Immune Effector Cell-associated Neurotoxicity Syndrome Research Articles

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.

Metabolic Tumor Volume Response after Bridging Therapy Determines Chimeric Antigen Receptor T-Cell Outcomes in Large B-Cell Lymphoma.

Greater disease burden is a well-established predictor of poorer outcomes following chimeric antigen receptor T-cell (CAR T) therapy. Although bridging therapy (BT) is widely used between leukapheresis and CAR T infusion, limited data have evaluated the impact of BT on CAR T outcomes. In this study, we hypothesized that the quantitative dynamics of radiomic cytoreduction during bridging are prognostic. Patients with large B-cell lymphoma treated with CD19-CAR T from 2016 to 2022 were included in the study. Metabolic tumor volume (MTV) was determined for all patients on pre-leukapheresis PET and on post-BT/pre-infusion PET in those who received BT. Patients were stratified into "High" and "Low" disease burden using an MTV cutpoint of 65.4cc established by maximally selected log-rank statistic for progression-free survival (PFS). Of 191 patients treated with CAR T, 144 (75%) received BT. In the BT cohort, 56% had a reduction in MTV post-BT. On multivariate analysis, the MTV trajectory across the bridging period remained significantly associated with PFS (P < 0.001); however, notably, patients with improved MTV (High->Low) had equivalent PFS compared with those with initially and persistently low MTV (Low->Low; HR for High->Low MTV: 2.74; 95% confidence interval, 0.82-9.18). There was a reduction in any grade immune effector cell-associated neurotoxicity syndrome in the High->Low MTV cohort as compared with the High->High MTV cohort (13% vs. 41%; P = 0.05). This is the first study to use radiomics to quantify disease burden pre- and post-BT in a large real-world large B-cell lymphoma cohort. We demonstrate that effective BT can enable initially high-disease burden patients to achieve post-CAR T outcomes comparable with low-disease burden patients.

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.

Safety and Efficacy of Bispecific Antibodies in Adults with Large B-Cell Lymphomas: A Systematic Review of Clinical Trial Data.

Bispecific antibodies (bsAbs) are an emerging therapy in the treatment of large B-cell lymphomas (LBCLs). There is a gap in the research on the safety and efficacy of bsAbs in adults with LBCL, with current research focusing on the wider non-Hodgkin's lymphoma population. To address this research gap, we conducted a systematic review aiming to evaluate the safety and efficacy outcomes of bsAbs in adults with LBCL. A systematized search was conducted in PubMed, EMBASE, and CENTRAL on 10 April 2024. Interventional clinical trials were eligible for inclusion. Observational studies, reviews, and meta-analyses were excluded. According to the Revised Risk of Bias Assessment Tool for Nonrandomized Studies, the included studies were largely of a high quality for safety outcome reporting, but of mixed quality for efficacy outcome reporting. Due to the heterogeneity of the included studies, the results were discussed as a narrative synthesis. Nineteen early phase studies were evaluated in the final analysis, with a pooled sample size of 1332 patients. Nine bsAbs were investigated across the studies as monotherapy (nine studies) or in combination regimes (10 studies). The rates of cytokine release syndrome were variable, with any grade events ranging from 0 to 72.2%. Infection rates were consistently high across the reporting studies (38-60%). Cytopenias were found to be common, in particular, anemia (4.4-62%), thrombocytopenia (3.3-69%), and neutropenia (4.4-70%). Immune effector cell-associated neurotoxicity syndrome (ICANS) and grade ≥3 adverse events were not commonly reported. Promising efficacy outcomes were reported, with median overall response rates of 95-100% in the front-line and 36-91% in terms of relapsed/refractory disease. The results of this systematic review demonstrate that bsAbs are generally well-tolerated and effective in adults with LBCL. BsAbs appear to have superior tolerability, but inferior efficacy to CAR T-cell therapies in adults with LBCL. Future research on safety and efficacy should focus on evaluating adverse event timing and management, the impact on the patient's quality of life, the burden on the healthcare system, and overall survival outcomes.

Fratricide-resistant CD7-CAR T cells in T-ALL.

T cell acute lymphoblastic leukemia (T-ALL) is difficult to treat when it relapses after therapy or is chemoresistant; the prognosis of patients with relapsed or refractory T-ALL is generally poor. We report a case series of 17 such patients who received autologous chimeric antigen receptor (CAR) T cells expressing an anti-CD7 CAR and an anti-CD7 protein expression blocker (PEBL), which prevented CAR T cell fratricide. Despite high leukemic burden and low CAR T cell dosing, 16 of the 17 patients attained minimal residual disease-negative complete remission within 1 month. The remaining patient had CD7- T-ALL cells before infusion, which persisted after infusion. Toxicities were mild: cytokine release syndrome grade 1 in ten patients and grade 2 in three patients; immune effector cell-associated neurotoxicity syndrome grade 1 in two patients. Eleven patients remained relapse-free (median follow-up, 15 months), including all nine patients who received an allotransplant. The first patient is in remission 55 months after infusion without further chemotherapy or transplantation; circulating CAR T cells were detectable for 2 years. T cells regenerating after lymphodepletion lacked CD7 expression, were polyclonal and responded to SARS-CoV-2 vaccination; CD7+ immune cells reemerged concomitantly with CAR T cell disappearance. In conclusion, autologous anti-CD7 PEBL-CAR T cells have powerful antileukemic activity and are potentially an effective option for the treatment of T-ALL.

Real-World Insights into CAR T-Cell Therapy: Efficacy and Safety of Kymriah in B-ALL and NHL

Background: Chimeric Antigen Receptor (CAR) T-cell therapy has emerged as a revolutionary treatment for certain cancers, particularly B-cell malignancies. This study focused on the real-world outcomes of Kymriah (tisagenlecleucel), a CAR T-cell therapy targeting CD19, by analyzing data from the Cellular Immunotherapy Data Resource (CIDR). A total of 410 patients with relapsed or refractory B-cell Acute Lymphoblastic Leukemia (B-ALL) and Non-Hodgkin Lymphoma (NHL) were included. Methods: Data were collected from 73 treatment centers across the U.S. and Canada. Key outcomes measured included Cytokine Release Syndrome (CRS), Immune-effector Cell-Associated Neurotoxicity Syndrome (ICANS), overall response rate (ORR), duration of response (DOR), and survival rates. Statistical analyses were performed using descriptive statistics, Kaplan-Meier methods, and logistic regression. Results: CRS was observed in 54.3% of B-ALL patients, with severe cases in 16.1%. The complete remission rate in B-ALL patients was 85.5%, with a 12-month overall survival rate of 76.4%. In NHL patients, the overall response rate was 62.4%, with 38.2% achieving complete remission. Severe CRS and ICANS were less frequent in NHL patients. Conclusion: Kymriah demonstrated high efficacy in both B-ALL and NHL, with manageable side effects. However, ongoing monitoring is essential to optimize outcomes and reduce adverse events. This study provides valuable real-world data, contributing to the growing understanding of CAR T-cell therapy’s potential in clinical practice.

Point of care CD19 chimeric antigen receptor (CAR) T-cells for relapsed/refractory acute myeloid leukemia (AML) with aberrant CD19 antigen expression

Relapsed/refractory (r/r) acute myeloid leukemia (AML) is associated with poor prognosis. CD19 is a B-cell marker, is aberrantly expressed in AML, mostly with t(8; 21)(q22; q22.1). Here we report the results of a phase 2 study giving point of care produced CD19 CAR T- cells for r/r AML with aberrant expression of CD19 (NCT04257175). Lymphodepletion included fludarabine and cyclophosphamide The response was evaluated by bone marrow (BM) aspiration on day 28. Six patients (5 adults and 1 child) were included. Median number of previous chemotherapy lines was 4 (range, 3–8) and four patients received CAR T-cells 8–18 months post allogeneic hematopoietic stem cell transplantation (allo-HSCT). Cytokine release syndrome (CRS) of any grade occurred in all patients, and 1 patient had grade 3 CRS. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 2 patients at low grades. Tocilizumab was administered to 2 patients and corticosteroids to 3 patients. Four patients achieved a complete remission (CR), while 2/6 progressed (PD). Three patients (2 with CR and 1 with PD) underwent allo-HSCT (it was the second transplant in 2) 2–5 months post CAR T-cells infusion. The median duration of response in patients achieving CR was 8.5 (range; 3–14) months. However, all patients eventually died within 5 (1–18) months.In conclusion, CD19 CAR T- cell treatment for AML is feasible and safe. However, the response is short and should be followed by allo-HSCT. Hopefully, future long term results will be improved by combining the CAR T- cell therapy with the emerging novel effective anti-leukemic compounds.

Case study of CD19 CAR T therapy in a subject with immune-mediate necrotizing myopathy treated in the RESET-Myositis phase I/II trial

Under compassionate use, chimeric antigen receptor (CAR) T-cells have elicited durable remissions in patients with refractory idiopathic inflammatory myopathies (IIM)1. Here, we report on the safety, efficacy, and correlative data of the first subject with the immune-mediated necrotizing myopathy (IMNM) subtype of IIM who received a fully human, 4-1BBz anti-CD19-CAR T-cell therapy (CABA-201) in the RESET-Myositis™ phase I/II trial (NCT06154252). CABA-201 was well-tolerated following infusion. Notably, no evidence of cytokine release syndrome (CRS) or immune effector-cell associated neurotoxicity syndrome (ICANS) was observed. CK levels decreased, and muscular strength improved post-infusion. Peripheral B-cells were depleted rapidly following infusion, and the subject achieved peripheral B-cell aplasia by day 15 post-infusion. Peripheral B-cells returned at 2 months post-infusion and were almost entirely transitional. Autoantibodies to SRP-9, SRP-72, SRP-54, and Ro-52, decreased relative to baseline whereas antibodies associated with pathogens and vaccinations remained stable. The infusion product consisted of predominantly CD4+ effector memory T-cells & exhibited in vitro cytolytic activity. Post-infusion, CABA-201 expansion peaked at day 15 and was preceded by a serum IFN-γ peak on day 8 with peaks in serum IL-12p40 and IP-10 on day 15. These data detail the safety, efficacy, and pharmacodynamics of CABA-201 in the first IMNM subject.

Targeting GPRC5D With Talquetamab: A New Frontier in Bispecific Antibody Therapy for Relapsed/Refractory Multiple Myeloma.

To evaluate the pharmacology, clinical efficacy, safety, dosing, administration, and clinical implications of talquetamab-tgvs, a novel bispecific antibody, in the treatment of relapsed or refractory (R/R) multiple myeloma (MM). A comprehensive English-language literature search of PubMed and Clinicaltrials.gov from January 2000 to May 2024 was conducted using the terms talquetamab, Talvey, JNJ-64407564, and "Multiple Myeloma." Relevant clinical trials, guidelines, and prescribing information were systematically reviewed and analyzed. Talquetamab-tgvs received accelerated approval from the United States Food and Drug Administration based on results from the pivotal phase I/II MonumenTAL-1 clinical trial, which demonstrated an overall response rate of nearly 74% in key cohorts. The median progression-free survival was 7.5 months in the 0.4 mg/kg weekly dosing cohort and 11.9 months in the 0.8 mg/kg biweekly dosing cohort. Treatment-related adverse events (AEs) included cytokine release syndrome, skin- and nail-related AEs, dysgeusia, infections, and immune effector cell-associated neurotoxicity syndrome. As a first-in-class anti-GPRC5D T-cell-redirecting bispecific antibody, talquetamab-tgvs represents a compelling treatment option for patients with R/R MM who have received at least 4 prior lines of therapy. No head-to-head clinical trials have been conducted comparing talquetamab-tgvs to other T-cell-redirecting therapies. While talquetamab-tgvs showed significant efficacy in the pivotal MonumenTAL-1 trial, long-term safety and efficacy data are needed. Additional clinical trials are necessary to establish the optimal timing, sequencing, patient population, and overall role of talquetamab-tgvs in the rapidly evolving treatment landscape of R/R MM.