Single-center experience using anakinra for steroid-refractory immune effector cell-associated neurotoxicity syndrome (ICANS)

In addition to remarkable antitumor activity, chimeric antigen receptor (CAR) T-cell therapy is associated with acute toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Current treatment guidelines for CRS and ICANS include use of tocilizumab, a monoclonal antibody that blocks the interleukin (IL)-6 receptor, and corticosteroids. In patients with refractory CRS, use of several other agents as third-line therapy (including siltuximab, ruxolitinib, anakinra, dasatinib, and cyclophosphamide) has been reported on an anecdotal basis. At our institution, anakinra has become the standard treatment for the management of steroid-refractory ICANS with or without CRS, based on recent animal data demonstrating the role of IL-1 in the pathogenesis of ICANS/CRS. Here, we retrospectively analyzed clinical and laboratory parameters, including serum cytokines, in 14 patients at our center treated with anakinra for steroid-refractory ICANS with or without CRS after standard treatment with tisagenlecleucel (Kymriah) or axicabtagene ciloleucel (Yescarta) CD19-targeting CAR T. We observed statistically significant and rapid reductions in fever, inflammatory cytokines, and biomarkers associated with ICANS/CRS after anakinra treatment. With three daily subcutaneous doses, anakinra did not have a clear, clinically dramatic effect on neurotoxicity, and its use did not result in rapid tapering of corticosteroids; although neutropenia and thrombocytopenia were common at the time of anakinra dosing, there were no clear delays in hematopoietic recovery or infections that were directly attributable to anakinra. Anakinra may be useful adjunct to steroids and tocilizumab in the management of CRS and/or steroid-refractory ICANs resulting from CAR T-cell therapies, but prospective studies are needed to determine its efficacy in these settings.

Intratumoural Effector Cell Subpopulations in Breast Cancer: a Literature Review and Own Data Report

Breast cancer (BC) is most prevalent female malignancy worldwide. Despite advances in BC diagnosis and progress in drug therapy, a series of challenges associated with emergent tumour resistance causing the disease escalation still remain. Immune evasion is among the driving forces of tumour resistance against modern treatments, which promotes world-active research into the mechanisms of tumour—immune interaction.Tumour microenvironment is known to contribute greatly to the nature of this interaction. Immune cells are constitutive of tumour microenvironment as tumour-associated macrophages, myeloid-derived suppressor cells and tumour-infi ltrating lymphocytes. Tumour-infi ltrating lymphocytes are represented by B-, T- and NK-cells, which localisation and subpopulation structure in tumour may possess a prognostic and clinical significance. Th e infi ltration density by certain effector cell types prior to chemotherapy is an important predictor of patient survival. Putting otherwise, the presence of effector lymphocyte subpopulations in tumour defi nes the strength of antitumour immunity and may establish the success of drug treatment.This study analysed the infiltration levels of CD3, CD4, CD20 and CD38 lymphocytes in several molecular BC subtypes. Tumour immunophenotyping was performed in cryosectioning and immunofl uorescence assays with a ZEISS AXIOSKOP microscope, Germany. We analysed 96 luminal BC (37 subtype A (38.5 %), 52 B-Her2-negative subtype (54.2 %), 7 B-Her2-positive subtype (7.3 %)) and non-luminal BC samples (3 HER2+ subtype (14.3 %), 18 triple-negative subtype (85.7 %)). The infiltration and antigen expression patterns have been assessed. Analyses of tumour-infi ltrating subpopulations revealed lower infiltration in luminal BC vs. other subtypes, albeit at no significance.

Adjunctive Thymosin Beta-4 Treatment Influences PMN Effector Cell Function during Pseudomonas aeruginosa-Induced Corneal Infection

Previous work examining the therapeutic efficacy of adjunct thymosin beta 4 (Tβ4) to ciprofloxacin for ocular infectious disease has revealed markedly reduced inflammation (inflammatory mediators and innate immune cells) with increased activation of wound healing pathways. Understanding the therapeutic mechanisms of action have further revealed a synergistic effect with ciprofloxacin to enhance bacterial killing along with a regulatory influence over macrophage effector cell function. As a natural extension of the aforementioned work, the current study uses an experimental model of P. aeruginosa-induced keratitis to examine the influence of Tβ4 regarding polymorphonuclear leukocyte (PMN/neutrophil) cellular function, contributing to improved disease response. Flow cytometry was utilized to phenotypically profile infiltrating PMNs after infection. The generation of reactive oxygen species (ROS), neutrophil extracellular traps (NETs), and PMN apoptosis were investigated to assess the functional activities of PMNs in response to Tβ4 therapy. In vitro work using peritoneal-derived PMNs was similarly carried out to verify and extend our in vivo findings. The results indicate that the numbers of infiltrated PMNs into infected corneas were significantly reduced with adjunctive Tβ4 treatment. This was paired with the downregulated expression of proinflammatory markers on these cells, as well. Data generated from PMN functional studies suggested that the corneas of adjunctive Tβ4 treated B6 mice exhibit a well-regulated production of ROS, NETs, and limited PMN apoptosis. In addition to confirming the in vivo results, the in vitro findings also demonstrated that neutrophil elastase (NE) was unnecessary for NETosis. Collectively, these data provide additional evidence that adjunctive Tβ4 + ciprofloxacin treatment is a promising option for bacterial keratitis that addresses both the infectious pathogen and cellular-mediated immune response, as revealed by the current study.

The impact of early versus late tocilizumab administration in patients with cytokine release syndrome secondary to immune effector cell therapy

Introduction Cytokine release syndrome is a life-threatening hyper-inflammatory state induced by immune effector cell therapy. Anti-interleukin 6-(IL-6) therapy, such as tocilizumab, is the standard treatment for cytokine release syndrome since it reverses symptoms without compromising immune effector cell therapy efficacy. Glucocorticoids are reserved for refractory or severe cytokine release syndrome due to concern for attenuating antitumor activity. Optimizing the timing of tocilizumab could avoid glucocorticoid use and improve outcomes. This study assesses tocilizumab timing on patient outcomes and healthcare resource utilization. Methods This is a retrospective single-institution analysis of 28 patients who received tocilizumab for cytokine release syndrome secondary to immune effector cell therapy. Patients were categorized into two groups: Early Tocilizumab (within 24 h) or Late Tocilizumab groups (more than 24 h) from fever onset. The composite primary endpoint was glucocorticoid use, intensive care unit admission, or inpatient mortality. Secondary outcomes include comparing the various presentations of cytokine release syndrome, need for vasopressors, length of stay, rates of neurotoxicity, and C-reactive protein and ferritin trends. Results The Early Tocilizumab group presented with more rapid fever onset (35 vs.113 h, P = 0.017) and higher maximum cytokine release syndrome grade (Median, Grade 2 vs. Grade 1, P = 0.025). Additionally, the Early Tocilizumab group required more doses of tocilizumab (Median, 2 vs. 1, P = 0.037). Despite the difference in cytokine release syndrome presentation, the primary composite endpoint was not statistically different between groups. Conclusion Earlier onset of fever appears to be associated with more severe, progressive cytokine release syndrome requiring multiple doses of anti-interleukin-6 therapy. Prompt and aggressive tocilizumab treatment could be protective against the negative consequences of cytokine release syndrome.

Plasma Exchange to Treat Cytokine Release Syndrome and Immune Effector Cell-Associated Neurotoxicity Syndrome after Anti-CD19 Chimeric Antigen Receptor-T Cell Infusion: A Case Report

Adoptive cell immunotherapy with chimeric antigen receptor-T (CAR-T) cells has shown remarkable clinical outcomes. However, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are the two most significant toxicities during this therapy and can be life-threatening. We described a 12-year-old juvenile who had been diagnosed with relapsed and refractory B-cell acute lymphocytic leukemia (r/r B-ALL). The patient was recruited into our phase I clinical trial concerning ssCAR-T-19 (anti-CD19 CAR-T cells with shRNA targeting IL-6), and 5*106 /kg of engineered ssCAR-T-19 cells were administered. After infusion, the patient underwent a typical CRS reaction, with fever and increased cytokine levels. He was treated with antipyretic drugs, methylprednisolone, and tocilizumab, but the effect was limited. He developed coagulation abnormalities, multiple organ dysfunction, lung infection and ICANS. Apart from the necessary supportive and symptomatic treatment, plasma exchange was performed three times in four days while methylprednisolone pulse was performed for two consecutive days. After that, the body temperature, heart rate, and especially the cytokine levels declined. But digestive tract hemorrhage occurred to him and he was transferred to intensive care unit. To make things worse, he developed acute respiratory failure and received intubation and mechanical ventilation. In addition, symptomatic treatment such as suppression of stomach acid and anti-infection was given. The bleeding was controlled, and his respiratory function improved, and the CRS and ICANS-related symptoms were relieved. He received extubation and was transferred back to the general ward. Additionally, abone marrow smear showed no lymphoblast cells, and minimal residual disease in bone marrow was negative on day +22 and day +30. The patient was eventually discharged in a normal condition. In conclusion, CRS and ICANS as two most common toxicities after CAR-T therapy, which often cause patient death. Several methods such as anti-IL-6 therapy and/or corticosteroids have been adopted in the management guidelines of CRS and ICANS except plasma exchange. This case shows the validity of plasma exchange in a patient with severe CRS and ICANS after receiving ssCAR-T.

Feasibility of a Supportive Mobile Health App for Chimeric Antigen Receptor T-Cell Therapy

BACKGROUND: The operationalization of chimeric antigen receptor (CAR-T) therapy for hematologic malignancies can be complex for patients and their caregivers. In the weeks before CAR-T therapy, patients must process large amounts of information and coordinate logistics involving caregivers, lodging, and transportation. Immediately following CAR-T therapy, patients must be monitored closely for toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). In the months following CAR-T therapy, patients may be referred back to local oncologists without a clear plan for managing potential late effects such as hypogammaglobulinemia or neuropsychiatric complications (Chakraborty 2021). Mobile health (mHealth) apps may be able to improve the patient experience during CAR-T therapy by facilitating care coordination, home-based toxicity monitoring, and patient education (Banerjee 2021). By empowering patients and caregivers to better understand CAR-T therapy and actively participate in their care, mHealth tools may ultimately augment workflows for CAR-T clinics as well. However, the feasibility and acceptability of such supportive mHealth apps during CAR-T therapy have not been established. STUDY DESIGN: We have designed a "Companion for CAR-T" mHealth app to assist with care coordination, toxicity monitoring, and patient education during CAR-T therapy. Key components of the app are summarized in the Figure. In brief, pre-CAR-T components include educational videos and dynamic calendars to assist patients with coordinating logistics. Post-CAR-T components include app-based prompts to input body temperature daily, an electronic Immune Effector Cell-Associated Encephalopathy (eICE) screening tool for ICANS that can be administered by caregivers, and a patient-specific long-term survivorship care plan. Global app components include an 'Appointment Companion' to facilitate patient-provider discussions during appointments as well as a digital CAR-T wallet card to convey key health-related information to other healthcare providers. We plan to investigate the "Companion for CAR-T" app through a pilot study of 20 patients receiving commercially available CAR-T therapies for any hematologic malignancy at our institution. Co-primary endpoints include (1) app feasibility, defined as the percentage of patients who access all 5 core modules shown in the Figure at least once; and (2) app acceptability, defined as the percentage of patients who agree that the app was helpful during their experience with CAR-T therapy. Secondary endpoints include the incidence of fevers or eICE deficits recorded via the app. Exploratory endpoints include longitudinal trends in patient-reported outcomes such as emotional distress at each clinic visit. DISCUSSION: If feasibility and acceptability of the "Companion for CAR-T" app are demonstrated through this pilot study, we plan to launch a multicenter randomized Phase 2 study of this mHealth tool versus usual care to assess its effect on perceived stress and decisional conflict. Other important steps for our group include the translation of app content into different languages and the provision of tablet computing devices for patients who do not own smartphones. Once validated and expanded in these aforementioned ways, potential strengths of the "Companion for CAR-T" app include its ability to be personalized easily with information specific to individual CAR-T therapies, malignancies, and centers. Figure 1 Figure 1. Disclosures Banerjee: Sanofi: Consultancy; SparkCures: Consultancy; Pack Health: Research Funding. Sykes: Patient Discovery Solutions, Inc.: Current Employment. Shah: Amgen: Consultancy; Indapta Therapeutics: Consultancy; Sutro Biopharma: Research Funding; Sanofi: Consultancy; Teneobio: Research Funding; Precision Biosciences: Research Funding; Poseida: Research Funding; Karyopharm: Consultancy; Janssen: Research Funding; GSK: Consultancy; Kite: Consultancy; Nektar: Research Funding; Oncopeptides: Consultancy; CSL Behring: Consultancy; Bluebird Bio: Research Funding; BMS/Celgene: Research Funding; CareDx: Consultancy. Andreadis: Incyte: Honoraria; Roche: Current equity holder in publicly-traded company, Ended employment in the past 24 months; GenMAB: Research Funding; Merck: Research Funding; Novartis: Research Funding; Epizyme: Honoraria; Crispr Therapeutics: Research Funding; Atara: Consultancy, Honoraria; Karyopharm: Honoraria; TG Therapeutics: Honoraria; Kite: Honoraria; BMS/Celgene: Research Funding. Martin: Amgen: Research Funding; GlaxoSmithKline: Consultancy; Oncopeptides: Consultancy; Janssen: Research Funding; Sanofi: Research Funding. Shore: Patient Discovery Solutions, Inc.: Current Employment. Sodowick: Patient Discovery Solutions, Inc.: Current Employment. Wong: Amgen: Consultancy; Genentech: Research Funding; Fortis: Research Funding; Janssen: Research Funding; GloxoSmithKlein: Research Funding; Dren Biosciences: Consultancy; Caelum: Research Funding; BMS: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees.

NCMP-20. PRE-INFUSION NEUROFILAMENT LIGHT CHAIN (NFL) LEVELS PREDICT THE DEVELOPMENT OF IMMUNE EFFECTOR CELL-ASSOCIATED NEUROTOXICITY SYNDROME (ICANS) – A MULTICENTER RETROSPECTIVE STUDY

BACKGROUND Neurological side effects after chimeric antigen receptor-modified (CAR) T cell therapy, termed immune effector cell-associated neurotoxicity syndrome (ICANS), are common and potentially devastating. We previously demonstrated that pre-infusion plasma neurofilament light chain (NfL), a well-established marker of neurodegeneration, may predict subsequent development of ICANS in a small, single-center cohort. This larger, retrospective multicenter study compares pre-infusion NfL to known post-infusion risk factors for developing ICANs including white blood cell (WBC) count, platelet count, C-reactive protein (CRP), fibrinogen, and ferritin levels. METHODS Inclusion criteria included available pre-infusion (up to 4 weeks prior to lymphodepletion) plasma from patients treated with a CAR T cell therapy (n = 30, 36% with ICANS, ASTCT consensus ICANS grade range 1-4). Exclusion criteria included confounding diagnoses known to elevate NfL levels (dementia, multiple sclerosis, recent stroke). Plasma NfL was assayed using a Simoa HD-1/HD-X kit (QuanterixTM). Post-infusion Day 3 or Day 5 WBC, Platelet, CRP, fibrinogen, and ferritin were obtained from the medical record. Group comparisons were done using log-rank tests with a Bonferroni-derived significance threshold, followed by receiver operating characteristic (ROC) curve classification. RESULTS Prior to infusion, individuals who ultimately developed ICANS had elevations in NfL ([87.6 v 29.4 pg/ml], p = 0.00004) with excellent classification (AUC 0.96), sensitivity (0.91) and specificity (0.95). Among known post-infusion risk factors, only post-infusion Day 3 ferritin (p = 0.004) and Day 5 ferritin (p = 0.003) differed between groups. Classification was inferior for both time points (Day 3 AUC = 0.87, specificity 0.71; Day 5 AUC 0.87, specificity 0.86). CONCLUSION Pre-infusion plasma NfL levels are a robust early marker for the development of ICANS that exceeds known post-infusion markers. Our findings suggest the risk of developing ICANS reflects pre-existing host-factors. Foreknowledge of ICANS development of may permit early, aggressive (preemptive or prophylaxis) ICANS-directed therapies, improving patient outcomes.