R/R DLBCL. Epcoritamab was associated with more favorable personnel and chair time relative to axi-cel and glofitamab and, as epcoritamab is administered subcutaneously, treatment with epcoritamab reduced personnel costs and inpatient costs despite more frequent dosing. Pressures on care delivery and patient scheduling due to capacity constraints at infusion centers may be alleviated with utilization uptake of epcoritamab, and the institutional resources saved (e.g., staff time, chair time, inpatient monitoring) may be redirected to other care needs to improve the availability and quality of healthcare services for patients. When examining total costs of care, epcoritamab was cost-saving vs axi-cel and had similar costs to glofitamab on a per-month basis, but cost differences vs glofitamab were shown to vary depending on the time horizon, which may be important to healthcare decision-makers who evaluate costs based on median treatment durations and over defined 6-month and 1-year time horizons. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Mutant KRAS promotes the proliferation, metastasis, and aggressiveness of various cancers including pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), and colorectal adenocarcinoma (CRC) respectively. Mutant KRAS therapeutics are limited, while Sotorasib and Adagrasib were the only FDA-approved drugs for the treatment of KRASG12C mutated NSCLC. Chimeric antigen receptor (CAR) T-cell therapy has been emerged as an effective strategy against hematological malignancies and being extended towards solid cancers including PDAC. mesothelin (MSLN) and Carcinoembryonic Antigen (CEA) were reported to be highly overexpressed in KRAS-mutated PDAC. Meanwhile, in clinical trials, several CAR T-cell therapy studies are mainly focused towards these two cancer antigens in PDAC, however, the dual targeting of these two neoantigens is not reported. In the present study, we have designed and developed a novel dual-targeting CAR protein by employing various bioinformatics approaches such as functional analysis (antigenicity, allergenicity, antigen binding sites & signalling cascades), qualitative analysis (physicochemical, prediction, refinement & validation of 2D and 3D structures), molecular docking, and in silico cloning. Our results revealed that the designed CAR protein specifically binds with both MSLN & CEA with significant binding affinities, and was predicted to be stable & non-allergenic. Additionally, the protein–protein interaction network reveals the T-cell mediated antitumor responses of each domain in the designed CAR. Conclusively, we have designed and developed a dual targeting (MSLN & CEA) CAR protein towards KRAS-mutated PDAC using computational approaches. Alongside, we further recommend to engineer this designed CAR in T-cells and evaluating their therapeutic efficiency in in vitro and in vivo studies in the near future. [ABSTRACT FROM AUTHOR]

Simple Summary: Peripheral T-cell lymphoma (PTCL) is a collection of aggressive malignancies with poor long-term survival and limited effective treatment options. Despite unique challenges associated with identifying and targeting malignant T-cell antigens, the use of antibody-based therapies holds great potential. Here, we review the current and future roles of antibody-based therapies for PTCL. While antibody-based immunotherapeutic strategies have revolutionized the treatment of B-cell lymphomas, progress in T-cell lymphomas has suffered from suboptimal targets, disease heterogeneity, and limited effective treatment options. Nonetheless, recent advances in our understanding of T-cell biology, the identification of novel targets, and the emergence of new therapies provide hope for the future. In this review, we explore four areas of current and evolving antibody-based strategies for the treatment of peripheral T-cell lymphoma (PTCL): monoclonal antibodies (mAbs), bispecific antibodies (BsAs), chimeric antigen receptor T-cell therapy (CAR-T), and antibody–drug conjugates (ADCs). As part of this discussion, we will also include limitations, lessons learned, and potential future directions. [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 CAR T-cell therapy approved in the USA and European Union (EU) for adults with relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL; aged ≥26 years in EU). Here, outcomes for patients with R/R B-ALL aged ≥26 years in ZUMA-3 treated with brexu-cel were compared with historical standard-of-care (SOC) therapy. After median follow-up of 26.8 months, the overall complete remission (CR) rate among patients treated with brexu-cel in Phase 2 (N = 43) was 72% and median overall survival (OS) was 25.4 months (95% CI, 15.9-NE). Median OS was improved in Phase 2 patients versus matched historical SOC-treated patients. Compared with aggregate historical trial data, Phase 1 and 2 patients had improved OS versus blinatumomab, inotuzumab, and chemotherapy in a matching-adjusted indirect comparison (MAIC) study. These data demonstrate clinical benefit of brexu-cel relative to SOC in patients ≥26 years with R/R B-ALL. [ABSTRACT FROM AUTHOR]

Importance: B-cell-targeting monoclonal antibodies have demonstrated safety and efficacy in multiple sclerosis or anti-aquaporin-4 IgG positive neuromyelitis optica spectrum disorder. However, these therapies do not facilitate drug-free remission, which may become possible with cell-based therapies, including chimeric antigen receptor (CAR) T cells. CAR T-cell therapy holds promise for addressing other antibody-mediated CNS disorders, e.g., MOG-associated disease or autoimmune encephalitis. Objective: To provide an overview of the current clinical knowledge on CAR T-cell therapy in central nervous system autoimmunity. Evidence review: We searched PubMed, Embase, Google Scholar, PsycINFO, and clinicaltrials.gov using the terms 'CAR T cell' and 'multiple sclerosis/MS' or 'neuromyelitis optica/spectrum diseases/NMOSD' or 'MOG-associated disease/MOGAD 'or' autoimmune encephalitis' or 'neuroimmunology'. Findings: An ongoing phase I clinical trial has indicated the safety and benefits of anti-BCMA CAR T cells in 12 patients with AQP4-IgG seropositive neuromyelitis optica spectrum disorder. Case reports involving two individuals with progressive multiple sclerosis and one patient with stiff-person syndrome demonstrated a manageable safety profile following treatment with anti-CD19 CAR T cells. Recruitment has commenced for two larger studies in MS, and a phase I open-label basket study is underway to evaluate BCMA-directed CAR T cells in various antibody-associated inflammatory diseases, including MOG-associated disease. Preclinical research on NMDA receptor antibody autoimmune encephalitis treated with chimeric autoantibody receptor T cells generated promising data. Conclusions and relevance: There is minimal evidence of the benefits of CAR T-cell therapy in individuals with central nervous system-directed autoimmunity. Nevertheless, multicenter controlled clinical trials with a manageable safety profile appear feasible and are warranted due to very promising case experiences. [ABSTRACT FROM AUTHOR]

There have been significant changes in the management of several haematological conditions over the last decade. This article focuses on three key areas – chimeric antigen receptor (CAR) T-cell therapy, haemophagocytic lymphohistiocytosis (HLH) and thrombotic thrombocytopenic purpura (TTP) – and the implications these areas have for clinicians working in intensive care medicine. There is particular focus on CAR T-cell therapy given its novel nature and implications for both critical care practice and resource utilization. [ABSTRACT FROM AUTHOR]

This paper focuses on optimizing resource management strategies in chimeric antigen receptor (CAR) T-cell therapies using reinforcement learning (RL). CAR T-cell therapy is an innovative and promising treatment within the field of immunotherapy, which is based on the isolation of patients' own T-cells, genetically modifying these cells to express a CAR for tumor recognition, cultivating and expanding these T cells and infusing them back to the patient. These therapies require several reusable but scarce resources, including special equipment, such as the bioreactor that is used to expand CAR T cells, and medical resources, such as the hospital staff, e.g., doctors and nurses. Considering the stochastic nature of medical procedures and the production of CAR T cells, the scheduling of the therapies and the efficient allocation of the required resources pose a significant challenge inside the hospital environment. Here, we propose a derivative-free policy gradient algorithm that utilizes a simulation model of the therapy, built using real-world data, to obtain efficient control policies for the resource management problem. The proposed method is designed to minimize the expected number of deviations from the therapy protocol as well as the expected overall completion time of the therapies for every patient. The effectiveness of the proposed resource management approach is demonstrated via simulation experiments. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion Chimeric antigen receptor (CAR) T‐cell therapy is an emerging therapeutic modality for relapsed and refractory hematological malignancies. Infectious complications following CAR T‐cell therapy are not well defined.This is a retrospective analysis of data on patients who received CAR T‐cell therapy between April 2018 and December 2022 at the Karmanos Cancer Center, Detroit. Patients’ data were collected up to their last known clinic or inpatient follow‐up visit. An infectious episode was defined as any microbiologically proven or clinically documented infection.Seventy‐six patients received therapy with FDA‐approved CAR T‐cell products. Thirty‐three patients (43.4%) had at least one infectious episode. There were 61 infectious episodes during a median follow‐up of 184 (96–340) days. Median duration for the onset of infection was 59 (22–209) days. Bacterial and viral infections occurred in 42.6% and 41% of the infectious episodes, respectively. COVID‐19 was the most common infectious complication (14.8%). Time‐to‐event analysis showed that most infections occurred within the first 100 days. Empirical antibiotic use during Cytokine Release Syndrome/Immune effector Cell‐Associated Neurotoxicity Syndrome (CRS/ICANS) in the absence of documented bacterial infection was reported in 85.7% of patients. Clostridioides difficile accounted for 11.5% of all infectious episodes. Five of six patients with C. difficile infection had CRS/ICANS and received antibiotics.COVID‐19 and C. difficile infection were the most common infections following CAR T‐cell therapy. Most infections occurred within the first 100 days. Empiric antibiotic use and C. difficile infection were common in patients with CRS/ICANS, in the absence of documented bacterial infection, thus providing an excellent opportunity for antimicrobial stewardship in this population. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of hematologic malignancies, offering remarkable remission rates in otherwise refractory conditions. However, its expansion into broader oncological applications faces significant hurdles, including limited efficacy in solid tumors, safety concerns related to toxicity, and logistical challenges in manufacturing and scalability. This review critically examines the latest advancements aimed at overcoming these obstacles, highlighting innovations in CAR T-cell engineering, novel antigen targeting strategies, and improvements in delivery and persistence within the tumor microenvironment. We also discuss the development of allogeneic CAR T cells as off-the-shelf therapies, strategies to mitigate adverse effects, and the integration of CAR T cells with other therapeutic modalities. This comprehensive analysis underscores the synergistic potential of these strategies to enhance the safety, efficacy, and accessibility of CAR T-cell therapies, providing a forward-looking perspective on their evolutionary trajectory in cancer treatment. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T‐cell therapy demonstrates efficacy for the treatment of hematologic cancers, but remains challenging in solid tumors because of the hostile tumor microenvironment and heterogeneity that restrict the infiltration and activity of CAR T‐cells. The lack of clinical imaging methods to monitor CAR T‐cell therapy in patients limits the potential to enhance the therapeutic approach and predict patient response. Here, a straightforward, non‐invasive method for Magnetic Resonance Imaging (MRI) tracking and magnetic targeting of CAR T‐cells to enhance T‐cell trafficking to solid tumors, in a setting that can be deployed in clinics, is reported. Iron oxide nanoparticles are loaded into T‐cells, allowing MRI detection and magnetic cell guidance, while preserving T‐cell viability, functions, and CAR specificity to target epidermal growth factor receptor (EGFR)‐expressing tumors. Longitudinal MRI monitoring of T‐cells over 14 days reveals differences in tumor infiltration rates and antitumor efficacy between EGFR‐targeted CAR T‐cells and non‐transduced T‐cell. Moreover, an external magnet placed over the tumor enhances the infiltration of CAR T‐cells and increases their antitumor effect. MRI monitoring and magnetic guidance represent a dual‐pronged clinically feasible therapeutic strategy to control and promote CAR T‐cells delivery into solid tumors, thereby improving the precision, efficacy, and safety of the treatment. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T (CAR T) cell therapy has shown remarkable success in treating various leukemias and lymphomas. Cellular kinetic (CK) and pharmacodynamic (PD) behavior of CAR T cell therapy is distinct from other therapies due to its living nature. CAR T CK is typically characterized by an exponential expansion driven by target binding, fast initial decline (contraction), and slow long-term decline (persistence). Due to the dependence of CK on target binding, CK and PD of CAR T therapies are inherently and bidirectionally linked. In this work, we develop a semi-mechanistic model of CAR T CK/PD, incorporating molecular-scale binding, T cell dynamics with multiple phenotypes, and tumor growth and killing. We calibrate this model to published CK and PD data for a CD19-targeting CAR T cell therapy. Using sensitivity analysis, we explore variability in response due to patient- and drug-specific properties. We further explore the impact of tumor characteristics on CAR T-cell expansion and efficacy through individual- and population-level parameter scans. [ABSTRACT FROM AUTHOR]

Immunotherapy represents a transformative shift in cancer treatment. Among myriad immune-based approaches, chimeric antigen receptor (CAR) T-cell therapy has shown promising results in treating hematological malignancies. Despite aggressive treatment options, the prognosis for patients with malignant brain tumors remains poor. Research leveraging CAR T-cell therapy for brain tumors has surged in recent years. Pre-clinical models are crucial in evaluating the safety and efficacy of these therapies before they advance to clinical trials. However, current models recapitulate the human tumor environment to varying degrees. Novel in vitro and in vivo techniques offer the opportunity to validate CAR T-cell therapies but also have limitations. By evaluating the strengths and weaknesses of various pre-clinical glioma models, this review aims to provide a roadmap for the development and pre-clinical testing of CAR T-cell therapies for brain tumors. [ABSTRACT FROM AUTHOR]

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Abstract Mutant KRAS promotes the proliferation, metastasis, and aggressiveness of various cancers including pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), and colorectal adenocarcinoma (CRC) respectively. Mutant KRAS therapeutics are limited, while Sotorasib and Adagrasib were the only FDA-approved drugs for the treatment of KRASG12C mutated NSCLC. Chimeric antigen receptor (CAR) T-cell therapy has been emerged as an effective strategy against hematological malignancies and being extended towards solid cancers including PDAC. mesothelin (MSLN) and Carcinoembryonic Antigen (CEA) were reported to be highly overexpressed in KRAS-mutated PDAC. Meanwhile, in clinical trials, several CAR T-cell therapy studies are mainly focused towards these two cancer antigens in PDAC, however, the dual targeting of these two neoantigens is not reported. In the present study, we have designed and developed a novel dual-targeting CAR protein by employing various bioinformatics approaches such as functional analysis (antigenicity, allergenicity, antigen binding sites & signalling cascades), qualitative analysis (physicochemical, prediction, refinement & validation of 2D and 3D structures), molecular docking, and in silico cloning. Our results revealed that the designed CAR protein specifically binds with both MSLN & CEA with significant binding affinities, and was predicted to be stable & non-allergenic. Additionally, the protein–protein interaction network reveals the T-cell mediated antitumor responses of each domain in the designed CAR. Conclusively, we have designed and developed a dual targeting (MSLN & CEA) CAR protein towards KRAS-mutated PDAC using computational approaches. Alongside, we further recommend to engineer this designed CAR in T-cells and evaluating their therapeutic efficiency in in vitro and in vivo studies in the near future.

Clinical trials evaluating chimeric antigen receptor (CAR) T‐cell therapy in relapsed/refractory multiple myeloma (RRMM) have typically excluded patients with AL amyloidosis. As a result, there are limited data on the safety and efficacy of CAR T‐cell therapy in this patient population. We retrospectively reviewed eight consecutive patients with RRMM and AL amyloidosis who were treated with standard of care CAR T‐cell therapy. Cytokine release syndrome was seen in 75% of patients (grade ≥3: 0%) and immune effector cell‐associated neurotoxicity syndrome (grade 1) in only one patient. Low‐grade cytopenias were common (any grade/grade ≥3: neutropenia 62.5%/37.5%, anemia 37.5%/0%, thrombocytopenia 25%/0%). CAR T‐cell therapy led to rapid and deep responses with a median time to best response of 43 days and a hematologic very good partial response or better rate of 62.5%. Overall, we found that commercial CAR T‐cell therapy was feasible, and effective in patients with RRMM and concurrent AL amyloidosis. [ABSTRACT FROM AUTHOR]

Background: Relapse/refractory B-cell acute lymphoblastic leukaemia (r/r B-ALL) represents paediatric cancer with a challenging prognosis. CAR T-cell treatment, considered an advanced treatment, remains controversial due to high relapse rates and adverse events. This study assessed the efficacy and safety of CAR T-cell therapy for r/r B-ALL. Methods: The literature search was performed on four databases. Efficacy parameters included minimal residual disease negative complete remission (MRD-CR) and relapse rate (RR). Safety parameters constituted cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Results: Anti-CD22 showed superior efficacy with the highest MRD-CR event rate and lowest RR, compared to anti-CD19. Combining CAR T-cell therapy with haploidentical stem cell transplantation improved RR. Safety-wise, bispecific anti-CD19/22 had the lowest CRS rate, and anti-CD22 showed the fewest ICANS. Analysis of the costimulatory receptors showed that adding CD28ζ to anti-CD19 CAR T-cell demonstrated superior efficacy in reducing relapses with favorable safety profiles. Conclusion: Choosing a more efficacious and safer CAR T-cell treatment is crucial for improving overall survival in acute leukaemia. Beyond the promising anti-CD22 CAR T-cell, exploring costimulatory domains and new CD targets could enhance treatment effectiveness for r/r B-ALL. [ABSTRACT FROM AUTHOR]

Abstract Pancreatic cancer is a major cause of cancer-related death, but despondently, the outlook and prognosis for this resistant type of tumor have remained grim for a long time. Currently, it is extremely challenging to prevent or detect it early enough for effective treatment because patients rarely exhibit symptoms and there are no reliable indicators for detection. Most patients have advanced or spreading cancer that is difficult to treat, and treatments like chemotherapy and radiotherapy can only slightly prolong their life by a few months. Immunotherapy has revolutionized the treatment of pancreatic cancer, yet its effectiveness is limited by the tumor's immunosuppressive and hard-to-reach microenvironment. First, this article explains the immunosuppressive microenvironment of pancreatic cancer and highlights a wide range of immunotherapy options, including therapies involving oncolytic viruses, modified T cells (T-cell receptor [TCR]-engineered and chimeric antigen receptor [CAR] T-cell therapy), CAR natural killer cell therapy, cytokine-induced killer cells, immune checkpoint inhibitors, immunomodulators, cancer vaccines, and strategies targeting myeloid cells in the context of contemporary knowledge and future trends. Lastly, it discusses the main challenges ahead of pancreatic cancer immunotherapy.

Historically, salvage chemoimmunotherapy with consolidative autologous hematopoietic stem cell transplantation (ASCT) was the only potentially curative therapeutic option for patients with relapsed/refractory large B-cell lymphoma (LBCL). Treatment options were few and outcomes poor for patients whose lymphoma failed to respond to salvage chemotherapy/ASCT and for patients not eligible for ASCT. The approval of chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory LBCL revolutionized the treatment landscape with unprecedented response rates and durability of responses. As a result, earlier intervention with CAR T-cell therapy has been explored, and the enthusiasm for CAR T-cell therapy has overshadowed ASCT. In this article, we will review the data available for ASCT and CAR T-cell therapy in relapsed LBCL and will examine the role for ASCT in relapsed/refractory LBCL in the era of CAR T-cell therapy. [ABSTRACT FROM AUTHOR]

Background: CD19-specific chimeric antigen receptor (CAR) T-cell therapy has shown promising disease responses in patients with high-risk B-cell malignancies. However, its use may be related to complications such as immune-mediated complications, infections, and end-organ dysfunction. The incidence of post-CAR T-cell therapy acute kidney injury (AKI) in the children, adolescent, and young adult (CAYA) patient population is largely unreported. Methods: The objectives of this study were to determine the incidence of AKI in CAYA patients with high-risk B-cell malignancies treated with CD19-CAR T-cell therapy, evaluate potential risk factors for developing AKI, and determine patterns of kidney function recovery. We conducted a retrospective analysis of 34 CAYA patients treated with CD19-CAR T-cell at a single institution. Results: There was a cumulative incidence of any grade AKI by day 30 post-infusion of 20% (n = 7), with four cases being severe AKI (stages 2–3) and one patient requiring kidney replacement therapy. All episodes of AKI developed within the first 14 days after receiving CAR T-cell therapy and 50% of patients with AKI recovered kidney function to baseline within 30 days post-infusion. No evaluated pre-treatment risk factors were associated with the development of subsequent AKI; there was an association between AKI and cytokine release syndrome and neurotoxicity. We conclude that the risk of developing AKI following CD19-CAR T-cell therapy is highest early post-infusion, with most cases of AKI being severe. Conclusions: Frequent monitoring to facilitate early recognition and subsequent management of kidney complications after CD19-CAR T-cell therapy may reduce the severity of AKI in the CAYA patient population. [ABSTRACT FROM AUTHOR]

In this study, we compared the similarities and differences in adverse events (AEs) among CAR T-cell products through signal mining via the FDA Adverse Event Reporting System (FAERS) and identified unknown AEs to provide a reference for safe clinical medication. Data from the FAERS database spanning from the fourth quarter of 2017 to the first quarter of 2024 were extracted. Signals were identified using the reporting odds ratio (ROR) method and the Medicines and Healthcare Products Regulatory Agency (MHRA) method. A total of 11,386 AE reports related to six CAR T-cell products were selected. The top three categories of AEs reported were nervous system disorders, immune system disorders, and general disorders and administration site conditions. However, there were variations in the AE spectra among the different CAR T-cell products. The BCMA-targeting drugs idecabtagene vicleucel (Ide-cel) and ciltacabtagene autoleucel (Cilta-cel) were found to be associated with parkinsonism, which were not observed in CD19-targeting drugs. Tisagenlecleucel (Tisa-cel) and axicabtagene ciloleucel (Axi-cel) exhibited cerebrovascular accident-related AEs, graft versus host disease, and abnormal coagulation indices. Cilta-cel was associated with cerebral hemorrhage, intracranial hemorrhage, cranial nerve disorder, and facial nerve disorder. Cardiopulmonary toxicity, including hypoxia, tachypnoea, cardiorenal syndrome, and hypotension, exhibited strong signal intensities and considerable overlap with CRS. The number of positive signals for cardiopulmonary toxicity associated with drugs targeting CD-19 is greater. Clinicians should assess patients prior to medication and closely monitor their vital signs, mental status, and laboratory parameters during treatment. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: Chimeric antigen receptor T-cell (CAR T) therapies have transformed diffuse large B-cell lymphoma (DLBCL) treatment. It is important to better understand their use in Medicare Fee-for-Service (FFS) patients, who often differ from commercially insured populations in important ways. Methods: We analyzed Medicare FFS claims data, focusing on the utilization patterns across three CAR T products—lisocabtagene maraleucel (liso-cel), tisagenlecleucel (tisa-cel), and axicabtagene autoleucel (axi-cel)—which are indicated for the treatment of DLBCL. Our investigation covered the period from 2021 through 2022. This analysis spanned a 180-day period prior to CAR T procedure and extended to a 90-day post-CAR T. Utilization of healthcare services, healthcare spending, and comorbidities were assessed in the pre- and post-periods. Clinical trial and PPS-exempt center claims were removed from the analysis. Statistical comparisons between inpatient and outpatient cohorts were made using Wilcoxon's rank-sum tests for continuous variables and Chi-square tests or Fisher's exact tests for categorical variables. Results: Among the total 391 CAR T claims assessed, most of the CAR T therapies were administered in the inpatient setting (79%) compared to outpatient (21%). CAR T therapy in the inpatient setting received an average Medicare cost of US$498,723 ($276,138—$1,066,524), while the average Medicare cost for outpatient CAR T claims was $414,393 ($276,980—$849,878). There was a higher 3-month average post-period cost for those hospitals utilizing CAR T in the outpatient setting than the inpatient setting ($15,794 vs. $10,244). Despite the higher post-period cost, when looking at the CAR T procedure and pre- and post-periods as a single episode, beneficiaries receiving outpatient CAR T had less cost for the total episode of care ($587,908 vs. $529,188). Follow-up inpatient claims were also assessed post-CAR T procedure for 30 days. The rate of post-CAR T inpatient re-admission was significantly lower for beneficiaries receiving the index CAR T in the inpatient setting (21%) compared to outpatient CAR T (59%). Days between index CAR T discharge and IP admission were also significantly shorter for OP CAR T compared to IP CAR T (8.0 vs. 14.1 days, p < 0.0001). Additionally, IP CAR T had a longer ALOS on the admission claim (6.9 vs. 6.2 days). Conclusion: CAR T therapy for the treatment of LBCL has become more common within the Medicare population, primarily in the inpatient setting. This study helps understand providers' cost and associated patient care around CAR T administration. The data show that the average cost received by hospitals encompasses the expenses related to both the CAR T drug and the medical services delivered to patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Immunotherapy has been introduced as a standard of care for several cancers, and its use is on the rise. However, the enhanced immune system frequently causes immune-related adverse events. Depending on the affected organ and tissue and the severity of the toxicity, immunotherapy is generally held, and steroids or immunosuppressive agents are introduced, impacting cancer treatment. Therefore, prompt identification of toxicity at an early stage and multidisciplinary management are mandatory. Since imaging is crucial to guide clinicians in managing immune-related adverse events, this imaging-based review presents the most frequent complications identifiable on imaging. Clues for identification and the most important differential diagnoses are discussed to enhance knowledge among imaging specialists and clinicians regarding these complications. Immunotherapy has revolutionized oncology care, improving patient outcomes in several cancers. However, these therapies are also associated with typical immune-related adverse events due to the enhanced inflammatory and immune response. These toxicities can arise at any time during treatment but are more frequent within the first few months. Any organ and tissue can be affected, ranging from mild to life-threatening. While some manifestations are common and more often mild, such as dermatitis and colitis, others are rarer and more severe, such as myocarditis. Management depends on the severity, with treatment being held for >grade 2 toxicities. Steroids are used in more severe cases, and immunosuppressive treatment may be considered for non-responsive toxicities, along with specific organ support. A multidisciplinary approach is mandatory for prompt identification and management. The diagnosis is primarily of exclusion. It often relies on imaging features, and, when possible, cytologic and/or pathological analyses are performed for confirmation. In case of clinical suspicion, imaging is required to assess the presence, extent, and features of abnormalities and to evoke and rule out differential diagnoses. This imaging-based review illustrates the diverse system-specific toxicities associated with immune checkpoint inhibitors and chimeric antigen receptor T-cells with a multidisciplinary perspective. Clinical characteristics, imaging features, cytological and histological patterns, as well as the management approach, are presented with insights into radiological tips to distinguish these toxicities from the most important differential diagnoses and mimickers—including tumor progression, pseudoprogression, inflammation, and infection—to guide imaging and clinical specialists in the pathway of diagnosing immune-related adverse events. [ABSTRACT FROM AUTHOR]

AbstractTo quantify the clinical unmet need of r/r MCL patients who progress on a covalent Bruton tyrosine kinase inhibitor (BTKi), we conducted a systematic review to identify studies that reported overall survival (OS), progression-free survival (PFS), or response outcomes of patients who received a chemo(immunotherapy) ± targeted agent standard therapy (STx) or brexucabtagene autoleucel (brexu-cel) in the post-BTKi setting. Twenty-six studies (23 observational; three trials) reporting outcomes from 2005 to 2022 were included. Using two-stage frequentist meta-analyses, the estimated median PFS/OS for patients treated with an STx was 7.6 months (95% CI: 3.9–14.6) and 9.1 months (95% CI: 7.3–11.3), respectively. The estimated objective response rate (ORR) was 45% (95% CI: 34–57%). For patients treated with brexu-cel, the estimated median PFS/OS was 14.9 months (95% CI: 10.5–21.0) and 32.1 months (95% CI: 25.2–41.2), with a pooled ORR of 89% (95% CI: 86–91%). Our findings highlight a significant unmet need for patients whose disease progresses on a covalent BTKi. [ABSTRACT FROM AUTHOR]

Summary: B and T cells collaborate to drive autoimmune disease (AID). Historically, B- and T-cell (B–T cell) co-interaction was targeted through different pathways such as alemtuzumab, abatacept, and dapirolizumab with variable impact on B-cell depletion (BCD), whereas the majority of patients with AID including rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and organ transplantation benefit from targeted BCD with anti-CD20 monoclonal antibodies such as rituximab, ocrelizumab, or ofatumumab. Refractory AID is a significant problem for patients with incomplete BCD with a greater frequency of IgD−CD27+ switched memory B cells, CD19+CD20− B cells, and plasma cells that are not directly targeted by anti-CD20 antibodies, whereas most lymphoid tissue plasma cells express CD19. Furthermore, B–T-cell collaboration is predominant in lymphoid tissues and at sites of inflammation such as the joint and kidney, where BCD may be inefficient, due to limited access to key effector cells. In the treatment of cancer, chimeric antigen receptor (CAR) T-cell therapy and T-cell engagers (TCE) that recruit T cells to induce B-cell cytotoxicity have delivered promising results for anti-CD19 CAR T-cell therapies, the CD19 TCE blinatumomab and CD20 TCE such as mosunetuzumab, glofitamab, or epcoritamab. Limited evidence suggests that anti-CD19 CAR T-cell therapy may be effective in managing refractory AID whereas we await evaluation of TCE for use in non-oncological indications. Therefore, here, we discuss the potential mechanistic advantages of novel therapies that rely on T cells as effector cells to disrupt B–T-cell collaboration toward overcoming rituximab-resistant AID. This graphical abstract compares the hypothetical timelines of CD19 CAR T-cell therapy (green line) and CD19-TCE (purple line) in the context of autoimmune disease flare. CAR T-cell therapy is often limited to specialized centers due to its high-production costs, labor-intensive process, delayed effector T-cell pool establishment, and tolerability issues with prerequisite toxic lymphodepleting chemotherapy, potentially restricting its use and impacting patient outcomes. In contrast, CD19-TCB, readily available and immediately deployable upon disease flare detection, mitigates the risks associated with disease progression due to delays in CAR T-cell therapy access. Graphical Abstract [ABSTRACT FROM AUTHOR]

The efficacy of chimeric antigen receptor (CAR) T-cell therapy for large B-cell lymphoma (LBCL) is well-established. This study, using the Premier PINC AI Healthcare Database, assessed hospital costs and healthcare resource utilization (HRU) between CAR T-cell therapy and autologous hematopoietic cell transplant (AHCT) for 733 LBCL patients from 01/01/2017-04/30/2021 (166 CAR T and 567 AHCT from 37 US hospital systems. CAR T-cell therapy had higher index costs but lower non-pharmacy costs, shorter hospital stays, lower ICU utilization than AHCT. The CAR T-cell cohort also presented fewer preparatory costs and HRU. At a 180-day follow-up, AHCT had lower hospitalization rates and costs. Overall, despite higher index costs, CAR T-cell therapy has lower non-pharmacy costs and HRU during the index procedure and requires less preparation time with lower preparation HRUs and costs than AHCT. This has important implications for resource management and informed decision-making for stakeholders. [ABSTRACT FROM AUTHOR]

Purpose of Review: Chimeric antigen receptor T-cells (CAR-T) and bispecific antibodies (BiTE) are novel therapies used to treat hematologic malignancies, lung cancer and melanoma. With the increasing use of these novel therapies, the incidence and prognosis of their cardiovascular side effects needs to be further elucidated. Recent Findings: Randomized trials have highlighted the systemic effects of CAR-T and BiTE therapy including cytokine release syndrome (CRS) and resultant hypotension and respiratory failure. Cohort studies have elucidated the cardiovascular effects associated with CAR-T and BiTE therapy including heart failure, cardiomyopathy, arrythmia, myocardial infarction, stroke and cardiovascular death. Summary: Cardiovascular events after CAR-T and BiTE therapy can occur and are often associated with CRS. CAR-T recipients experiencing severe cardiovascular events may have worse survival. Further prospective studies are needed to understand the full scope of cardiovascular effects and mitigation strategies for these therapies. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is a major cause of cancer-related death, but despondently, the outlook and prognosis for this resistant type of tumor have remained grim for a long time. Currently, it is extremely challenging to prevent or detect it early enough for effective treatment because patients rarely exhibit symptoms and there are no reliable indicators for detection. Most patients have advanced or spreading cancer that is difficult to treat, and treatments like chemotherapy and radiotherapy can only slightly prolong their life by a few months. Immunotherapy has revolutionized the treatment of pancreatic cancer, yet its effectiveness is limited by the tumor's immunosuppressive and hard-to-reach microenvironment. First, this article explains the immunosuppressive microenvironment of pancreatic cancer and highlights a wide range of immunotherapy options, including therapies involving oncolytic viruses, modified T cells (T-cell receptor [TCR]-engineered and chimeric antigen receptor [CAR] T-cell therapy), CAR natural killer cell therapy, cytokine-induced killer cells, immune checkpoint inhibitors, immunomodulators, cancer vaccines, and strategies targeting myeloid cells in the context of contemporary knowledge and future trends. Lastly, it discusses the main challenges ahead of pancreatic cancer immunotherapy. [ABSTRACT FROM AUTHOR]

On behalf of Cell Therapy Transplant Canada (CTTC), we are pleased to present the Abstracts of the CTTC 2023 Annual Conference. The conference was held in-person, 31 May–2 June 2023, in Halifax, Nova Scotia at the Westin Nova Scotian hotel. Poster authors presented their work during a lively and engaging welcome reception on Thursday, 1 June, and oral abstract authors were featured during the oral abstract session in the afternoon of Friday, 2 June 2023. Twenty-three (23) abstracts were selected for presentation as posters and four (4) as oral presentations. Abstracts were submitted within four categories: (1) Basic/Translational Sciences, (2) Clinical Trials/Observations, (3) Laboratory/Quality, and (4) Pharmacy/Nursing/Other Transplant Support. The top four (4) oral abstracts and top four (4) poster abstracts were selected to receive an award. All of these were marked as "Award Recipient" within the relevant category. We congratulate all the presenters on their research and contributions to the field. [ABSTRACT FROM AUTHOR]

Simple Summary: Chimeric antigen receptor (CAR) T-cell therapies dramatically changed the treatment strategies for relapsed/refractory diffuse large B-cell lymphoma and displaced autologous stem cell transplantation as the standard of care for patients with refractory disease or early relapse. However, for patients responding to salvage therapy, autologous stem cell transplantation remains a valid therapy approach. Recently, CD19-directed chimeric antigen receptor (CAR) T-cell therapies have revolutionized treatment strategies for diffuse large B-cell lymphoma (DLBCL). CAR T-cell therapy is increasingly used as a second-line therapy for patients with DLBCL with early relapse or refractoriness to initial chemoimmunotherapy and displaced high-dose chemotherapy, followed by autologous stem cell transplantation (ASCT) as the standard of care for these patients. However, patients with late relapse or chemosensitive disease still benefit from autologous stem cell transplantation. We will review practice-changing studies in early relapse (ZUMA-7 and TRANSFORM) under consideration of the negative BELINDA trial, with a focus on register data, comparing CAR T-cell therapy and ASCT for patients responding to salvage therapy. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of hematologic malignancies, offering remarkable remission rates in otherwise refractory conditions. However, its expansion into broader oncological applications faces significant hurdles, including limited efficacy in solid tumors, safety concerns related to toxicity, and logistical challenges in manufacturing and scalability. This review critically examines the latest advancements aimed at overcoming these obstacles, highlighting innovations in CAR T-cell engineering, novel antigen targeting strategies, and improvements in delivery and persistence within the tumor microenvironment. We also discuss the development of allogeneic CAR T cells as off-the-shelf therapies, strategies to mitigate adverse effects, and the integration of CAR T cells with other therapeutic modalities. This comprehensive analysis underscores the synergistic potential of these strategies to enhance the safety, efficacy, and accessibility of CAR T-cell therapies, providing a forward-looking perspective on their evolutionary trajectory in cancer treatment.

Radiation therapy (RT) is utilized as a bridging strategy for patients with aggressive B-cell lymphoma prior to CD19-targeted chimeric antigen receptor (CAR T)-cell therapy. RT has been shown to provide local control without exacerbating the toxicities associated with subsequent CAR T-cell infusion. However, a consensus on the optimal radiation dose and fractionation for bridging purposes has yet to be established. We present a case of a patient with relapsed aggressive B-cell lymphoma who underwent bridging adaptive RT on a CT-linac prior to receiving CAR T-cell therapy. At month 6 post-CAR T infusion, the patient demonstrates no signs of disease recurrence or relapse, nor any unexpected toxicities attributable to the combined treatment. This underscores the feasibility and success of this innovative approach in treating lymphoma patients undergoing CAR T-cell therapy.

On behalf of Cell Therapy Transplant Canada (CTTC), we are pleased to present the Abstracts of the CTTC 2023 Annual Conference. The conference was held in-person, 31 May–2 June 2023, in Halifax, Nova Scotia at the Westin Nova Scotian hotel. Poster authors presented their work during a lively and engaging welcome reception on Thursday, 1 June, and oral abstract authors were featured during the oral abstract session in the afternoon of Friday, 2 June 2023. Twenty-three (23) abstracts were selected for presentation as posters and four (4) as oral presentations. Abstracts were submitted within four categories: (1) Basic/Translational Sciences, (2) Clinical Trials/Observations, (3) Laboratory/Quality, and (4) Pharmacy/Nursing/Other Transplant Support. The top four (4) oral abstracts and top four (4) poster abstracts were selected to receive an award. All of these were marked as “Award Recipient” within the relevant category. We congratulate all the presenters on their research and contributions to the field.

Abstract Background The autologous anti–B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy LCAR-B38M has been approved for the treatment of relapsed and refractory multiple myeloma in many countries across the world under the name ciltacabtagene autoleucel. LEGEND-2 was the first-in-human trial of LCAR-B38M and yielded deep and durable therapeutic responses. Here, we reported the outcomes in LEGEND-2 after a minimal 5-year follow-up. Methods Participants received an average dose of 0.5 × 106 cells/kg LCAR-B38M in split or single unfractionated infusions after cyclophosphamide-based lymphodepletion therapy. Investigator-assessed response, survival, safety and pharmacokinetics were evaluated. Results Seventy-four participants enrolled and had a median follow-up of 65.4 months. The 5-year progression-free survival (PFS) and overall survival (OS) rates were 21.0% and 49.1%, with progressive flattening of the survival curves over time. Patients with complete response (CR) had longer PFS and OS, with 5-year rates of 28.4% and 65.7%, respectively. Twelve patients (16.2%) remained relapse-free irrespective of baseline high-risk cytogenetic abnormality and all had normal humoral immunity reconstituted. An ongoing CR closely correlated with several prognostic baseline indices including favorable performance status, immunoglobulin G subtype, and absence of extramedullary disease, as well as a combination cyclophosphamide and fludarabine preconditioning strategy. Sixty-two (83.8%) suffered progressive disease (PD) and/or death; however, 61.1% of PD patients could well respond to subsequent therapies, among which, the proteasome inhibitor-based regimens benefited the most. Concerning the safety, hematologic and hepatic function recovery were not significantly different between non-PD and PD/Death groups. A low rate of second primary malignancy (5.4%) and no severe virus infection were observed. The patients who tested positive for COVID-19 merely presented self-limiting symptoms. In addition, a sustainable CAR T population of one case with persistent remission was delineated, which was enriched with indolently proliferative and lowly cytotoxic CD4/CD8 double-negative functional T lymphocytes. Conclusions These data, representing the longest follow-up of BCMA-redirected CAR T-cell therapy to date, demonstrate long-term remission and survival with LCAR-B38M for advanced myeloma. Trial registration LEGEND-2 was registered under the trial numbers NCT03090659, ChiCTRONH-17012285.

Abstract Chimeric antigen receptors (CAR) are engineered fusion proteins that target T-cells to specific surface antigens of tumor cells to generate effective anti-tumor responses. CAR T-cell therapy is playing an increasingly important role in the treatment of relapsed/refractory B-cell malignancies (R/R BCM). Attempting to make CAR T-cells safer and more effective in treating R/R BCM, various novel engineered CAR T-cell agents are currently in the research and development or clinical trial stages. We have summarized here the latest reports on the novel CAR T-cell therapies for R/R BCM presented at the 2023 ASH Annual Meeting as well as the latest updates in related clinical trials.

AbstractBackground Relapse/refractory B-cell acute lymphoblastic leukaemia (r/r B-ALL) represents paediatric cancer with a challenging prognosis. CAR T-cell treatment, considered an advanced treatment, remains controversial due to high relapse rates and adverse events. This study assessed the efficacy and safety of CAR T-cell therapy for r/r B-ALL.Methods The literature search was performed on four databases. Efficacy parameters included minimal residual disease negative complete remission (MRD-CR) and relapse rate (RR). Safety parameters constituted cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).Results Anti-CD22 showed superior efficacy with the highest MRD-CR event rate and lowest RR, compared to anti-CD19. Combining CAR T-cell therapy with haploidentical stem cell transplantation improved RR. Safety-wise, bispecific anti-CD19/22 had the lowest CRS rate, and anti-CD22 showed the fewest ICANS. Analysis of the costimulatory receptors showed that adding CD28ζ to anti-CD19 CAR T-cell demonstrated superior efficacy in reducing relapses with favorable safety profiles.Conclusion Choosing a more efficacious and safer CAR T-cell treatment is crucial for improving overall survival in acute leukaemia. Beyond the promising anti-CD22 CAR T-cell, exploring costimulatory domains and new CD targets could enhance treatment effectiveness for r/r B-ALL.

Background: Advances in multiple myeloma (MM) treatment have shifted the therapeutic landscape. Understanding patients' perspectives can assist physicians in helping patients make informed decisions. This study aimed to understand the patient decision-making process and gain insights into patient perspectives on B-cell maturation antigen (BCMA)-targeted therapies for MM. Methods: An 18-question survey was completed by patients with MM enrolled in HealthTree® Cure Hub, an online portal helping patients with plasma cell dyscrasias navigate their disease. Results: From October 28, 2022, to January 12, 2023, 325 patients with MM participated in the survey. The mean age (standard deviation) of the respondents was 66 (8) years; 54% were female and 90% were White. Among 218 patients with complete clinical records in the database, the median (min, max) lines of therapy (LOT) was 2 (1,16). Among 61 (28%) patients who had received ≥4 LOTs, 55 (90%) were triple-class exposed. Of the 290 patients who responded to the question about openness to new therapies, 76 (26%) were open to trying a new therapy immediately and 125 (43%) wanted more information on safety and efficacy. Most respondents reported likely or very likely to try a BCMA CAR T-cell therapy (60%) or a bispecific antibody (74%) and some needed more information to decide (16% for CAR T-cell therapy and 13% for bispecific antibody). The most requested information included efficacy, side effects (SEs), eligibility, and administration process for both CAR T-cell and bispecific therapies. When 2 therapies with the same efficacy and duration of response were offered, 69% of respondents would prefer the therapy with a lower risk of severe SEs but requires continuous dosing with no treatment-free interval, and 31% preferred a therapy given once followed by a treatment-free interval but with a potentially higher risk of severe SEs. To receive an effective therapy, the top acceptable trade-offs included frequent monitoring of SEs and initiating a new therapy in a hospital setting, and the least acceptable compromise was caregiver burden. Conclusions: This study found a high level of openness in patients with MM to try BCMA-targeted therapies. Information on efficacy, safety, availability, and eligibility may assist patients on decision-making. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T‐cell therapy is a form of immunotherapy where the lymphocytes, mostly T‐cells, are redirected to specifically recognize and eliminate a target antigen by coupling them with CARs. The binding of CAR and target cell surface antigens leads to vigorous T cell activation and robust anti‐tumor immune responses. Areas of implication of CAR T‐cell therapies include mainly hematological malignancies (i.e., advanced B‐cell cancers); however, recent studies have proven the unprecedented success of the new immunotherapy also in autoimmune rheumatic diseases. We aim to review the recent advances in CAR T‐cell therapies in rheumatology but also to address the limitations of their use in the real clinical practice based on the data on their efficacy and safety. [ABSTRACT FROM AUTHOR]

Background: The autologous anti–B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy LCAR-B38M has been approved for the treatment of relapsed and refractory multiple myeloma in many countries across the world under the name ciltacabtagene autoleucel. LEGEND-2 was the first-in-human trial of LCAR-B38M and yielded deep and durable therapeutic responses. Here, we reported the outcomes in LEGEND-2 after a minimal 5-year follow-up. Methods: Participants received an average dose of 0.5 × 106 cells/kg LCAR-B38M in split or single unfractionated infusions after cyclophosphamide-based lymphodepletion therapy. Investigator-assessed response, survival, safety and pharmacokinetics were evaluated. Results: Seventy-four participants enrolled and had a median follow-up of 65.4 months. The 5-year progression-free survival (PFS) and overall survival (OS) rates were 21.0% and 49.1%, with progressive flattening of the survival curves over time. Patients with complete response (CR) had longer PFS and OS, with 5-year rates of 28.4% and 65.7%, respectively. Twelve patients (16.2%) remained relapse-free irrespective of baseline high-risk cytogenetic abnormality and all had normal humoral immunity reconstituted. An ongoing CR closely correlated with several prognostic baseline indices including favorable performance status, immunoglobulin G subtype, and absence of extramedullary disease, as well as a combination cyclophosphamide and fludarabine preconditioning strategy. Sixty-two (83.8%) suffered progressive disease (PD) and/or death; however, 61.1% of PD patients could well respond to subsequent therapies, among which, the proteasome inhibitor-based regimens benefited the most. Concerning the safety, hematologic and hepatic function recovery were not significantly different between non-PD and PD/Death groups. A low rate of second primary malignancy (5.4%) and no severe virus infection were observed. The patients who tested positive for COVID-19 merely presented self-limiting symptoms. In addition, a sustainable CAR T population of one case with persistent remission was delineated, which was enriched with indolently proliferative and lowly cytotoxic CD4/CD8 double-negative functional T lymphocytes. Conclusions: These data, representing the longest follow-up of BCMA-redirected CAR T-cell therapy to date, demonstrate long-term remission and survival with LCAR-B38M for advanced myeloma. Trial registration: LEGEND-2 was registered under the trial numbers NCT03090659, ChiCTRONH-17012285. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptors (CAR) are engineered fusion proteins that target T-cells to specific surface antigens of tumor cells to generate effective anti-tumor responses. CAR T-cell therapy is playing an increasingly important role in the treatment of relapsed/refractory B-cell malignancies (R/R BCM). Attempting to make CAR T-cells safer and more effective in treating R/R BCM, various novel engineered CAR T-cell agents are currently in the research and development or clinical trial stages. We have summarized here the latest reports on the novel CAR T-cell therapies for R/R BCM presented at the 2023 ASH Annual Meeting as well as the latest updates in related clinical trials. [ABSTRACT FROM AUTHOR]

Purpose: The emergence of chimeric antigen receptor (CAR) T-cell therapy fundamentally changed the management of individuals with relapsed and refractory large B-cell lymphoma (LBCL). However, real-world data have shown divergent outcomes for the approved products. The present study therefore set out to evaluate potential risk factors in a larger cohort. Methods: Our analysis set included 88 patients, treated in four German university hospitals and one Italian center, who had undergone 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography (PET) before CAR T-cell therapy with tisagenlecleucel or axicabtagene ciloleucel. We first determined the predictive value of conventional risk factors, treatment lines, and response to bridging therapy for progression-free survival (PFS) through forward selection based on Cox regression. In a second step, the additive potential of two common PET parameters was assessed. Their optimal dichotomizing thresholds were calculated individually for each CAR T-cell product. Results: Extra-nodal involvement emerged as the most relevant of the conventional tumor and patient characteristics. Moreover, we found that inclusion of metabolic tumor volume (MTV) further improves outcome prediction. The hazard ratio for a PFS event was 1.68 per unit increase of our proposed risk score (95% confidence interval [1.20, 2.35], P = 0.003), which comprised both extra-nodal disease and lymphoma burden. While the most suitable MTV cut-off among patients receiving tisagenlecleucel was 11 mL, a markedly higher threshold of 259 mL showed optimal predictive performance in those undergoing axicabtagene ciloleucel treatment. Conclusion: Our analysis demonstrates that the presence of more than one extra-nodal lesion and higher MTV in LBCL are associated with inferior outcome after CAR T-cell treatment. Based on an assessment tool including these two factors, patients can be assigned to one of three risk groups. Importantly, as shown by our study, metabolic tumor burden might facilitate CAR T-cell product selection and reflect the individual need for bridging therapy. [ABSTRACT FROM AUTHOR]

Patients with hematological malignancies who also have a hepatitis B virus (HBV) infection need to be aware of the potential risk of HBV reactivation when undergoing anti-cancer treatments. Among these treatments, CAR T-cell therapy has gained significant attention as a promising option, but it also raises concerns regarding HBV reactivation. This review aims to provide an overview of published reports on HBV reactivation during CAR T-cell therapy, along with an assessment of the effectiveness of prophylactic antiviral therapy. Additionally, we propose a systematic approach for monitoring and managing HBV reactivation during CAR T-cell therapy to enhance the safety of this treatment for patients with HBV infection. [ABSTRACT FROM AUTHOR]