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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]

Objectives Methods Results Conclusion Despite major advances in treatment options for multiple myeloma (MM), patients refractory to the main drug classes and those with aggressive, especially extramedullary disease, still face a dismal outcome. For these patients, effective therapeutic options are urgently warranted.In this retrospective study, we report on the safety and efficacy of the intensive combination regimen of pomalidomide plus cisplatin, doxorubicin, cyclophosphamide, and etoposide (Pom‐PACE) in patients with relapsed refractory MM (RRMM) or plasma cell leukemia (PCL). A study population of 20 consecutive patients treated with Pom‐PACE at two academic centers was included for analysis. All patients had to have a confirmed relapse according to International Myeloma Working Group criteria and adequate organ function prior to the start of therapy. Data were collected by reviewing medical charts. Exploratory analyses were performed with regard to efficacy and safety.Patients were heavily pretreated with a median number of four prior therapies (range: 1–10). All patients were exposed to immunomodulators, proteasome inhibitors, and alkylating agents, 80% were double‐class refractory, 40% were triple‐class refractory. Extramedullary MM or PCL were present in 15 patients (75%). Overall response rate (ORR) was 68%, with 31% achieving at least a very good partial response. Responses were achieved rapidly with an ORR of 64% after one cycle. Median progression‐free survival was 8.9 months (0.92–not reached [NR]) and median overall survival was 11.8 months (3–40.6). Pom‐PACE was associated with significant toxicity. All evaluable patients experienced Grade 4 hematological toxicity. However, no treatment related mortality was observed.Pomalidomide‐PACE was able to induce rapid responses in heavily pretreated, aggressive RRMM with a manageable toxicity profile and therefore offers an effective salvage regimen and a potential bridging strategy to further treatment options such as chimeric antigen receptor T‐cell therapy. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T‐cell therapy has become a commercially available treatment option for relapsed or refractory (r/r) diffuse large B‐cell lymphoma (DLBCL) with two or more lines of prior therapies, and recently for high‐risk r/r DLBCL with one prior line of therapy. The successful development of CAR T‐cell therapy for multiple relapsed DLBCL has led to a boom in subsequent trials that investigated its utility in patients with other r/r B‐cell lymphoma subtypes. However, CAR T‐cell therapy is a multistep process that includes leukapheresis and manipulation which take several weeks. Therefore, patients with rapidly progressing or bulky disease may not be able to complete the therapeutic regimen involving CAR T‐cell products. This raises the question of the generalizability of the results of pivotal studies to the entire population. In this review, we summarize the development of CAR‐T cell therapy for B‐cell lymphoma and discuss strategies to further improve the clinical outcomes of this treatment. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T‐cell (CAR‐T) therapy has become an important intervention in the management of relapsed and relapsed/refractory multiple myeloma (MM). Currently, B‐cell maturation antigen (BCMA) is the most targeted surface protein due to its ubiquitous expression on plasma cells, with increasing expression of this essential transmembrane protein on malignant plasma cells as patients develop more advanced disease. This review will explore the earliest CAR‐T trials in myeloma, discuss important issues involved in CAR‐T manufacturing and processing, as well as review current clinical trials that led to the approval of the two commercially available CAR‐T products, Idecabtagene vicleucel and ciltacabtagene autoleucel. The most recent data from trials investigating the use of CAR‐T as an earlier line of therapy will be presented. Finally, the problem of relapses after CAR‐T will be presented, including several theories as to why CAR‐T therapies fail and possible clinical caveats. The next generation of MM‐specific CAR‐T will likely include new targets such as G‐protein‐coupled receptor class C, Group 5, member D (GPRC5D) and signaling lymphocyte activation molecular Family 7 (SLAMF7). The role of CAR‐T in the treatment of MM will undoubtedly increase exponentially in the next decade. [ABSTRACT FROM AUTHOR]

Background: While chimeric antigen receptor (CAR) T‐cell therapy has revolutionized the treatment outcomes of relapsed/refractory hematological malignancies, this therapy is associated with post‐treatment cytopenias, which can pose a challenge to its safe administration. This study describes the management of post‐CAR T cytopenias using the thrombopoietin mimetic eltrombopag. Methods: This retrospective analysis included adult patients with lymphoma or myeloma who received CAR T‐cell therapy at two academic medical centers. Eltrombopag was initiated for patients who had persistent high‐grade leukopenia and/or thrombocytopenia beyond 21 days post‐CAR T infusion. Risk factors and outcomes were assessed and compared for patients who did or did not receive eltrombopag. Results: Among the 185 patients analyzed, a majority (88%) experienced thrombocytopenia or leukopenia at day +30 post‐CAR T infusion. A total of 42 patients met the criteria for eltrombopag treatment and initiated therapy. Patients who received eltrombopag were more likely to have pre‐existing cytopenias at lymphodepletion, receive bridging therapy, experience an infection, or require intensive care. Recovery from cytopenias occurred within 180 days for a majority (94%) of patients. Conclusions: The use of eltrombopag for post‐CAR T leukopenia and thrombocytopenia was considered safe without any significant toxicities. The use of eltrombopag for post‐CAR T cytopenias might be effective in a high‐risk patient population but requires further study. [ABSTRACT FROM AUTHOR]

Background: We described the real‐life epidemiology and causes of infections on the different therapy phases in patients undergoing chimeric antigen receptor (CAR) T‐cells directed towards CD19+ or BCMA+ cells. Methods: All consecutive patients receiving CAR T‐cell therapy at our institution were prospectively followed‐up. We performed various comparative analyses of all patients and subgroups with and without infections. Results: Ninety‐one adults mainly received CAR T‐cell therapy for acute leukaemia (53%) and lymphoma (33%). We documented a total of 77 infections in 47 (52%) patients, 37 (48%) during the initial neutropenic phase and 40 (52%) during the non‐neutropenic phase. Infections during the neutropenic phase were mainly due to bacterial (29, 78%): catheter infections (11 [38%] cases), endogenous source (5 [17%]), and Clostridioides difficile (5 [17%]). Patients receiving corticosteroids after CAR T‐cell therapy had a higher risk of endogenous infection (100% vs. 16%; p =.006). During the non‐neutropenic phase, bacterial infections remained very frequent (24, 60%), mainly with catheter source (8, 33%). Respiratory tract infections were common (17, 43%). Conclusions: Infections after CAR T‐cell therapy were frequent. During the neutropenic phase, it is essential to prevent nosocomial infections and balance the use of antibiotics to lower endogenous bacteraemia and Clostridial infection rates. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T‐cell (CAR‐T) therapy has demonstrated unprecedented success in the treatment of various hematologic malignancies including relapsed or refractory (R/R) B‐cell acute lymphoblastic leukemia (B‐ALL). Currently, there are two FDA‐approved CD19‐directed CAR‐T cell products for the treatment of adults with R/R B‐ALL. Despite high remission rates following CD19 CAR‐T cell therapy in R/R B‐ALL, remission durability remains limited in most adult patients, with relapse observed frequently in the absence of additional consolidation therapy. Furthermore, the burden of CAR‐T cell toxicity remains significant in adults with R/R B‐ALL and further limits the wide utilization of this effective therapy. In this review, we discuss patient and disease factors that are linked to CAR‐T cell therapy outcomes in R/R B‐ALL and strategies to optimize durability of response to reduce relapse and mitigate toxicity in the adult population. We additionally discuss future approaches being explored to maximize the benefit of CAR‐T in adults with B‐ALL. [ABSTRACT FROM AUTHOR]

Chimeric receptor antigen T cell (CAR‐T cell) therapy has demonstrated effectiveness and therapeutic potential in the immunotherapy of hematological malignancies, representing a promising breakthrough in cancer treatment. Despite the efficacy of CAR‐T cell therapy in B‐cell lymphoma, response variability, resistance, and side effects remain persistent challenges. The tumor microenvironment (TME) plays an intricate role in CAR‐T cell therapy of B‐cell lymphoma. The TME is a complex and dynamic environment that includes various cell types, cytokines, and extracellular matrix components, all of which can influence CAR‐T cell function and behavior. This review discusses the design principles of CAR‐T cells, TME in B‐cell lymphoma, and the mechanisms by which TME influences CAR‐T cell function. We discuss emerging strategies aimed at modulating the TME, targeting immunosuppressive cells, overcoming inhibitory signaling, and improving CAR‐T cell infiltration and persistence. Therefore, these processes enhance the efficacy of CAR‐T cell therapy and improve patient outcomes in B‐cell lymphoma. Further research will be needed to investigate the molecular and cellular events that occur post‐infusion, including changes in TME composition, immune cell interactions, cytokine signaling, and potential resistance mechanisms. Understanding these processes will contribute to the development of more effective CAR‐T cell therapies and strategies to mitigate treatment‐related toxicities. [ABSTRACT FROM AUTHOR]

The success of chimeric antigen receptor T‐cell (CAR‐T) therapy in hematologic malignancies has realized a longstanding effort toward harnessing the immune system to fight cancer in a truly personalized fashion. Second generation chimeric antigen receptors (CAR) incorporating co‐stimulatory molecules like 4‐1BB or CD28 were able to overcome some of the hindrances with initial CAR constructs resulting in efficacious products. Many second‐generation CAR‐T products have been approved in the treatment of relapsed/refractory hematologic malignancies including multiple myeloma (MM), non‐Hodgkin lymphoma (NHL), and acute lymphoblastic leukemia. However, challenges remain in optimizing the manufacturing, timely access, limiting the toxicity from CAR‐T infusions and improving sustainability of responses derived with CAR‐T therapy. Here, we summarize the clinical trial data leading to approval CAR‐T therapies in MM and NHL, discuss the limitations with current CAR‐T therapy strategies and review emerging strategies for overcoming these limitations. [ABSTRACT FROM AUTHOR]

Chimeric Antigen Receptor T‐cell (CAR‐T cell) therapy has emerged as a groundbreaking immunotherapeutic approach for treating various hematological malignancies. CAR‐T cells are engineered to express synthetic receptors that target specific antigens on cancer cells, leading to their eradication. While the therapy has shown remarkable efficacy, a significant challenge that has been observed in 30%–70% of patients showing recurrent disease is antigen loss or downregulation. We searched PubMed/MEDLINE, EMBASE, and Google scholar for articles on antigen loss/escape following Chimeric antigen receptor T‐cell therapy in malignancies. Antigen loss refers to the loss or reduction in the expression of the target antigen on cancer cells, rendering CAR‐T cells ineffective. This phenomenon poses a significant clinical concern, as it can lead to disease relapse and limited treatment options. This review explores the mechanisms underlying antigen loss following CAR‐T cell therapy, its implications on treatment outcomes, and potential strategies to overcome the problem. [ABSTRACT FROM AUTHOR]

Objectives: We aim to analyze the predictive value of thromboelastography on bleeding severity of patients with chimeric antigen receptor (CAR)‐T cell therapy. Methods: A total of 80 patients with refractory/relapsed hematological malignancy were enrolled and divided into two groups: the severe bleeding group and the non‐severe bleeding group. The thromboelastography data was collected on the day of CAR‐T infusion and the 3rd, 7th, 10th, 13th, 17th, and 20th day after CAR‐T cell infusion. Results: The patients of the severe bleeding group had lower platelet (p <.007), maximum amplitude (p =.002), coagulation index (p =.005), and longer coagulation time (p =.019). Increasing trend in reaction time and coagulation time and decreasing trend in Alpha, maximum amplitude, and coagulation index on Days 0–10, opposite on Days 10–20. Univariate logistic regression analysis and multivariable logistic regression analysis showed maximum amplitude on the 3rd day after CAR‐T cell infusion (MA3) (OR = 0.9; 95% CI = 0.84–0.95; p <.001) and cytokine release syndrome grade (OR = 2.57; 95% CI = 1.35–5.32; p =.006) were significantly associated with high bleeding severity. Conclusions: Thromboelastography was considered to be a good predictor of bleeding severity. [ABSTRACT FROM AUTHOR]

Although chimeric antigen receptor (CAR) T‐cell therapy has demonstrated remarkable efficacy in patients with chemo‐refractory B‐cell lymphoma, a significant portion is refractory or relapse. Resistance is a major barrier to improving treatment efficacy and long‐term survival in CAR T‐cell therapy, and clinicians have very limited tools to discriminate a priori patients who will or will not respond to treatment. While CD19‐negative relapses due to loss of target antigen is well described, it accounts for only about 30% of cases with treatment failure. Recent efforts have shed light on mechanisms of CD19‐positive relapse due to tumor intrinsic resistance, T‐cell quality/manufacturing, or CAR T‐cell exhaustion mediated by hostile tumor microenvironment. Here, we review the latest updates of preclinical and clinical trials to investigate the mechanisms of resistance and relapse post CAR T‐cell therapy in B cell lymphoma and discuss novel treatment strategies to overcome resistance as well as advances that are useful for a CAR T therapist to optimize and personalize CAR T‐cell therapy. [ABSTRACT FROM AUTHOR]

CD19‐chimeric antigen receptor T‐cell (CAR T‐cell) therapy has improved the outcomes of relapsed/refractory large B cell lymphoma significantly. However, about 50% of patients relapsed post‐CAR‐T therapy. Late relapse composed of 1/3 to 1/2 of CAR‐T cell therapy failure, with no previous reports of isolated relapse in immune‐privileged sites. Here, we report the first case series of late‐onset post CAR‐T cell therapy isolated central nervous system (CNS) relapses, in systemic relapsed/refractory large B cell lymphoma patients. With these cases, we suggest that additional CNS prophylaxis should be administrated for primary refractory patients on CAR‐T cell therapy with previous neurological involvements, multiple extra‐nodular lesions, and high CNS‐IPI score pre‐CAR, as well as early disappearance of circulating CAR‐T cells post infusion. [ABSTRACT FROM AUTHOR]

Impaired function of hematopoiesis after treatment with chimeric antigen T‐cells (CAR‐T) is a frequent finding and can interest a wide range of patients, regardless of age and underlying disease. Trilinear cytopenias, as well as hypogammaglobulinemia, B‐cell aplasia, and T‐cell impairment, can severely affect the infectious risk of CAR‐T recipients, as well as their quality of life. In this review, we provide an overview of defects in hematopoiesis after CAR‐T, starting with a summary of different definitions and thresholds. We then move to summarize the main pathogenetic mechanisms of cytopenias, and we offer insight into cytomorphological aspects, the role of clonal hematopoiesis, and the risk of secondary myeloid malignancies. Subsequently, we expose the major findings and reports on T‐cell and B‐cell quantitative and functional impairment after CAR‐T. Finally, we provide an overview of current recommendations and leading experiences regarding the management of cytopenias and defective B‐ and T‐cell function. [ABSTRACT FROM AUTHOR]

The future of chimeric antigen receptor T (CAR‐T) therapy remains unclear. New studies are constantly being published confirming the efficacy and favorable safety profile of its innovative enhancements. Currently approved CAR‐T drugs are manufactured exclusively for a specific patient from the recipient's own cells. This does not close the door to further modifications with subsequent personalization and better adaptation to the individual needs. Bringing such a drug to market would involve raising the already high costs, so it is necessary to lower the existing ones. On the other hand, so‐called universal CAR‐T are also getting closer to the patient's bed, but its implementation may struggle with multiple challenges, including development of graft‐versus‐host disease (GvHD) and alloimmunity. However, that off‐the‐shelf therapy could prove useful as a quick solution for patients in very poor condition or excluded from current therapy due to manufacturing limitations. The introduction of currently tested solutions may undoubtedly change the current paradigm of treatment. [ABSTRACT FROM AUTHOR]

Mesenchymal stromal cells (MSCs) and chimeric antigen receptor (CAR)‐T cells are two core elements in cell therapy procedures. MSCs have significant immunomodulatory effects that alleviate inflammation in the tissue regeneration process, while administration of specific chemokines and adhesive molecules would primarily facilitate CAR‐T cell trafficking into solid tumors. Multiple parameters affect cell homing, including the recipient's age, the number of cell passages, proper cell culture, and the delivery method. In addition, several chemokines are involved in the tumor microenvironment, affecting the homing procedure. This review discusses parameters that improve the efficiency of cell homing and significant cell therapy challenges. Emerging comprehensive mechanistic strategies such as non‐systemic and systemic homing that revealed a significant role in cell therapy remodeling were also reviewed. Finally, the primary implications for the development of combination therapies that incorporate both MSCs and CAR‐T cells for cancer treatment were discussed. [ABSTRACT FROM AUTHOR]

Objectives: Multiple myeloma (MM) accounts for 10% of hematologic malignancies. However, most of the patients suffered from relapsed/refractory disease. We would like to expand CAR T cell therapy to treat MM using our current platform. Methods: BCMA CAR T lymphocytes were generated for volunteers or MM patients. The transduction efficiency was detected by the ddPCR technique. Immunophenotyping and exhaustion markers were monitored by flow cytometry. The efficacy of BCMA CAR T cells was tested using coculturing with BCMA CAR or mock, and the positive and negative targets, K562/hBCMA‐ECTM and K562, respectively. Results: BCMA CAR T cells were generated from consented volunteers or MM patients and could be detected CAR BCMA expression at a mean of 4.07 ± 1.95 or 4.65 ± 1.21 copies/cell, respectively. Those modified T cells were primarily effector memory T cells. Our BCMA CAR T cells could explicitly eradicate the K562/hBCMA‐ECTM cell line while the K562 cell line survived. Interestingly, the BCMA CAR, mock T cells, and peripheral blood mononuclear cells from MM patients expressed similar levels of the exhaustion makers, TIM‐3, LAG‐3, and PD1. Conclusions: Our BCMA CAR T cells, mainly effector/effector memory, could eliminate BCMA‐expressing cells in vitro and had similar levels of exhaustion markers among different populations. [ABSTRACT FROM AUTHOR]

Objectives: The treatment of refractory and recurrent acute myeloid leukaemia (AML) is still a challenge with poor response rates and short survival times. In an attempt to solve this problem, we constructed a tandem bispecific chimeric antigen receptor (CAR) targeting CD123 and C‐type lectin‐like molecule 1 (CLL‐1), two different AML antigens, and verified its cytotoxic effects in vitro. Methods: We established and cultured K562 cell lines expressing both CD123 and CLL1 antigens. Single‐target CAR‐T cells specific to CD123 and CLL1 were engineered, alongside tandem CD123/CLL1 bispecific CAR‐T cells. Flow cytometry was used to determine cell phenotypes, transfection efficiencies, cytokine release, and CAR‐T‐cell proliferation, and an lactate dehydrogenase assay was used to detect the cytotoxicity of CD123/CLL‐1 bispecific tandem CAR‐T cells in vitro. Results: Two types of tandem CAR‐T cells exhibited significant killing effects on CLL‐1 + CD123+ leukaemia cell lines and primary AML tumour cells. The killing efficiency of tandem CAR‐T cells in the case of single antigen expression is comparable to that of single target CAR‐T cells. When faced with dual target tumour cells, dual target CAR‐T cells significantly surpass single target CAR‐T cells. CD123/CLL‐1 CAR‐T cells in tandem targeted and killed CD123‐ and CLL‐1‐positive leukaemia cell lines and released a large number of cytokines. Conclusions: CD123/CLL‐1 CAR‐T cells in tandem can simultaneously target CD123 and CLL‐1 on AML cells, demonstrating a significant ability to kill single antigens and multi‐target tumour cells. This suggests that CD123/CLL‐1 CAR‐T cells exhibit significant advantages in the expression of multiple antigens in a wide range of target cells, which may help overcome the challenges posed by tumour heterogeneity and evasion mechanisms. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular events, including heart failure and arrhythmias, following chimeric antigen receptor (CAR) T‐cell therapy are increasingly recognized. Although global longitudinal strain (GLS) has demonstrated prognostic utility for other cancer therapy‐related cardiac dysfunction, less is known regarding the association of GLS with adverse cardiac events following CAR T‐cell therapy. Objectives: To determine the association of baseline GLS with adverse cardiovascular events in adults receiving CAR‐T cell therapy. Methods: Patients who had an echocardiogram within 6 months prior to receiving CAR T‐cell therapy were retrospectively identified. Clinical data and cardiac events were collected via chart review. Echocardiograms were analyzed offline for GLS, left ventricular ejection fraction, and Doppler parameters. Multivariable logistic regression was used to determine the association between adverse cardiovascular events and echocardiographic parameters. Results: Among 75 CAR T‐cell therapy patients (mean age 63.9, 34.7% female), nine patients (12%) experienced cardiac events (CEs) including cardiovascular death, new/worsening heart failure, and new/worsening arrhythmia within 1 year of treatment. In univariable models, higher baseline GLS (OR 0.78 [0.63, 0.96], p =.021) was associated with a lower risk of CE and higher baseline mitral E/e' (OR 1.40 [1.08, 1.81], p =.012) was associated with a higher risk of CE. After adjusting for age and LDH, higher baseline GLS (OR 0.65 [0.48–0.88], p = <.01) was associated with a lower risk of CE and higher baseline mitral E/e' (OR 1.56 [1.06, 2.29], p =.024) was associated with a higher risk of CE. Conclusion: Lower GLS and higher mitral E/e' on a baseline echocardiogram were associated with higher risk for CEs in patients receiving CAR T‐cell therapy. [ABSTRACT FROM AUTHOR]

Relapsed and refractory B‐cell acute lymphoblastic leukemia (B‐ALL) is an aggressive B‐cell neoplasm associated with poor outcomes. Conventional multiagent chemotherapy and bispecific antibody therapy may induce remission; however, relapse rates remain high and overall survival is poor. Chimeric antigen receptor T‐cell (CAR‐T) therapy provides durable, deep complete remission, and long‐term cures in relapsed and refractory B‐ALL. However, with this new treatment modality, 10%–30% of patients do not achieve remission, and over 50% experience relapse after therapy. Currently, there are two approved CD19‐specific CAR‐T cell constructs in B‐ALL, Tisagenlecleucel and Brexucabtagene Autoleucel by the United States Food and Drug Administration, and the European Medicines Agency (EMA). In this review, we discuss patients, disease, and CAR‐T predictors of outcomes in B‐ALL. We describe the two approved CD19‐directed CAR‐T cell products, review the current literature, and discuss factors associated with high risks of therapy failure and future direction in CAR‐T cell therapy for B‐ALL. [ABSTRACT FROM AUTHOR]

Background: Bone marrow (BM) assessment after CAR‐T cell immunotherapy infusion is not routinely performed to monitor adverse events such as cytopenias, hemophagocytic lymphohistiocytosis, or infections. Our institution has performed BM biopsies as part of CAR‐T cell treatment protocols, encompassing pre‐ and post‐treatment time points and during long‐term follow‐up. Methods: We conducted a systematic retrospective review of BM abnormalities observed in samples from 259 patients following CAR‐T cell immunotherapy. We correlated BM pathology findings with mortality, relapse/residual disease, and laboratory values. Results: At a median of 35.5 days post‐CAR‐T infusion, 25.5% showed severe marrow hypocellularity, and 6.2% showed serous atrophy, and peripheral blood cytopenias corroborated these observations. Marrow features associated with reduced disease burden post‐CAR‐T infusion include increased lymphocytes seen in 16 patients and an increase of macrophages or granulomatous response seen in 25 patients. However, a 100‐day landmark analysis also showed increased marrow histiocytes were associated with lower survival (median OS 6.0 vs. 21.4 months, p =.026), as was grade 2–3 marrow reticulin (18 patients) (median OS 12.5 vs. 24.2 months, p =.034). Conclusions: These data represent the first systematic observations of BM changes in patients receiving CAR‐T cell immunotherapy. [ABSTRACT FROM AUTHOR]

While cytokine release syndrome and immune effector cell‐associated neurotoxicity syndrome are well‐recognized acute toxicities of chimeric antigen receptor (CAR) T cell therapy, these complications have become increasingly manageable by protocolized treatment algorithms incorporating the early administration of tocilizumab and corticosteroids. As CAR‐T cell therapy expands to new disease indications and the number of long‐term survivors steadily increases, there is growing recognition of the need to appropriately evaluate and manage the late effects of CAR‐T cell therapy, including late‐onset or persistent neurotoxicity, prolonged cytopenias, delayed immune reconstitution and infections, subsequent malignancies, organ dysfunction, psychological distress, and fertility implications. In this review, we provide a practical approach to the long‐term survivorship care of the CAR‐T cell recipient, with a focus on the optimal strategies to address the common and challenging late complications affecting this unique population. [ABSTRACT FROM AUTHOR]

Objective: Chimeric antigen receptor (CAR) T‐cell therapy has transformed the treatment approach for pediatric patients suffering from relapsed/refractory B‐cell acute lymphoblastic leukemia (B‐ALL). However, there was a paucity of data on the challenges associated with second‐round CAR‐T therapy in this population. Methods: Medical records of nine pediatric patients who received second‐round CAR‐T therapy in a single center from June 2019 to May 2023 were analyzed. Throughout the course of the clinical trial, we evaluated adverse events including CRS, CRES, infections, hematologic toxicity, and organ injury, as well as CAR‐T responses. Results: Except for one patient who chose CART therapy due to testicular relapse, the remaining patients had indications for CAR‐T therapy due to relapse with bone marrow alone or combined with other site. There were no difference between the transfusion dose of CART1 and CART2. No differences of incidence and grade of CRS was found between the first‐round CAR‐T therapy (CART1) and second‐round CAR‐T therapy (CART2). Additionally, we found that the incidence of CRES was higher for CART1(3/9,33.3%) than CART2(1/9,11.1%). Our findings revealed that there were no differences of IL‐2, IL‐4, IL‐6, IL‐10, IFN‐γ, and TNF‐α between CART1 and CART2, but the peak level of IL‐17A was significantly higher in patients receiving CART1 compared to those receiving CART2 (p =.011). Early and late infection rates after CART1 were higher than CART2. Based on the dynamic changes of ANC, hemoglobin and platelet, ANC, and platelet were reduced obviously post CART. It seems that the incidences of severe thrombocytopenia and severe anemia were higher in the CART1 group compared to CART2. The MRD‐negative CR rates for CART1 and CART2 are 100% and 44.4%, respectively (p =.029). All patients experienced events (relapse, chemotherapy, transplantation, or death) after receiving CART2, including one died, three discharged automatically, and the remaining five patients survived. Conclusion: Although the remission rate of CART2 is not as high as the CART1 due to the severity of the disease, its safety regarding CRS, CRES, infections, and organ injury is still excellent. Therefore, CART2 remains a viable option for treating pediatric relapsed B‐ALL. [ABSTRACT FROM AUTHOR]

The introduction of chimeric antigen receptor (CAR) T cells revolutionized treatment of relapsed and refractory multiple myeloma (RRMM) in recent years. Currently, two CAR T cell products—idecabtagene vicleucel and ciltacabtagene autoleucel—are approved in the United States and the European Union to treat patients with three prior lines of therapy, including a proteasome inhibitor, an immunomodulatory drug, and an anti‐CD38 antibody. Moreover, seminal phase III trials of both agents in earlier lines of therapy have been published recently. Despite unprecedented rates of deep and lasting remissions in RRMM, there are still areas of uncertainty regarding the optimal use and distribution of CAR T cells in multiple myeloma. In the current review, we discuss the available data on approved CAR T cell products as well as unmet clinical needs and ongoing developments to optimize usage of this promising treatment modality in multiple myeloma. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T (CAR‐T) therapy has emerged as a revolutionary new pillar in cancer care, particularly in relapsed/refractory (r/r) B‐cell malignancies. Following impressive clinical outcomes in hematological malignancies, the FDA‐approved six CAR‐T cell products for indications such as lymphoma, leukemia, and myeloma. Despite the numerous advantages of CAR‐T cell treatment, several challenges exist that interfere with its therapeutic efficacy. Serious adverse effects connected with the treatment continue to be a major concern. In addition, poor persistence of therapeutics and antigen escape frequently result in tumor relapse. Exorbitant treatment cost further remains a significant barrier to its effective implementation, limiting its accessibility. This review presents progress of CAR‐T research, the key obstacles that hamper promising outcomes for patients with hematological malignancies, and a few strategies to overcome them. [ABSTRACT FROM AUTHOR]

The use of T cells expressing chimeric antigen receptors (CARs) that can target and eliminate cancer cells has revolutionized the treatment of B‐cell malignancies. In contrast, CAR T cells have not yet become a routine treatment for myeloid malignancies such as acute myeloid leukemia (AML) or myeloproliferative neoplasms (MPNs). For these disease entities, allogeneic hematopoietic cell transplantation (allo‐HCT) relying on polyclonal allo‐reactive T cells is still the major cellular immunotherapy used in clinical routine. Here, we discuss major hurdles of CAR T‐cell therapy for myeloid malignancies and novel approaches to enhance their efficacy and reduce toxicity. Heterogeneity of the malignant myeloid clone, CAR T‐cell induced toxicity against normal hematopoietic cells, lack of long‐term CAR T‐cell persistence, and loss or downregulation of targetable antigens on myeloid cells are obstacles for successful CAR T cells therapy against AML and MPNs. Strategies to overcome these hurdles include pharmacological interventions, for example, demethylating therapy to increase target antigen expression, multi‐targeted CAR T cells, and gene‐therapy based approaches that delete the CAR target antigen in the hematopoietic cells of the recipient to protect them from CAR‐induced myelotoxicity. Most of these approaches are still in preclinical testing but may reach the clinic in the coming years. In summary, we report on barriers to CAR T‐cell use against AML and novel therapeutic strategies to overcome these challenges, with the goal of clinical treatment of myeloid malignancies with CAR T cells. [ABSTRACT FROM AUTHOR]

Objectives: The treatment of relapsed/refractory (R/R) diffuse large B‐cell lymphoma (DLBCL) changed remarkably since the European Medicines Agency‐approved chimeric antigen receptor T‐cell (CAR‐T) therapies (axicabtagene ciloleucel [axi‐cel], lisocabtagene maraleucel [liso‐cel], tisagenlecleucel [tisa‐cel]) for the third‐line onwards (3+L), and targeted therapies (polatuzumab vedotin–bendamustine–rituximab [pola‐BR], tafasitamab–lenalidomide [Tafa‐L]) for the second‐line (2L) onwards. As associated rising treatment costs represent an economic burden, the cost‐effectiveness of transplant‐ineligible R/R DLBCL interventions was assessed from a German healthcare payer's perspective, using the efficiency frontier (EF) approach. Methods: A systematic literature review was performed to determine the clinical benefit concerning median overall survival (OS) of bendamustine–rituximab (BR), rituximab–gemcitabine–oxaliplatin (R‐GemOx), axi‐cel, liso‐cel, tisa‐cel, pola‐BR, and Tafa‐L. First‐year treatment costs (drug and medical services costs) were calculated. Results were merged on two‐dimensional graphs illustrating 2L and 3+L EFs. Results: Second‐line EF is formed by BR (median OS 11.49 months, €23 958) and Tafa‐L (45.7, €104 541), 3+L EF is formed by R‐GemOx (12.0, €29 080), Tafa‐L (15.5, €104 541), and axi‐cel (18.69, €308 516). These interventions build the respective cost‐effectiveness thresholds for novel interventions. Conclusions: Using the EF approach, the currently most cost‐effective interventions (based on cost‐effectiveness ratios) in the indication of R/R DLBCL were identified to guide international reimbursement decisions. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T‐cells (CAR‐T) are widely used for the treatment of relapsed/refractory diffuse large B cell lymphoma (DLBCL). The data for CAR‐T cell therapy in patients with extra‐nodal (EN) lymphoma is restricted. We included 126 consecutive patients with DLBCL treated with commercially available CAR‐T cells (tisagenlecleucel, n = 100, 79.4% and axicabtagene ciloleucel, n = 26, 20.6%). At lymphodepletion, 72 of 126 (57%) patients had EN disease, 42 of 126 (33%) patients had nodal disease (ND)‐only and 12 of 126 (10%) showed no disease assessed by PET‐CT. There were no significant differences in CAR‐T related toxicities and in the median Progression free survival (PFS) between EN patients and ND (10.76 [95% CI: 7.8–13.6] vs. 14.1 [95% CI: 10–18.1] months, p =.126). Similarly, median overall survival (OS) was not significantly different (15.36 [95% CI 12.5–18.2] vs. 18.4 [95% CI 14.8–22.1] months, p =.100). Subgroup analysis according to the number of EN involved sites showed that median PFS and OS were significantly higher in patients with <3 EN sites (12.3 months [95% CI 9–15.5] vs. 4.28 months [95% CI 0.6–7.9], p =.010) compared to patients with >2 EN sites, respectively (16.5 months [95% CI 13.4–19.6] vs. 8.7 months [95% CI 4.6–12.8], p =.05). In multivariate cox regression analysis, increased number sites of EN disease and high lactate dehydrogenase (LDH) at lymphodepletion negatively impacted PFS (p =.021 and <.001, respectively), while sex, type of product administered, age and performance status did not predict PFS and OS. Of note, all the patients with involvement of gastrointestinal tract (n = 9), urinary tract (n = 9), or pharynx (n = 3) at lymphodepletion, progressed or had an early relapse. In conclusions, patients with >2 EN sites at lymphodepletion have significantly worse clinical outcomes compared to patients with <3 EN sites. Patients with specific sites of EN disease may demonstrate grim prognosis. [ABSTRACT FROM AUTHOR]

We performed a phase I study of weekly selinexor, carfilzomib, and dexamethasone (wSKd) in patients with relapsed/refractory multiple myeloma (MM). The primary objective was to identify the maximum tolerated dose (MTD) of wSKd. Secondary endpoints included overall response rate (ORR), progression‐free survival (PFS), and overall survival (OS). Prior exposure/refractoriness to carfilzomib was permitted. Thirty patients were enrolled; 26 (87%) had triple‐class exposed disease and 6 (20%) received chimeric antigen receptor (CAR) T‐cell therapy. Dose level 2 (carfilzomib 70 mg/m2 Intravenous [IV] on Days 1, 8, and 15; selinexor 100 mg PO on Days 1, 8, 15, 22; dexamethasone 40 mg on Days 1, 8, 15, 22 of 28‐day cycles) was chosen as the MTD, with no DLTs having occurred. The most common hematologic adverse events (AE) were thrombocytopenia (83%), anemia (70%), lymphopenia (50%), and neutropenia (50%). The most common nonhematologic AE were fatigue (70%), nausea (70%), diarrhea (53%), and anorexia (47%). The ORR was 21/30 (70%) overall and 18/23 (78%) at the MTD. At a median follow‐up of 12.3 months, the median PFS was 5.3 months and median OS 23.3 months. Responses were similar in carfilzomib naïve and exposed patients. Long‐term efficacy of wSKd is modest; wSKd could be employed as a bridging strategy to immunotherapies. [ABSTRACT FROM AUTHOR]

Hematological malignancies represent defying clinical conditions, with high levels of morbidity and mortality, particularly considering patients who manifest multiple refractory diseases. Recently, chimeric antigen receptor (CAR)‐T cell therapy has emerged as a potential treatment option for relapsed/refractory B cell malignancies, which have motivated the Food and Drug Administration approval of a series of products based on this technique. The objective of this systematic review was to assess the efficacy and safety of CAR‐T cell therapy for patients with hematological malignancies. A comprehensive literature search was conducted in the electronic databases (CENTRAL, Embase, LILACS, and MEDLINE), clinical trials register platforms (Clinicaltrials.gov and WHO‐ICTRP), and grey literature (OpenGrey). The Cochrane Handbook for Reviews of Interventions was used for developing the review and the PRISMA Statement for manuscript reporting. The protocol was prospectively published in PROSPERO database (CRD42020181047). After the selection process, seven RCTs were included, three of which with available outcome results. The available results are from studies assessing axicabtagene, lisocabtagene, and tisagenlecleucel for patients with B cell lymphoma, and the certainty of evidence ranged from very low to low for survival and progression‐related outcome and for safety outcomes. Additionally, four randomized controlled trials comparing CAR‐T cell therapy to the standard treatment for various types of relapsed/refractory B cell non‐Hodgkin lymphomas and multiple myeloma included in this systematic review still did not have available outcome data. The results of this review may be used to guide clinical practice but evidence concerning the safety and efficacy of CAR‐T Cell therapy for hematological malignancies is still immature to recommend its application outside of clinical trials or compassionate use context for advanced and terminal cases. It is expected the results of the referred comparative studies will provide further elements to subsidize the broader application of this immunotherapy. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T (CAR-T) cell therapy has shown great success in treating certain types of hematological malignancies, such as B-cell acute lymphoblastic leukemia (ALL), large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and multiple myeloma. However, there are still challenges to overcome, including improving safety, reducing relapses, lowering costs, and addressing barriers in solid tumors. This special issue focuses on the management of CAR-T cell therapy, including apheresis, implementation, toxicities, and long-term survivorship care. The issue also explores optimizations of CAR-T design and biomarkers for predicting toxicities and detecting relapses. [Extracted from the article]

The characteristics of infections following chimeric antigen receptor T (CAR‐T) cells targeting CD19 in real‐word population are obscure. We analyzed infections' characteristics in the first month among consecutive patients with diffuse large B‐cell lymphoma (DLBCL) (n = 60, median age, 69.3 years), treated with commercial CAR‐T cells. ECOG performance status (PS) was 2‐3 in most patients (58%). Infections were observed in 45% of patients (16, 27%, bacterial infections, and 14, 23%, viral infections). Bacterial infection included clinically documented infection in 7 (Pneumonia, n = 5; periodontal infection, n = 1; and cellulitis, n = 1) and microbiology documented infection (MDI) in 9 patients (Gram‐negative rod, n = 5; Gram‐positive cocci, n = 3, bacteremia; polymicrobial, n = 1). The most common viral infection was cytomegalovirus (CMV) reactivation (n = 10, 17%) leading to initiation of anti‐CMV treatment in 6 (60%) among these patients. None had CMV disease. In univariate analysis, immune effector cell‐associated neurotoxicity syndrome (ICANS) was associated with higher incidence of bacterial infection (OR=4.5, P =.018), while there was a trend for lower incidence of bacterial infections in patients with chemosensitive disease to bridging therapy (OR=0.375, P =.074). Age or PS was not associated with increased risk of bacterial infection. Increase in C‐reactive protein (CRP) prior to fever onset was associated with microbiologically documented infections. We conclude that infections are common in the first month following CAR‐T‐cell administration, however, were not increased in elderly patients or those presenting with poorer PS. Increase in CRP prior to fever onset could support infection over cytokine release syndrome. [ABSTRACT FROM AUTHOR]

Progressive multifocal leukoencephalopathy (PML) is a life‐threatening infection of the central nervous system in immunocompromised patients, with an established predilection in non‐Hodgkin's lymphoma and stem cell transplant recipients. In the era of chimeric antigen receptor T‐cell therapy (CAR T‐cell), the occurrence of new‐onset neurological symptoms and encephalopathy in this patient population can be attributed to a variety of factors, including therapy‐related neurotoxicity or disease progression. PML has not been implicated as a common cause of encephalopathy in CAR T‐cell therapy recipients, and the identification of such rare infections is important to guide prognosis and treatment decisions. We hereby report the first case of late occurrence of PML, over one year after CAR T‐cell therapy, for a patient with relapsed large B‐cell lymphoma. [ABSTRACT FROM AUTHOR]

Introduction: In several studies, the chimeric antigen receptor T‐cell therapy tisagenlecleucel demonstrated encouraging rates of remission and lasting survival benefits in pediatric patients with relapsed/refractory (r/r) acute lymphoblastic leukemia (ALL). We assessed the cost‐effectiveness of tisagenlecleucel (list price: 320 000 EUR) among these patients when compared to clofarabine monotherapy (Clo‐M), clofarabine combination therapy (Clo‐C), and blinatumomab (Blina) from both a healthcare and a societal perspective. We also assessed future medical and future non‐medical consumption costs. Methods: A three‐state partitioned survival model was used to simulate a cohort of pediatric patients (12 years of age) through different disease states until the end of life (lifetime horizon). Relevant outcomes were life years, quality‐adjusted life years (QALYs), healthcare costs, societal costs, and the incremental cost‐effectiveness ratio (ICER). Uncertainty was explored through deterministic and probabilistic sensitivity analyses as well as through several scenario analyzes. Results: Total discounted costs for tisagenlecleucel were 552 679 EUR from a societal perspective, which was much higher than the total discounted costs from a healthcare perspective (ie, 409 563 EUR). Total discounted societal costs for the comparator regimens ranged between 160 803 EUR for Clo‐M and 267 259 EUR for Blina. Highest QALYs were estimated for tisagenlecleucel (11.26), followed by Blina (2.25), Clo‐C (1.70) and Clo‐M (0.74). Discounted societal ICERs of tisagenlecleucel ranged between 31 682 EUR/QALY for Blina and 37 531 EUR/QALY for Clo‐C and were considered cost‐effective with a willingness‐to‐pay (WTP) threshold of 80 000 EUR/QALY. None of the scenarios exceeded this threshold, and more than 98% of the iterations in the probabilistic sensitivity analysis were cost‐effective. Discussion: At the current price and WTP threshold, tisagenlecleucel is cost‐effective from both a healthcare and a societal perspective. Nevertheless, long‐term effectiveness data are needed to validate the several assumptions that were necessary for this model. [ABSTRACT FROM AUTHOR]

Introduction: Chimeric antigen receptor (CAR) T cells targeting B cell maturation antigen (BCMA) have shown impressive results in clinical studies for relapsed/refractory multiple myeloma (RRMM). We performed a systematic literature review to summarize the current body of evidence on the role of anti‐BCMA CAR T cells for RRMM. Objectives and Methods: Fifteen studies comprising a total of 285 patients with heavily pretreated RRMM were included using a conventional meta‐analysis. Main efficacy outcomes were response, relapse, and survival. Safety outcomes were cytokine release syndrome (CRS) and neurotoxicity. Results: Anti‐BCMA CAR T cells resulted in a pooled overall response of 82% (95% confidence interval [CI], 74%‐88%) and complete response of 36% (24%‐50%). Higher CAR+ cell doses were associated with higher response rates. The pooled relapse rate of responders was 45% (27%‐64%), and median progression‐free survival was 10 months. Present extramedullary disease did not show worse outcome. Severe CRS grades 3‐4 and neurotoxicity occurred in 15% (10%‐23%) and 18% (10%‐31%). Conclusion: Anti‐BCMA CAR T cells showed high response rates, even in patients with present extramedullary disease, while relapse occurred in half of the patients who achieved a response. Larger studies with longer follow‐up especially evaluating the association of response and survival are needed. [ABSTRACT FROM AUTHOR]

Low levels of peripheral blood natural killer T (NKT) cells in cancer patients and a favorable outcome associated with a high number of tumor‐infiltrating NKT cells demonstrated in several studies indicated the important role of these immune cells in the antitumor response. With effective antitumor immunity via direct tumor lysis, cytokine modulation of effector cells and regulation of immunosuppressive cells, type I NKT cells display interesting features/properties for the rapidly developing chimeric antigen receptor (CAR) technology. Due to their restriction to the monomorphic HLA‐like molecule CD1d, but not to the polymorphic human leukocyte antigen (HLA), NKT CAR cells show potential for enabling autologous and allogeneic/off‐the‐shelf cancer immunotherapy. Promising results were obtained in preclinical NKT CAR cell studies, but clinical trials have not yet been conducted. In this review, we summarize the biological features of NKT cells, their role in antitumor immunity and recent advances in the development of NKT CAR cells. [ABSTRACT FROM AUTHOR]