Immune Effector Cell-associated Neurotoxicity Syndrome Research Articles

Siltuximab for Chimeric Antigen Receptor T-Cell Therapy Related CRS and ICANS – A Multicenter Retrospective Analysis

Chimeric Antigen Receptor T-Cell therapies (CAR-T) are effective in many hematologic malignancies; however, adverse events including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) can affect a significant number of patients. Those who develop refractory CRS or ICANS have few treatment options. Siltuximab, a monoclonal antibody binding circulating IL-6, has been proposed to have clinical activity in both CRS and ICANS. We conducted a multi-center retrospective analysis of siltuximab treatment for CRS and ICANS following CAR-T cell therapy in a real-world cohort from six academic centers. Fifty-four patients were evaluated. Sixteen patients had CRS previously treated with tocilizumab and 17 patients had ICANS previously treated with steroids. Of the all the patients with CRS at the time of siltuximab, 75% had improvement in CRS grade. Of the all the patients with ICANS at the time of siltuximab, 60% had improvement in ICANS grade. To our knowledge, this is the largest cohort of patients treated with siltuximab for CRS and/or ICANS following CAR-T. Siltuximab appeared to be effective for both CRS and ICANS, including previously treated toxicities. These data support the use of siltuximab in CRS and ICANS as well as provide rationale for future prospective studies.

CD27-Armored BCMA CAR T Cell Therapy (CBG-002) for Relapsed and Refractory Multiple Myeloma: A Phase I Clinical Trial.

B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell therapy has been approved for the treatment of relapsed and refractory multiple myeloma (RRMM); however, whether patients have long-term response has yet to be established. We investigated the feasibility of CBG-002, an CD27-armored BCMA CAR T therapy, to improve clinical efficacy in patients with RRMM. We present preclinical data showing the activity of CBG-002 against myeloma and results from a phase I clinical trial (NCT04706936) evaluating its safety and efficacy in patients with RRMM. The primary endpoint was safety, as assessed by grade 3 or 4 adverse events(AEs). Key secondary endpoints were overall response rate (ORR), duration of response (DOR), progression-free survival (PFS) and overall survival (OS). A total of 11 patients were enrolled and received CBG-002 therapy. Nine patients developed grade 1 or 2 cytokine release syndrome (CRS), while no patients experienced grade 3 or higher CRS or immune effector cell-associated neurotoxicity syndrome. Other grade 3 or higher AEs included neutropenia (72.7%), thrombocytopenia (45.5%) and anemia (36.4%). At a median follow-up of 16.7 months, the ORR was 81.8%, including a stringent complete response/complete response rate of 45.5%, very good partial response rate of 18.2%, and partial response rate of 18.2%, with a median DOR of 8.9 (range 1.8-21.9) months. The median OS was not reached, and the median PFS was 8.5 (2.7-22.9) months. In this phase I study, CBG-002, a CD27-armored BCMA CAR T therapy, demonstrated safety and clinical efficacy in patients with RRMM.

Impact of Allogeneic Stem Cell Transplant on Safety and Outcomes of Chimeric Antigen Receptor T Cell (CAR-T) Therapy in Patients with Multiple Myeloma (MM).

Background: Allogeneic stem cell transplantation (allo-SCT) has seen limited use in treating multiple myeloma (MM), despite its potential to offer long-term survival or even cure through the graft-versus-myeloma effect. Its limited application is largely due to concerns over serious complications like infections and graft-versus-host disease (GVHD). The possibility of GVHD exacerbation when CAR-T cells are administered to patients previously treated with allo-SCT remains a topic of concern. Ciltacabtagene autoleucel (Cilta-cel) and idecabtagene vicleucel (Ide-cel) are CAR-T therapies that have been FDA-approved for relapsed/refractory (R/R) MM. A recent study using data from the CARTITUDE-1 trial has shown promising safety and efficacy of Cilta-Cel in patients with a prior history of allo-SCT. This report outlines our real-world experience with CAR-T treatment in such patients. The objective of this study is to assess the safety and effectiveness of CAR-T therapy in R/R MM patients who have previously undergone allo-SCT. Methods: We conducted a retrospective analysis of adult patients (18-70 years old) with R/R MM treated with CAR-T therapy as part of an institutional IRB-approved protocol. Data were collected on safety and efficacy outcomes from the institution's records. Adverse events (AEs) were evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded based on American Society for Transplantation and Cellular Therapy (ASTCT) criteria. Efficacy metrics included overall response rate (ORR) and progression-free survival (PFS), analyzed through the Kaplan-Meier method, with PFS defined as the time from CAR-T initiation to disease progression or death. Results: Of the 56 patients treated with CAR-T therapy, 8 (14.3%) had previously undergone allo-SCT. These patients had a median of seven prior therapy lines (LOTs), compared to five LOTs in the non-allo-SCT group (p = 0.04). CAR-T infusion occurred a median of 98.8 months after allo-SCT, with a range from 57.9 months to 178.5 months. CRS occurred in 87.5% of the allo-SCT group versus 77.1% in the non-allo-SCT group (p = 0.48). One patient in the allo-SCT group developed hemophagocytic lymphohistiocytosis (HLH), requiring anakinra. At a median follow-up of 4.8 months, the ORR was 87.5% in the allo-SCT group versus 75% in the non-allo-SCT group (p = 0.4). Median PFS had not been reached for the allo-SCT group at the time of analysis compared to 11.9 months in the non-allo-SCT group (p = 0.5). No treatment-related mortality or acute GVHD was noted in the allo-SCT cohort. Conclusions: The study suggests that prior allo-SCT does not adversely affect the safety or efficacy of CAR-T therapy in patients with R/R MM. These findings highlight the need for further investigations with larger patient samples and longer follow-up to better understand the interaction between allo-SCT and CAR-T therapy.

Extracorporeal cytokine adsorption as therapeutic option for immune effector cell-associated neurotoxicity syndrome.

With the rising number of patients receiving chimeric antigen receptor T-cells, the treatment of this therapy's complications is of growing concern to intensivists and neurologists. We used extracorporeal cytokine adsorption as an add-on therapy in a patient suffering from immune effector cell-associated neurotoxicity syndrome. Interleukin-6 level, which as a readily available parameter is generally used to evaluate course of disease, was rapidly reduced using this method. The patient made a full recovery and is still in hematological remission.

Outcomes After Brexucabtagene Autoleucel Administered as a Standard Therapy for Adults With Relapsed/Refractory B-Cell ALL.

On the basis of the results of the ZUMA-3 trial, brexucabtagene autoleucel (brexu-cel), a CD19-directed chimeric antigen receptor T-cell therapy, gained US Food and Drug Administration approval in October 2021 for adults with relapsed/refractory (R/R) B-cell ALL (B-ALL). We report outcomes of patients treated with brexu-cel as a standard therapy. We developed a collaboration across 31 US centers to study adults with B-ALL who received brexu-cel outside the context of a clinical trial. Data were collected retrospectively from October 2021 to October 2023. Toxicities were graded per American Society for Transplantation and Cellular Therapy guidelines for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). At the time of data lock, 204 patients had undergone apheresis and 189 were infused. Median follow-up time was 11.4 months. Forty-two percent of patients received brexu-cel in morphologic remission and would have been ineligible for participation in ZUMA-3. After brexu-cel, 151 achieved complete remission (CR), of which 79% were measurable residual disease (MRD) negative remissions. Median progression-free survival (PFS) was 9.5 months and median overall survival was not reached. Grade 3-4 CRS or ICANS occurred in 11% and 31%, respectively. In multivariable analysis, patients receiving consolidative hematopoietic cell transplantation (HCT; hazard ratio, 0.34 [95% CI, 0.14 to 0.85]) after brexu-cel had superior PFS compared with those who did not receive any consolidation or maintenance therapy. Similar to ZUMA-3, high rates of MRD-negative CR were observed after brexu-cel treatment for R/R B-ALL. The use of HCT as consolidation after brexu-cel resulted in improved PFS.

FDA Approval Summary: Teclistamab - A Bispecific CD3 T-cell Engager for Patients with Relapsed or Refractory Multiple Myeloma.

On October 25, 2022, the U.S. Food and Drug Administration (FDA) granted accelerated approval to teclistamab-cqyv (TECVAYLI; Janssen Biotech) for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody. Substantial evidence of effectiveness was obtained from the MajesTEC-1 trial, a phase 1/2, single-arm, open-label, multi-center study. Patients received step-up doses of teclistamab at 0.06 mg/kg and 0.3 mg/kg followed by 1.5 mg/kg subcutaneously once weekly until disease progression or unacceptable toxicity. An overall response rate of 61.8% was observed, with a complete response or better rate of 28.2%. Cytokine release syndrome (CRS) occurred in 72% of patients and neurologic toxicity (NT) occurred in 57%, including immune effector cell-associated neurotoxicity syndrome (ICANS) in 6%. Due to the risk of CRS and NT, including ICANS, the U.S. prescribing information for teclistamab includes a boxed warning and teclistamab is available only through a restricted program under a risk evaluation and mitigation strategy. Here, we summarize the data and FDA review supporting the accelerated approval of teclistamab, a BCMA-directed bispecific antibody that was the first bispecific CD3 T-cell engager approved for treatment of multiple myeloma.

Safety and efficacy of standard-of-care ciltacabtagene autoleucel for relapsed/refractory multiple myeloma

AbstractCiltacabtagene autoleucel (cilta-cel) chimeric antigen receptor (CAR) T-cell therapy was approved in 2022 for patients with relapsed/refractory multiple myeloma (RRMM). We report outcomes with cilta-cel in the standard-of-care setting. Patients with RRMM who underwent leukapheresis for cilta-cel manufacturing between 1 March 2022 and 31 December 2022 at 16 US academic medical centers were included. In terms of results, 255 patients underwent leukapheresis and 236 (92.5%) received cilta-cel. Of patients who underwent leukapheresis, 56% would not have met the CARTITUDE-1 trial eligibility criteria. Manufacturing failure rates at first attempt and overall were 6% and 1%, respectively. The median of prior lines of therapy was 6. In treated patients (n = 236), cytokine release syndrome was seen in 75% (grade ≥3, 5%), immune effector cell–associated neurotoxicity syndrome in 14% (grade ≥3, 4%), and delayed neurotoxicity in 10%. Best overall and complete response or better rates were as follows: for patients who received infusion (n = 236), 89% and 70%; patients receiving conforming CAR T-cell product (n = 191), 94% and 74%; and conforming CAR T-cell product with fludarabine/cyclophosphamide lymphodepletion (n = 152), 95% and 76%, respectively. Nonrelapse mortality was 10%, most commonly from infection. After a median follow-up of 13 months from CAR T-cell therapy, the median progression-free survival (PFS) was not reached, with the 12-month estimate being 68% (95% confidence interval, 62-74). High ferritin levels, high-risk cytogenetics, and extramedullary disease were independently associated with inferior PFS, with a signal for prior B-cell maturation antigen–targeted therapy (P = .08). Second primary malignancies excluding nonmelanoma skin cancers were seen in 5.5% and myeloid malignancies/acute leukemia in 1.7%. We observed a favorable efficacy profile of standard-of-care cilta-cel in RRMM, despite more than half the patients not meeting the CARTITUDE-1 eligibility criteria.

S100 as marker for immune effector cell-associated neurotoxicity syndrome.

Chimeric antigen receptor (CAR)-Tcell therapy is anew and successful treatment for otherwise refractory malignancies but despite the growing number of applications, this form of treatment is still associated with significant toxicity. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) in particular are common and dangerous side effects. This report is about two patients who received CAR‑T cell therapy and subsequently developed ICANS. This was successfully treated. During CAR‑T cell therapy, ablood marker, S100, was monitored daily. It correlated with the occurrence and progression of ICANS.

EASIX-guided risk stratification for complications and outcome after CAR T-cell therapy with ide-cel in relapsed/refractory multiple myeloma

BackgroundChimeric antigen receptor (CAR) T-cell therapy has demonstrated significant benefits in the treatment of relapsed/refractory multiple myeloma (RRMM). However, these outcomes can be compromised by severe complications, including cytokine release...

Safe and potent anti-CD19 CAR T-cells with shRNA-IL-6 gene silencing element in patients with refractory or relapsed B-cell acute lymphoblastic leukemia.

Severe cytokine release syndrome (sCRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) have limited the widespread use of chimeric antigen receptor T (CAR T)-cell therapy. We designed a novel anti-CD19 CAR (ssCART-19) with a small hairpin RNA (shRNA) element to silence the interleukin-6 (IL-6) gene, hypothesizing it could reduce sCRS and ICANS by alleviating monocyte activation and proinflammatory cytokine release. In a post hoc analysis of two clinical trials, we compared ssCART-19 with common CAR T-cells (cCART-19) in relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL). Among 87 patients, 47 received ssCART-19 and 40 received cCART-19. Grade ≥3 CRS occurred in 14.89% (7/47) of the ssCART-19 group versus 37.5% (15/40) in the cCART-19 group (p = 0.036). ICANS occurred in 4.26% (2/47) of the ssCART-19 group (all grade 1) compared to 15% (2/40) of the cCART-19 group. Patients in the ssCART-19 group showed comparable rates of treatment response (calculated with rates of complete remission and incomplete hematological recovery) were 91.49% (43/47) for ssCART-19 and 85% (34/40) for cCART-19 (p = 0.999). With a median follow-up of 21.9 months, cumulative nonrelapse mortality was 10.4% for ssCART-19 and 13.6% for cCART-19 (p = 0.33). Median overall survival was 37.17 months for ssCART-19 and 32.93 months for cCART-19 (p = 0.40). Median progression-free survival was 24.17 months for ssCART-19 and 9.33 months for cCART-19 (p = 0.23). These data support the safety and efficacy of ssCART-19 for r/r B-ALL, suggesting its potential as a promising therapy.

C-CAR066, a novel fully human anti-CD20 CAR-T therapy for relapsed or refractory large B-cell lymphoma after failure of anti-CD19 CAR-T therapy: A phase I clinical study.

Managing large B-cell lymphoma (LBCL) that is refractory to or relapsed after chimeric antigen receptor (CAR)-T therapy remains a significant challenge. Here we aimed to investigate the safety and efficacy of C-CAR066, an autologous fully human anti-CD20 specific CAR-T, for relapsed/refractory LBCL after failure of anti-CD19 CAR-T therapy. This first-in-human, single-arm, phase 1 study was conducted at two sites in China. Eligible patients had to be histologically confirmed with CD20-positive LBCL and must have received prior anti-CD19 CAR-T therapy. Patients received a single intravenous infusion of C-CAR066 at a target dose of 2.0 × 106 or 3.0 × 106 CAR-T cells/kg. The primary endpoint was the incidence of adverse events (AEs). As of October 10, 2023, 14 patients had received C-CAR066. The most common AEs of Grade 3 or higher were hematological toxicities. Cytokine release syndrome occurred in 12 (85.7%) patients, with only one was Grade 4 event. No patient experienced immune effector cell-associated neurotoxicity syndrome events. The overall response rate was 92.9% with a complete response rate of 57.1%. With a median follow-up of 27.7 months (range, 3.3-40.9), the median progression-free survival and overall survival were 9.4 months (95% CI, 2.0 to NA) and 34.8 months (95% CI, 7.5 to NA), respectively. C-CAR066 demonstrated a manageable safety profile and promising efficacy in patients in whom prior anti-CD19 CAR-T therapies had failed, providing a promising treatment option for those patients. This trial was registered with ClinicalTrials.gov, NCT04316624 and NCT04036019.

EASIX and m-EASIX predict CRS and ICANS in pediatric and AYA patients after CD19-CAR T-cell therapy

AbstractCytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) are complications of CD19-directed chimeric antigen receptor (CD19-CAR) T-cell therapy. The Endothelial Activation and Stress Index (EASIX) and modified EASIX (m-EASIX) scores have been retrospectively proven to be predictive of CRS and ICANS in adult CAR T-cell recipients. However, these scores have not been evaluated in pediatric cohorts. We retrospectively report on 76 pediatric and adolescent and young adult (AYA) patients with relapsed/refractory B-cell acute lymphoblastic leukemia treated with CD19-CAR T cells at St. Jude Children’s Research Hospital or John’s Hopkins Hospital. Data included patient, disease, and treatment characteristics. EASIX and m-EASIX scores were calculated at days –5 before, 0, and +3 after CAR T-cell infusion. CRS and ICANS occurred in 47 and 17 patients, respectively. At all evaluated time points, the median EASIX scores were higher for patients who developed severe CRS and any grade ICANS, and the median m-EASIX scores were higher in patients who developed severe CRS and severe ICANS than those with no/mild CRS/ICANS. Receiver operating characteristic curve analysis showed that both scores were strong predictors of CRS, especially severe CRS, at all time points. Any grade and severe ICANS were best predicted by both scores at day +3. m-EASIX uniformly outperformed EASIX, except for predicting any grade ICANS. Our results validate the potential utility of EASIX and m-EASIX scores for predicting CAR T-cell–related complications for pediatric and AYA patients.

Advancement and Challenges in Monitoring of CAR-T Cell Therapy: A Comprehensive Review of Parameters and Markers in Hematological Malignancies.

Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment for relapsed/refractory B-cell lymphomas. Despite its success, this therapy is accompanied by a significant frequency of adverse events, including cytokine release syndrome (CRS), immune-effector-cell-associated neurotoxicity syndrome (ICANS), or cytopenias, reaching even up to 80% of patients following CAR-T cell therapy. CRS results from the uncontrolled overproduction of proinflammatory cytokines, which leads to symptoms such as fever, headache, hypoxia, or neurological complications. CAR-T cell detection is possible by the use of flow cytometry (FC) or quantitative polymerase chain reaction (qPCR) assays, the two primary techniques used for CAR-T evaluation in peripheral blood, bone marrow (BM), and cerebrospinal fluid (CSF). State-of-the-art imaging technologies play a crucial role in monitoring the distribution and persistence of CAR-T cells in clinical trials. Still, they can also be extended with the use of FC and digital PCR (dPCR). Monitoring the changes in cell populations during disease progression and treatment gives an important insight into how the response to CAR-T cell therapy develops on a cellular level. It can help improve the therapeutic design and optimize CAR-T cell therapy to make it more precise and personalized, which is crucial to overcoming the problem of tumor relapse.

Earlier intrathecal dexamethasone effectively alleviate immune effector cell-associated neurotoxicity syndrome

Chimeric antigen receptor T cell (CAR-T) therapy is effective in treating relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL). However, the side effects of immune effector cell-associated neurotoxicity syndrome (ICANS) remain a problem. The current frontline therapies for ICANS include steroids and supportive care. For the steroid-refractory and severe ICANS, several studies have reported excellent efficacy of intrathecal (IT) corticosteroids alone or in combination with chemotherapy. However, whether patients can benefit from IT dexamethasone (dex) before grade 3 or refractory ICANS remains unclear. In this study, the patients with ICANS (≥1) after CAR-T cell therapy were assigned to the IT group and non-IT group. Clinical information, laboratory parameters, and serum cytokine levels were analyzed. A significant and rapid reduction in inflammatory cytokines and biomarkers was observed after 24 h of IT dex treatment. With IT dex, 83.3 % (15/18) of patients recovered from neurotoxicity. Moreover, this option significantly shortens the recovery time of ICANS without affecting the efficacy of CAR-T cell therapy. Earlier initiation of IT dex is the optimal management of ICANS resulting from CAR-T cell therapy, but larger sample studies are needed to determine its efficacy in these settings.

A Cost-Effectiveness Analysis of Axicabtagene Ciloleucel versus Tisagenlecleucel in the Treatment of Diffuse Large B-cell Lymphoma Based on a Real-World French Registry.

Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are chimeric antigen receptor T-cell therapies that were evaluated in third and later line (3L+) relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) in the ZUMA-1 and JULIET trials, respectively. As of October 2021, the DESCAR-T registry included 729 French patients with 3L+r/r DLBCL who received axi-cel or tisa-cel. Using these data, propensity score matching was used to conduct an adjusted comparison between axi-cel and tisa-cel. Axi-cel was associated with statistically significant improvements in overall survival (OS) and progression-free survival (PFS), and significantly more frequent Grade≥3 immune effector cell-associated neurotoxicity syndrome (ICANS), compared with tisa-cel. There was no significant difference in Grade≥3 cytokine release syndrome (CRS). The current analysis assessed the cost-effectiveness of axi-cel versus tisa-cel in the treatment of 3L+r/r DLBCL using propensity score-matched data from the DESCAR-T registry. A partitioned survival model was used to extrapolate costs and quality-adjusted life years (QALYs) over a lifetime. Survival curves for PFS and OS were based on independent mixture cure models fitted to digitized Kaplan-Meier data for the propensity score-matched DESCAR-T populations. Average duration of intensive care unit stays for each of axi-cel and tisa-cel in DESCAR-T were used to inform adverse event costs. Selected parametric survival distributions were based on clinical expert validation. Utility values were derived from ZUMA-1, and costs were obtained from French registries and published sources. List prices were used for both axi-cel and tisa-cel. Costs and outcomes were discounted at an annual rate of 2.5%. Axi-cel is associated with an incremental cost-effectiveness ratio of €15,520 per QALY compared with tisa-cel. Based on explicit willingness-to-pay thresholds applied in Europe, axi-cel is expected to be a cost-effective use of healthcare resources in real-world clinical settings compared with tisa-cel in 3L+r/r DLBCL.

Overcoming Antigen Escape and T-Cell Exhaustion in CAR-T Therapy for Leukemia.

Leukemia is a prevalent pediatric cancer with significant challenges, particularly in relapsed or refractory cases. Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a personalized cancer treatment, modifying patients' T cells to target and destroy resistant cancer cells. This study reviews the current therapeutic options of CAR-T therapy for leukemia, addressing the primary obstacles such as antigen escape and T-cell exhaustion. We explore dual-targeting strategies and their potential to improve treatment outcomes by preventing the loss of target antigens. Additionally, we examine the mechanisms of T-cell exhaustion and strategies to enhance CAR-T persistence and effectiveness. Despite remarkable clinical successes, CAR-T therapy poses risks such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Our findings highlight the need for ongoing research to optimize CAR-T applications, reduce toxicities, and extend this innovative therapy to a broader range of hematologic malignancies. This comprehensive review aims to provide valuable insights for improving leukemia treatment and advancing the field of cancer immunotherapy.

Statins in Mitigating Anticancer Treatment-Related Cardiovascular Disease.

Certain anticancer therapies inevitably increase the risk of cardiovascular events, now the second leading cause of death among cancer patients. This underscores the critical need for developing effective drugs or regimens for cardiovascular protection. Statins possess properties such as antioxidative stress, anti-inflammatory effects, antifibrotic activity, endothelial protection, and immune modulation. These pathological processes are central to the cardiotoxicity associated with anticancer treatment. There is prospective clinical evidence confirming the protective role of statins in chemotherapy-induced cardiotoxicity. Numerous preclinical studies have demonstrated that statins can ameliorate heart and endothelial damage caused by radiotherapy, although clinical studies are scarce. In the animal models of trastuzumab-induced cardiomyopathy, statins provide protection through anti-inflammatory, antioxidant, and antifibrotic mechanisms. In animal and cell models, statins can mitigate inflammation, endothelial damage, and cardiac injury induced by immune checkpoint inhibitors. Chimeric antigen receptor (CAR)-T cell therapy-induced cardiotoxicity and immune effector cell-associated neurotoxicity syndrome are associated with uncontrolled inflammation and immune activation. Due to their anti-inflammatory and immunomodulatory effects, statins have been used to manage CAR-T cell therapy-induced immune effector cell-associated neurotoxicity syndrome in a clinical trial. However, direct evidence proving that statins can mitigate CAR-T cell therapy-induced cardiotoxicity is still lacking. This review summarizes the possible mechanisms of anticancer therapy-induced cardiotoxicity and the potential mechanisms by which statins may reduce related cardiac damage. We also discuss the current status of research on the protective effect of statins in anticancer treatment-related cardiovascular disease and provide directions for future research. Additionally, we propose further studies on using statins for the prevention of cardiovascular disease in anticancer treatment.

Nanotechnology in Advancing Chimeric Antigen Receptor T Cell Therapy for Cancer Treatment.

Chimeric antigen receptor (CAR) T cell therapy has emerged as a groundbreaking treatment for hematological cancers, yet it faces significant hurdles, particularly regarding its efficacy in solid tumors and concerning associated adverse effects. This review provides a comprehensive analysis of the advancements and ongoing challenges in CAR-T therapy. We highlight the transformative potential of nanotechnology in enhancing CAR-T therapy by improving targeting precision, modulating the immune-suppressive tumor microenvironment, and overcoming physical barriers. Nanotechnology facilitates efficient CAR gene delivery into T cells, boosting transfection efficiency and potentially reducing therapy costs. Moreover, nanotechnology offers innovative solutions to mitigate cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Cutting-edge nanotechnology platforms for real-time monitoring of CAR-T cell activity and cytokine release are also discussed. By integrating these advancements, we aim to provide valuable insights and pave the way for the next generation of CAR-T cell therapies to overcome current limitations and enhance therapeutic outcomes.

B - 105 ICANS, CAR-T, and Cognition: a Case Study

Abstract Objective Immune effector cell-associated neurotoxicity syndrome (ICANS), an autoimmune delirious condition, affects 37.5% to 77% of individuals during or after chimeric antigen receptor T-cell (CAR-T) treatment for hematologic cancers (Grant et al., 2022). Initial clinical response varies widely but may include apraxia, aphasia, disorientation, and hallucinations (Möhn et al., 2022). Recent research indicates complete symptom resolution in most patients a month post-ICANS onset (Sales et al., 2023). However, a self-report study suggested more than 1 in 3 report persisting cognitive sequelae 1–5 years post-ICANS onset (Rurak et al., 2020). This discrepancy may be due to subtle changes missed by the Montreal Cognitive Objective Assessment (Sales et al., 2023; Möhn et al., 2022). The current case report investigates neurobehavioral outcome post-ICANS via comprehensive neuropsychological assessment. Method Two weeks post-CAR-T therapy, a 53-year-old male exhibited abrupt onset facial palsy and cognitive slowing prompting hospitalization. His wife reported new-onset apathy, atypical behaviors exacerbation (e.g., licking plate), and cognitive lapses (e.g., short-term memory, slowing, repeating questions) with little insight. Neuroimaging revealed supratentorial white matter hyperintensities plus calvarium and R skull base enhancing lesion regression. Results Neuropsychological assessment 10-months post-ICANS revealed subtle executive inefficiencies with family reports of improved yet ongoing social disinhibition and apathy. Conclusions This is the first comprehensive neuropsychological assessment of a patient who developed ICANS post-CAR-T therapy. Neuropsychologists should be aware of delayed cognitive sequelae possibility of this advancing treatment option. Future studies will be useful for patient/family preparation.

Targeting cytokine networks in neuroinflammatory diseases.

In neuroinflammatory diseases, systemic (blood-borne) leukocytes invade the central nervous system (CNS) and lead to tissue damage. A causal relationship between neuroinflammatory diseases and dysregulated cytokine networks is well established across several preclinical models. Cytokine dysregulation is also observed as an inadvertent effect of cancer immunotherapy, where it often leads to neuroinflammation. Neuroinflammatory diseases can be separated into those in which a pathogen is at the centre of the immune response and those of largely unknown aetiology. Here, we discuss the pathophysiology, cytokine networks and therapeutic landscape of 'sterile' neuroinflammatory diseases such as multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), neurosarcoidosis and immune effector cell-associated neurotoxicity syndrome (ICANS) triggered by cancer immunotherapy. Despite successes in targeting cytokine networks in preclinical models of neuroinflammation, the clinical translation of targeting cytokines and their receptors has shown mixed and often paradoxical responses.