Immune Effector Cell-associated Neurotoxicity Syndrome Research Articles

CAR T-cell therapy to treat multiple myeloma: current state and future directions.

Chimeric antigen receptor (CAR) T-cell therapy represents a transformative advancement in treating relapsed or refractory multiple myeloma (MM) in both early- and late-line settings. MM, a plasma cell malignancy, traditionally requires ongoing complex drug regimens, posing significant burdens on patients. In contrast, CAR T-cell therapy offers a one-time treatment option without the need for continuous maintenance therapy. CAR T-cell therapy leverages engineered T-cells to target specific antigens on tumor cells, leading to their elimination. Current approved therapies target B-cell maturation antigen (BCMA); new targets are under investigation, such as G-protein-coupled receptor class C group 5 member D (GPRC5D). Despite its efficacy, CAR T-cell therapy is associated with serious toxicities such as cytokine release syndrome (CRS) and immune-effector cell-associated neurotoxicity syndrome (ICANS), necessitating careful management. The review will provide an overview of the design and manufacturing of CAR T-cells and current FDA indications, as well as challenges and future directions of CAR-T therapy for MM treatment.

Severe Immune Effector Cell-Associated Neurotoxicity Syndrome in a Patient With Multiple Myeloma Treated With Elranatamab

Severe Immune Effector Cell-Associated Neurotoxicity Syndrome in a Patient With Multiple Myeloma Treated With Elranatamab

CAR-T Cells for the Treatment of Central Nervous System Tumours: Known and Emerging Neurotoxicities

The advent of chimeric antigen receptor (CAR)-T cells has recently changed the prognosis of relapsing/refractory diffuse large B-cell lymphomas, showing response rates as high as 60 to 80%. Common toxicities reported in the pivotal clinical trials include the cytokine release syndrome (CRS) and the Immune effector Cell-Associated Neurotoxicity Syndrome (ICANS), a stereotyped encephalopathy related to myeloid cell activation and blood–brain barrier dysfunction, presenting with a distinctive cascade of dysgraphia, aphasia, disorientation, attention deficits, vigilance impairment, motor symptoms, seizures, and diffuse brain oedema. The tremendous oncological efficacy of CAR-T cells observed in systemic B-cell malignancies is leading to their growing use in patients with primary or secondary central nervous system (CNS) lymphomas and in patients with solid tumours, including several CNS cancers. Early studies conducted in adult and paediatric patients with solid CNS tumours reported a distinct profile of neurotoxicity referred to as Tumour inflammation-associated neurotoxicity (TIAN), corresponding to local inflammation at the tumour site manifesting with focal neurological deficits or mechanical complications (e.g., obstructive hydrocephalus). The present review summarises available data on the efficacy and safety of CAR-T cells for solid and haematological CNS malignancies, emphasising known and emerging phenotypes, ongoing challenges, and future perspectives.

A Phase 1/2 study of teclistamab, a humanized BCMA × CD3 bispecific Ab in Japanese patients with relapsed/refractory MM.

We characterized the safety and efficacy of the bispecific antibody teclistamab in Japanese patients with relapsed/refractory multiple myeloma (RRMM). Patients were pretreated with a proteasome inhibitor (PI), immunomodulatory drug (IMiD), and anti-CD38 monoclonal antibody (mAb). The primary endpoint was frequency and type of treatment-emergent adverse events (TEAEs) in phase 1, and overall response rate (ORR; ≥ partial response [PR]) in phase 2. In phase 1, 14 patients received once-weekly (QW) subcutaneous teclistamab (0.72mg/kg [n = 5]; 1.5mg/kg [n = 5]; 3mg/kg [n = 4]). No dose-limiting toxicities were observed. As of April 2024, 26 phase-2 patients received the recommended phase-2 dose (QW) (RP2D: 1.5mg/kg) of teclistamab. Biweekly (Q2W) dosing was allowed after maintaining response for ≥ 6months. At a median follow-up of 14.32months, ORR was 76.9% (≥ very good PR: 76.9%; ≥ complete response: 65.4%). Median duration of response, progression-free survival, and overall survival were not reached. Common TEAEs included CRS (grade ≤ 2), neutropenia, and infections. No patient had immune effector cell-associated neurotoxicity syndrome (ICANS) and dose reductions. Teclistamab demonstrated deep and durable responses in Japanese patients with RRMM, consistent with the global pivotal MajesTEC-1 study, supporting the potential for a new standard of care for Japanese RRMM patients.

Obecabtagene Autoleucel in Adults with B-Cell Acute Lymphoblastic Leukemia.

Obecabtagene autoleucel (obe-cel) is an autologous 41BB-ζ anti-CD19 chimeric antigen receptor (CAR) T-cell therapy which uses an intermediate-affinity CAR to reduce toxic effects and improve persistence. We conducted a phase 1b-2 multicenter study of obe-cel in adults (≥18 years of age) with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). The main cohort, cohort 2A, included patients with morphologic disease; patients in cohort 2B had measurable residual disease. The primary end point was overall remission (complete remission or complete remission with incomplete hematologic recovery) in cohort 2A. Secondary end points included event-free survival, overall survival, and safety. Of the 153 enrolled patients, 127 (83.0%) received at least one infusion of obe-cel and were evaluable. In cohort 2A (94 patients; median follow-up, 20.3 months), overall remission occurred in 77% (95% confidence interval [CI], 67 to 85), with complete remission in 55% (95% CI, 45 to 66) and complete remission with incomplete hematologic recovery in 21% (95% CI, 14 to 31). The prespecified null hypotheses of overall remission (≤40%) and complete remission (≤20%) were rejected (P<0.001). In the 127 patients who received at least one obe-cel infusion (median follow-up, 21.5 months), the median event-free survival was 11.9 months (95% CI, 8.0 to 22.1); estimated 6- and 12-month event-free survival was 65.4% and 49.5%, respectively. The median overall survival was 15.6 months (95% CI, 12.9 to not evaluable); estimated 6- and 12-month overall survival was 80.3% and 61.1%, respectively. Grade 3 or higher cytokine release syndrome developed in 2.4% of the patients, and grade 3 or higher immune effector cell-associated neurotoxicity syndrome developed in 7.1% of the patients. Obe-cel resulted in a high incidence of durable response among adults with relapsed or refractory B-cell ALL, with a low incidence of grade 3 or higher immune-related toxic effects. (Funded by Autolus Therapeutics); FELIX ClinicalTrials.gov number, NCT04404660.).

Accelerating CAR-T Cell Therapies with Small-Molecule Inhibitors.

Chimeric antigen receptor T-cell therapies have markedly improved the survival rates of patients with B-cell malignancies. However, their efficacy in other hematological cancers, such as acute myeloid leukemia, and in solid tumors has been limited. Key obstacles include the downregulation or loss of antigen expression on cancer cells, restricted accessibility to target cells, and the poor persistence of these "living drugs" because of the highly immunosuppressive tumor microenvironment. Additionally, manufacturing these immunotherapies presents significant challenges, and patients frequently experience side effects such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. This review emphasizes the potential of small-molecule inhibitors, many of which are already approved for clinical use, to facilitate chimeric antigen receptor T-cell manufacturing, enhance their anti-tumor efficacy, and mitigate their side effects. Although substantial work remains, the robust pre-clinical data and the growing clinical interest suggest significant promise for using cancer signaling pathway inhibitors to enhance and refine chimeric antigen receptor T-cell therapy for both hematological and solid tumors. Exploring these combination strategies could lead to more effective therapies, offering new hope for patients with resistant forms of cancer.

Predicting survival, neurotoxicity and response in B-cell lymphoma patients treated with CAR-T therapy using an imaging features-based model

BackgroundThis multicentre retrospective observational study aims to develop imaging-based prognostic and predictive models for relapsed/refractory (R/R) B-cell lymphoma patients undergoing CAR-T therapy by integrating clinical data and imaging features. Specifically, our aim was to predict 3- and 6-month treatment response, overall survival (OS), progression-free survival (PFS), and the occurrence of the immune effector cell-associated neurotoxicity syndrome (ICANS).ResultsSixty-five patients of R/R B-cell lymphoma treated with CAR-T cells in two centres were included. Pre-infusion [18F]FDG PET/CT scans and clinical data were systematically collected, and imaging features, including kurtosis, entropy, maximum diameter, standardized uptake value (SUV) related features (SUVmax, SUVmean, SUVstd, SUVmedian, SUVp25, SUVp75), total metabolic tumour volume (MTVtotal), and total lesion glycolysis (TLGtotal), were extracted using the Quibim platform. The median age was 62 (range 21–76) years and the median follow-up for survivors was 10.47 (range 0.20–45.80) months. A logistic regression model accurately predicted neurotoxicity (AUC: 0.830), and Cox proportional-hazards models for CAR-T response at 3 and 6 months demonstrated high accuracy (AUC: 0.754 and 0.818, respectively). Median predicted OS after CAR-T therapy was 4.73 months for high MTVtotal and 37.55 months for low MTVtotal. Median predicted PFS was 2.73 months for high MTVtotal and 11.83 months for low MTVtotal. For all outcomes, predictive models, combining imaging features and clinical variables, showed improved accuracy compared to models using only clinical variables or imaging features alone.ConclusionThis study successfully integrates imaging features and clinical variables to predict outcomes in R/R B-cell lymphoma patients undergoing CAR-T. Notably, the identified MTVtotal cut-off effectively stratifies patients, as evidenced by significant differences in OS and PFS. Additionally, the predictive models for neurotoxicity and CAR-T response show promising accuracy. This comprehensive approach holds promise for risk stratification and personalized treatment strategies which may become a helpful tool for optimizing CAR-T outcomes in R/R lymphoma patients.

Acute Kidney Injury Following CAR-T Cell Therapy: A Nephrologist Perspective

Abstract Chimeric antigen receptor T-cell (CAR-T cell) therapy, an emerging personalized immunotherapy for various hematologic malignancies, autoimmune diseases, and other conditions, involves the modification of patients’ T cells to express a chimeric antigen receptor which recognizes tumor or autoimmune cell antigens. Thereby CAR-T cells destroy cancerous and other target cells selectively. Despite remarkable clinical improvements in patients, multiple adverse effects have been associated with CAR-T cell therapy. Among the most recognized adverse effects are cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and tumor lysis syndrome. Even though less recognized, the incidence of acute kidney injury (AKI) ranges from 5% to 33%. The wide range of reported AKI incidence rates might depend on patient population characteristics and comorbidities and specific CAR-T cell therapy features. Even though the exact pathophysiology remains unknown, several key mechanisms including cytokine release syndrome, tumor lysis syndrome, and other factors such as direct renal toxicity of CAR-T cell therapy, conditioning regimens or other medications (e.g. antibiotics), and infectious complications (e.g. sepsis) have been proposed. Risk factors for CAR-T-related AKI include lower baseline glomerular filtration rate, higher rates of allopurinol or rasburicase use, intravenous contrast material exposure, elevated baseline lactate dehydrogenase, and grade 3 or higher cytokine release syndrome. Future prospective studies with larger patient populations are needed to gain more insight regarding the pathophysiology of CAR-T-related AKI, and, more importantly, to be able to prevent as well as to develop novel and more efficient treatment modalities. In this narrative review, we discuss the underlying pathophysiology, risk factors, potential interventions, and future directions related to AKI following CAR-T cell therapy.

Immunotherapy-Related Neurotoxicity in the Central Nervous System of Children with Cancer.

Significant gaps remain in our understanding of immunotherapy-related neurotoxicity in pediatric patients, largely because much of our knowledge comes from studies in adults. Accurately identifying the adverse effects of immunotherapy in children is also challenging, owing to variations in terminology and grading systems. Moreover, the manifestation of immunotherapy-related neurotoxicity differs greatly across different diseases, various modalities, dosages, and delivery methods. Combining immunotherapy with other treatments might improve outcomes but introduces new complexities and potential for increased toxicities. Additionally, pediatric patients with intracranial malignancy have unique responses to immunotherapies and distinct neurotoxicity compared to those with extracranial malignancy. Consequently, we must enhance our understanding of the pathophysiology, prevalence, severity, and management of immunotherapy's neurotoxic effects in this vulnerable group. This review consolidates the current knowledge of immunotherapy-related neurotoxicity in pediatric oncology, highlighting various types of neurotoxicity including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and tumor inflammation-associated neurotoxicity (TIAN), among others. Furthermore, we examine the unique features of neurotoxicity associated with adoptive cellular therapy (ACT), antibody-based therapies, immune checkpoint inhibitors (ICIs), oncolytic viruses (OV), and cancer vaccines.

Detection of Brain-Derived Cell-Free DNA in Plasma.

Background: Neuronal loss is a major pathological feature of neurodegenerative diseases. The analysis of plasma cell-free DNA (cfDNA) is an emerging approach to track cell death events in a minimally invasive way and from inaccessible areas of the body, such as the brain. Previous studies showed that DNA methylation (DNAm) profiles can be used to map the tissue of origin of cfDNA and to identify molecules released from the brain upon cell death. The aim of the present study is to contribute to this research field, presenting the development and validation of an assay for the detection of brain-derived cfDNA (bcfDNA). Methods: To identify CpG sites with brain-specific DNAm, we compared brain and non-brain tissues for their chromatin state profiles and genome-wide DNAm data, available in public datasets. The selected target genomic regions were experimentally validated by bisulfite sequencing on DNA extracted from 44 different autoptic tissues, including multiple brain regions. Sequencing data were analysed to identify brain-specific epihaplotypes. The developed assay was tested in plasma cfDNA from patients with immune effector cell-associated neurotoxicity syndrome (ICANS) following chimeric antigen receptor T (CAR-T) therapy. Results: We validated five genomic regions with brain-specific DNAm (four hypomethylated and one hypermethylated in the brain). DNAm analysis of the selected genomic regions in plasma samples from CAR-T patients revealed higher levels of bcfDNA in participants with ongoing neurotoxicity syndrome. Conclusions: We developed an assay for the analysis of bcfDNA in plasma. The assay is a promising tool for the early detection of neuronal loss in neurodegenerative diseases.

Plain language summary: tarlatamab for patients with previously treated small cell lung cancer.

This is a summary of a phase 2 clinical study called DeLLphi-301. The study looked at how effective and safe a medicine called tarlatamab was in participants with small cell lung cancer (SCLC). Participants previously received at least two other treatments for their SCLC. Tarlatamab is a new medicine that locates a protein called DLL3 on the cancer, which allows T cells to attack the cancer. T cells belong to the body's natural defense system known as the immune system. The DeLLphi-301 study separated participants into two groups to receive tarlatamab 10mg or 100mg to determine which dose best shrank SCLC with minimal side effects. All participants received a small first dose (1mg tarlatamab) to decrease the risk of an immune system reaction called cytokine release syndrome (CRS). Tarlatamab was given through the participant's vein once every 2weeks. This method of administration is known as intravenous (IV) infusion. In the group given 10mg tarlatamab, 40% of participants responded to treatment (cancer shrank). In the group given 100mg tarlatamab, 32% of participants responded to treatment (cancer shrank). After taking tarlatamab at either dose, 59% of participants lived for at least 6months without their cancer growing or getting worse.The most common side effect was CRS, which occurred in 51% of participants in the group given 10mg tarlatamab and 61% of participants in the group given 100mg tarlatamab. Other common side effects were decreased appetite, fever, constipation, and anemia. Some participants had a type of immune reaction called immune effector cell-associated neurotoxicity syndrome (ICANS). A small number of participants (3%) stopped taking tarlatamab because of side effects related to tarlatamab. The study found that tarlatamab given every 2weeks shrank SCLC in participants with SCLC who received previous treatments. Participants given the 10mg tarlatamab dose had fewer side effects than those given the 100mg tarlatamab dose.Clinical Trial Registration: NCT05740566 (DeLLphi-304) (ClinicalTrials.gov).

CTIM-04. MODULATION OF THE INTRATUMORAL IMMUNE MICROENVIRONMENT BY LOCAL THERAPY WITH NATURAL KILLER CELLS ENGINEERED WITH A HER2-TARGETED CHIMERIC ANTIGEN RECEPTOR IN COMBINATION WITH SYSTEMIC ANTI-PD-1 CHECKPOINT INHIBITION IN PATIENTS WITH RECURRENT GLIOBLASTOMA

Abstract Glioblastoma (GB) is characterized by a marked immunosuppressive tumor microenvironment. In the multicenter CAR2BRAIN phase I first-in-human clinical trial, we investigated the modulation of the tumor microenvironment by repetitive local injection of clonal chimeric antigen receptor (CAR)-NK cells (NK-92/5.28.z) targeting HER2 alone and in combination with systemic anti-PD-1 checkpoint inhibitor therapy in patients with recurrent HER2-positive GB. 6 patients were treated with repetitive doses of CAR-NK cells as monotherapy and 12 patients received a combination therapy with the anti-PD-1 checkpoint inhibitor ezabenlimab. In three of those, we were able to implement a biopsy-treat-resect-treat strategy. After initial biopsy, combination treatment was initiated before planned tumor resection, enabling analysis of the transformation of the tumor immune microenvironment by highplex multispectral fluorescent analyses and cytokine quantification. None of the patients developed a cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. Profound alterations of the immune cell distribution in the cerebrospinal fluid (CSF) and in the tumor were observed. In CSF sampled from the resection cavity, combination immunotherapy induced a local immune response with elevated pro-inflammatory cytokines and cell counts. In post-treatment tissue samples, we observed an increase of CD4+ and CD8+ T cells, and a decrease of regulatory CD4+FoxP3+ T cells. The three patients treated following the biopsy-treat-resect-treat strategy achieved a median progression-free survival (PFS) of 24 weeks, compared to 10 weeks for patients with upfront resection. Local immunotherapy with HER2-targeted CAR-NK cells is feasible and safe both as monotherapy and in combination with the systemic checkpoint inhibitor ezabenlimab and induces local immune reactions in CSF and tumor tissue. Given the signal for possible clinical benefit provided by the increase in PFS in the patients of the biopsy-treat-resect-treat cohort, further trials are warranted.

RADT-39. CENTRAL NERVOUS SYSTEM BRIDGING RADIOTHERAPY (CNS-BRT) ACHIEVES RAPID CYTOREDUCTION PRIOR TO CAR T-CELL THERAPY FOR AGGRESSIVE B-CELL LYMPHOMAS

Abstract BACKGROUND CAR T-cell therapy (CART) for central nervous system lymphoma (CNSL) is a promising strategy, yet responses are frequently not durable. Bridging radiotherapy (BRT) is used for extra-cranial lymphoma to improve CART outcomes through cytoreduction of high-risk lesions. We hypothesized that CNS-BRT would achieve similar, significant cytoreduction prior to CART for CNSL. METHODS We analyzed CNSL patients with non-Hodgkin B-cell lymphomas who received CNS-BRT prior to commercial CART. Best CNS response post-CART was evaluated using the International Primary CNS Lymphoma Collaborative Group (IPCG) or RANO for parenchymal or leptomeningeal lesions, respectively. Cytoreduction from CNS-BRT was calculated as change in lesion size prior to CART. RESULTS Twelve patients received CNS-BRT, with median follow up of 11.8m (IQR: 8.5–21.9). Ten had CNSL (9 secondary, 1 primary) and 2 patients had epidural disease (evaluable for toxicity). All ten CNSL patients had progressive disease at the time of CNS-BRT. RT targets included whole brain (n=3), involved site (partial) brain (n=4), involved site spine (n=4), and orbits (n=1) with median dose 24Gy (range: 15-33). 1/12 patients experienced grade ≥3 cytokine release syndrome (CRS), and 3/12 patients experienced grade ≥3 immune effector cell-associated neurotoxicity syndrome (ICANS). CNS-BRT achieved a 74.0% (95%CI: 62.0–86.0) mean reduction in lesion size from baseline (p=0.014) at a median of only 12d from BRT completion and pre-CART infusion. Best CNS response included 8 complete responses (CR), 1 partial response (PR), and 1 progressive disease (PD). Three patients experienced CNS relapse outside the BRT field for a 12-month estimated risk of CNS progression post-CART of 20.0% (95%CI: 3–49). CONCLUSIONS Early data suggest CNS-BRT achieves rapid cytoreduction and favorable CNS response. The rates of severe CRS/ICANS were similar to comparison series of CNSL patients treated with CART without BRT suggesting an acceptable safety profile. Our data support further study of BRT as a bridging strategy for CNSL-directed CART.

Equecabtagene Autoleucel in Patients With Relapsed or Refractory Multiple Myeloma

Equecabtagene autoleucel (eque-cel), a fully human-derived B-cell maturation antigen-targeting chimeric antigen receptor (CAR) T-cell therapy, has exhibited potential for the treatment of relapsed or refractory multiple myeloma (RRMM), and further investigation in a larger cohort is necessary. To evaluate whether eque-cel can benefit patients with RRMM and determine the overall response rate postinfusion. The FUMANBA-1 trial was a single-arm, open-label, phase 1b/2 trial that evaluated eque-cel in adult patients with RRMM. Enrollment began in April 2020, and patients who received eque-cel will be monitored for a minimum of 15 years following the infusion. As of September 2022, patients with heavily pretreated RRMM who received at least 3 prior courses of therapy from 14 centers were enrolled. Data were analyzed from April 2020 to September 2022. Patients received a single infusion of eque-cel at 1.0 × 106 CAR-positive T cells/kg after the lymphodepletion. Efficacy was the primary objective, and safety, pharmacokinetics, and pharmacodynamics were secondary objectives. Of 103 patients who received an eque-cel infusion, 55 (53.4%) were male, and the median (range) age was 58 (39-70) years. A total of 101 patients were evaluable for efficacy. At a median (range) follow-up of 13.8 (0.4-27.2) months, the overall response rate was 96.0% (97 of 101), with 74.3% (75 of 103) achieving a complete response or better. Among the 12 patients who had prior CAR T-cell treatment, 75% (9 of 12) achieved a response. The median progression-free survival was not reached, with a 12-month progression-free survival rate of 78.8% (95% CI, 68.6-86.0). A total of 96 patients (95.0%) achieved minimal residual disease negativity at a sensitivity threshold of 10-5. Adverse events were favorable: 96 of 103 patients (93.2%) experienced cytokine release syndrome (grade 1 to 2 in 95 patients [92.3%]) and 2 (1.9%) experienced immune effector cell-associated neurotoxicity syndrome (grade 1 to 2). All cases of immune effector cell-associated neurotoxicity syndrome and 94 of 96 cases of cytokine release syndrome resolved with treatment. Additionally, only 20 patients (19.4%) developed antidrug antibodies. Cellular kinetic analysis confirmed CAR-positive T cells in all patients, with the longest duration at 735 days. In this trial, eque-cel led to early, deep, and durable responses in patients with heavily pretreated RRMM with a manageable safety profile. Patients with prior CAR T-cell therapy also benefitted from eque-cel. Chinese Clinical Trial Registry Identifier: ChiCTR2000033946.

Human herpesvirus 6 (HHV-6) encephalitis secondary to chimeric antigen receptor (CAR)-T cell therapy.

Human herpesvirus (HHV)-6 encephalitis secondary to chimeric antigen receptor (CAR)-T cell therapyis relatively rare in clinical practice and needs to be differentiated from immune effector cell-associatedneurotoxicity syndrome (ICANS). We retrospectively reported a case of HHV-6 encephalitis secondary to CAR-T cell therapy. A male patient from China with diffuse large B-cell lymphoma underwent chimeric CAR-T cell therapy anddeveloped a generalized rash on the 8th day, followed by cognitive changes, memory loss, and disorientation onthe 14th day after CAR-T cell therapy. Initially, ICANS was suspected. A lumbar puncture was performed on the 18th day. The cerebrospinal fluid (CSF) analysis revealed slightly elevated protein levels and a high presence of HHV-6B sequences by mNGS. Brain MRI showed bilateral hippocampal abnormalities. The patient was ultimatelydiagnosed with HHV-6 encephalitis and treated with ganciclovir and dexamethasone. After one week of treatment,follow-up CSF analysis showed a reduction in HHV-6B sequences. The patient was discharged with improvedmemory and orientation. HHV-6 encephalitis secondary to CAR-T cell therapy may be easily confused with ICANS. Timely andaggressive diagnostic procedures, such as mNGS of CSF and cranial imaging, along with prompt antiviral therapy,are crucial for improving patient outcomes.

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.

Fluctuation of physical function during chimeric antigen receptor T‐cell therapy during rehabilitation intervention: Real‐world data and risk factor analyses

AbstractIntroductionPatients undergoing chimeric antigen receptor (CAR) T‐cell therapy face prolonged treatment timelines and are prone to cytokine release syndrome (CRS) and immune effector cell‐associated neurotoxicity syndrome (ICANS) after infusion. Disabilities in physical function and the importance of rehabilitation during CAR‐T‐cell therapy to maintain physical function have been poorly documented.MethodWe performed a retrospective cohort study to assess changes in exercise tolerance via differences in a 6‐min‐walking distance (Δ6MWD) and factors influencing it.ResultsA total of 77 patients who underwent rehabilitation during CAR‐T‐cell therapy were enrolled, and their 6MWD was 450 m (median, range 180–705 m) before and 450.5 m (107.0–735.0 m) 30 days after CAR‐T treatment. No significant alteration in Δ6MWD was observed overall (11.0 m, 95% confidence interval, −56.1 to 88.2 m). Multiple regression analyses indicated that age (over vs. under 65 years) revealed no notable differences in Δ6MWD (20 vs. 10 m), while ΔHb (β = 0.24, p = 0.03), moderate/severe CRS (grade 1 with continuous fever or grade ≥2; β = −0.25, p = 0.03), and ICANS (any grade; β = −0.22, p = 0.04) were significantly associated with lower Δ6MWD.ConclusionThis real‐world study indicated that CAR‐T‐cell therapy is less likely to reduce physical function even in older patients if rehabilitation is properly performed, whereas CRS and ICANS can be risk factors to deprive exercise tolerance.

Management of complications of chimeric antigen receptor T-cell therapy: a report by the European Society of Blood and Marrow Transplantation.

Chimeric antigen receptor (CAR) T cells are in standard clinical use to treat relapsed or refractory hematologic malignancies, such as non-Hodgkin lymphoma, multiple myeloma and acute lymphoblastic leukemia. Owing to the rapidly progressing field of CAR T-cell therapy and the lack of generally accepted treatment guidelines, we hypothesized significant differences between European centers in prevention, diagnosis and management of short- and long-term complications. To capture the current CAR T-cell management among European Society for Blood and Marrow Transplantation (EBMT) centers and to determine the medical need and specific areas for future clinical research the EBMT Transplant Complications Working Party performed a survey among 227 EBMT CAR T-cell centers. We received complete servey answers from 106 centers (47%) addressing questions in the areas of product selection, CAR T-cell logistics, management of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome as well as management in later phases including prolonged cytopenias. We identified common patterns in complication management, but also significant variety in clinical management of the centers in important aspects. Our results demonstrate a high medical need for treatment harmonization and future clinical research in the following areas: treatment of steroid-refractory and very severe cytokine release syndrome/neurotoxicity, treatment of cytopenia, early discharge and outpatient management, as well as immunoglobulin substitution.

Timeline and outcomes of viral and fungal infections after Chimeric Antigen Receptor (CAR) T-cell therapy: A large database analysis

ObjectivesThis large database analysis aims to describe the incidence, timeline, and risk factors for viral and fungal infections after chimeric antigen receptor (CAR) T-cell therapy. MethodsWe queried a global research network database, TriNetX, for patients who received CAR T-cell therapy, who were identified and followed for the development of viral and fungal infections. Baseline demographic, oncologic history, laboratory data and medication histories were collected. We evaluated risk factors for respiratory viral infections (RVI), herpesvirus, fungal infections and mortality using Cox regression. ResultsA total of 2,256 patients who received CAR T-cell therapy were included, 1,867 (82.7%) were CD19-targeted and 400 (17.7%) were BCMA-targeted. Following CAR T-cell infusion, RVI were the most prevalent (23.3%) with a median onset of 160 days (IQR 52-348 days), while herpesvirus and fungal infections were less frequent, occurring in 13.6% and 11.4% of cases with median onsets of 71 (IQR 18-252) and 73 days (IQR 14-236 days), respectively. On multivariable Cox regression, independent predictors of RVI included acute lymphoblastic leukemia (ALL, HR 1.61), prior hematopoietic cell transplant (HCT, HR 1.29), cytokine release syndrome (CRS, HR 1.41), hemophagocytic lymphohistiocytosis (HLH, HR 1.96), and glucocorticoids (HR 3.37). Prior HCT (HR 2.00), hypogammaglobulinemia (HR 1.51), immune-effector cell-associated neurotoxicity syndrome (ICANS, HR 1.52), and HLH (HR 1.99) were associated with a higher risk of herpesviruses. Independent predictors of fungal infections included prior HCT (HR 1.59), CRS (HR 1.58) and hypogammaglobulinemia (HR 1.40). Idecabtagene vicleucel was associated with a lower risk of herpesvirus and fungal infections (HR 0.39 and 0.44, respectively). ConclusionsIn a large cohort of CAR T-cell therapy recipients, respiratory viral infections were the most common but occurred later, while herpesvirus and fungal infections were less frequent but occurred earlier. Prospective studies investigating prophylaxis and pre-emptive monitoring strategies are needed in this population.

Optimizing CAR-NK Cell Transduction and Expansion: Leveraging Cytokine Modulation for Enhanced Performance.

Cellular immunotherapy has emerged as one of the most potent approaches to treating cancer patients. Adoptive transfer of chimeric antigen receptor (CAR) T cells as well as the use of haploidentical natural killer (NK) cells can induce remission in patients with lymphoma and leukemia. Although the use of CAR T cells has been established, this approach is currently limited for wider use by the risk of severe adverse events, including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. Moreover, the risk of triggering graft vs host reactions in settings of allogeneic T cell infusion limits the use to autologous CAR T cells if advanced CRISPR engineering is not applied. In contrast, NK cell-based cancer immunotherapy has emerged as a safe approach even in allogeneic settings. However, efficient transduction of primary blood NK cells with vesicular stomatitis virus G glycoprotein (VSV-G) pseudotyped lentivirus commonly used for T cell modification remains challenging. This article presents a detailed method that significantly enhances the transduction efficiency of NK cells by utilizing a short-term culture in cytokine-supplemented medium. It also encompasses the preparation of high-titer and high-quality lentiviral particles for optimal NK cell transduction. Overall, this protocol details the step-by-step culture of NK cells in cytokine-supplemented medium, their transduction with VSV-G lentiviral vectors, and subsequent expansion for functional assays. © 2024 Wiley Periodicals LLC. Basic Protocol 1: Isolation of NK cells from human peripheral blood mononuclear cells (PBMCs) Basic Protocol 2: NK cell expansion and transduction with lentivirus for generating CAR-NK cells Support Protocol 1: Plasmid amplification Support Protocol 2: Lentivirus preparation Support Protocol 3: Lentivirus titration.