Evidence Of Cytokine Release Syndrome Research Articles

Efficacy of Siltuximab for Chimeric Antigen Receptor T-Cell Therapy Toxicities - a Multicenter Retrospective Analysis

Background: Chimeric Antigen Receptor T-Cell therapies (CAR-T) are effective in a variety of hematologic (hem) malignancies; however, adverse events including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) can affect a significant number of patients (pts). Tocilizumab, a monoclonal antibody (mAb) binding the interleukin-6 (IL-6) receptor, is the standard of care for managing CRS, but is ineffective for ICANS. Corticosteroids remain the standard of care for managing ICANS. Pts who develop refractory CRS or ICANS have few treatment options. Siltuximab, a mAb binding circulating IL-6, has been proposed to have clinical activity in both CRS and ICANS (Patel, ASH, 2022; Narkhede, TCT, 2023). This study assesses the efficacy of siltuximab for managing CRS and ICANS in a real-world cohort from six academic medical centers. Methods: We conducted a multicenter retrospective review of adult pts with hem malignancies treated with CAR-T therapy who received siltuximab for treatment of CRS and/or ICANS. Siltuximab administration occurred between January 2020 and August 2022. Pts who died within 48 hours of siltuximab administration (n=2) were excluded from this analysis. The co-primary endpoints were the percentage of pts who had improvement in CRS or ICANS after receiving siltuximab. Secondary endpoints included time to improvement of CRS or ICANS and overall survival (OS) from the date of CAR-T infusion. Time to event endpoints were evaluated by Kaplan-Meier methodology. Results: Fifty-two pts were eligible and evaluated. The median age was 60 years (range 23-81). Diffuse large B-cell lymphoma was the most common hem malignancy (52%). Axicabtagene ciloleucel (42%) was the most common cellular therapy product. Table 1 describes disease subtypes and cell therapy products in detail. Fifty-one pts (98%) developed CRS with median time to onset of 2 days (range 0-9). Max CRS grade prior to siltuximab administration was grade 1-2 in 83% and grade 3-4 in 15%. ICANS occurred in 65% with median time to onset of 6 days (range 0-16). Max ICANS grade prior to siltuximab administration was grade 1-2 in 29% and grade 3-4 in 37%. Prior to siltuximab, 52% of pts received tocilizumab with the majority (59%) receiving more than 1 dose, 69% of pts received corticosteroids, and 10 pts received additional treatments: anakinra (7/10 pts), LP with intrathecal (IT) chemo (3/10 pts), LP with IT steroids (2/10 pts), ruxolitinib (1/10 pt). Reasons for siltuximab administration included steroid refractory ICANS in 17 pts (33%), tocilizumab refractory CRS in 8 pts (15%), tocilizumab shortage in 26 pts (50%), and non-steroid refractory grade 4 ICANS in 1 pt (2%). At the time of siltuximab administration, 42 pts (81%) had evidence of CRS (10% grade 3-4 CRS) and 28 pts (54%) had evidence of ICANS (31% grade 3-4 ICANS). 18 pts (35%) had concurrent CRS and ICANS. Thirty-six pts (86%) had improved CRS grade following siltuximab treatment. The median time to CRS resolution after siltuximab was 1.5 days (range 0-18). Twelve pts with CRS received more than 1 dose of siltuximab. 4/8 pts (50%) with tocilizumab refractory CRS had improved CRS grade after siltuximab. Nineteen pts (68%) had improved ICANS grade following siltuximab treatment. The median time to ICANS resolution after siltuximab was 5 days (range 1-40). Nine pts with ICANS received more than 1 dose of siltuximab. 13/17 pts (76%) with steroid refractory ICANS had improved ICANS grade after siltuximab. The median time to discharge after siltuximab administration was 14 days (range 7-90). CAR-T therapy objective response rate was 73% and complete response rate was 48%. Twenty-one pts had died at the time of data collection; 4 deaths were deemed secondary to CAR-T toxicity. The median OS was 13.8 months (95% CI 9.6-NR) and was not statistically different based on indication of CAR-T therapy, Figure 1. Conclusions: To our knowledge, this is the largest cohort of pts treated with siltuximab for CRS and/or ICANS following CAR-T therapy. Half of the pts had CRS or ICANS refractory to tocilizumab and/or steroids. Siltuximab appeared to be effective for both CRS and ICANS, including refractory toxicities. These data support the use of siltuximab for refractory CRS and ICANS and warrant further investigation of siltuximab in earlier lines of therapy for CRS and ICANS management.

Abstract CT131: Initial preclinical and clinical experience of autologous engineered monocytes in T cell lymphoma patients

Abstract For many patients with T cell lymphomas (TCL), sustained clinical benefit with standard treatment options is elusive. Myeloid cells, such as monocytes, dendritic cells and macrophages, readily accumulate in tumors, whereby they support tumor progression. The ability to harness the capability of myeloid cells to penetrate into tumors, and to subsequently program them to activate and elicit broad anti-tumor immunity has the potential to transform cancer therapies. With this goal we developed the first engineered monocyte cell product, by manipulating autologous monocytes to express a novel chimeric antigen receptor (CAR). This CAR contains a tumor recognition domain fused to a CD8 hinge domain, Fcγ and PI3K intracellular signaling domains. In addition to imparting tumor specificity, the Fcγ and PI3K signaling domains promote phagocytosis, cytokine production and antigen presentation upon activation. In a rodent model of melanoma (gp75+ B16/F10-OVA), Ly6C+ monocytes engineered with this receptor were able to phagocytose tumor cells and cross present antigen in vitro. In vivo infusion of engineered monocytes was associated with significant suppression of tumor growth. FACS analysis of tumor-infiltrates demonstrated that engineered monocytes preferentially infiltrated tumors and differentiated into antigen presenting cells. Adoptive T cell transfer of CFSE-labeled OT-I CD8+ T cells confirmed that treatment was also associated with increased accumulation of tumor specific T cells in tumor and spleen. Based on these promising data, MT-101 is being assessed in humans in the Phase 1, open-label, first-in-human trial in patients with refractory or relapsed T cell lymphoma, IMAGINE trial (NCT05138458). The primary objective is the assessment of safety and tolerability at Day 28, following 3 weekly cycles of 2 infusions. Secondary objectives include assessment of correlative markers of response, pharmacokinetics, and efficacy. In the first 3 subjects, MT-101 has been well-tolerated, with no evidence of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), or infusion reactions. Examination of biomarkers by CyTOF in one subject shows changes in circulating leukocytes, including B cells. In this subject, survival has been greater than 10 months, while the median overall survival of patients with R/R PTCL is 5.5 months. Continued patient enrollment and data collection is ongoing to confirm these observations. Citation Format: Michele Gerber, Thomas Prod'homme, Yuxiao Wang, Kyong-Rim Kieffer-Kwon, Neha Diwanji, Josephine D'Alessandro, Xing Du, Edward Cochran, Michael Gorgievski, Zheng Ling, Nicholas King, Siddhartha Mukherjee, Daniel Getts. Initial preclinical and clinical experience of autologous engineered monocytes in T cell lymphoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT131.

Abstract CT245: Clinical development of a novel form of interleukin-12 with extended pharmacokinetics

Abstract Recombinant interleukins (IL) have had limited clinical success due to inefficient tumor targeting and short pharmacokinetics (PK), requiring frequent dosing that leads to aberrant immunostimulation and toxicity. IL-12 is a promising cancer treatment due to its activation of T and natural killer (NK) lymphocytes to produce interferon (IFN)-γ, yet dosing strategies have failed to provide adequate therapeutic benefit in humans. To address these issues, we developed a novel platform that delivers either mono- or bifunctional immunomodulator(s) linked to a Fully-Human, Albumin Binding scFv domain (FHAB®), which provides enhanced tumor targeting and retention through albumin binding to over-expressed FcRn, GP60, and SPARC, an improved PK profile, a dose-sparing effect that decreases the toxicity risk, and a broader therapeutic index. Excellent tumor growth inhibition was seen using a “cold” immunosuppressive B16F10 melanoma model for comparing the efficacy of IL12-FHAB with rIL-12, resulting in significant increases in activated NK, NKT, Th1, and cytotoxic CD8 T cells. We are conducting a first-in-human, dose-escalation trial to evaluate the safety and tolerability of SON-1010 (IL12-FHAB) and to determine the maximum tolerated dose (MTD) in patients with advanced solid tumors. The study has a traditional 3+3 design, modified to take advantage of the known tachyphylaxis of IL-12 with the introduction of a desensitizing first dose to allow administration of higher maintenance doses. No dose-limiting toxicities have been encountered in the first 3 dose cohorts and the MTD is at least 300 ng/kg. While adverse events seen in other studies of IL-12 have occurred, they have been transient and tolerable, allowing further dose escalation. Increases in IFN-γ were dose-related, controlled, and prolonged. The levels peaked at 24 to 48 hours and returned to baseline after 2 to 4 weeks. Low levels of IL-10 were induced in a dose-dependent manner. No drug-related increase was seen with IL-1β, IL-6, IL-8, or TNF-α and there was no evidence of cytokine release syndrome at these doses. The preliminary geomean elimination half-life (T½) was 122 hrs with first-order kinetics, compared with 12 hrs for SC rhIL-12. The accumulation estimates are within the margin of error and are not likely to be physiologically significant with subcutaneous dosing of SON-1010 every 3 weeks. Eight of 11 patients had stable disease at the first follow-up CT, 4 of whom were progressing at study entry. Two patients were stable at 4 months and 2 had unconfirmed progressive disease; 1 patient remains stable after 8 months on SON-1010 with evidence of tumor regression. SON-1010 may have a positive synergistic effect with an immune checkpoint inhibitor (ICI), particularly with ‘cold’ tumors that over-express SPARC. The next stage of development will be to explore the MTD of SON-1010 in combination with an ICI, then to compare that approach with the standard of care in Phase 2. Citation Format: Sant P. Chawla, Victoria S. Chua, Erlinda M. Gordon, John Cini, Susan Dexter, Manual DaFonseca, Justus Bingham, Grantham W. Hogeland, Richard T. Kenney. Clinical development of a novel form of interleukin-12 with extended pharmacokinetics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT245.

P721 Treatment of Ulcerative Colitis with OSE-127 (lusvertikimab), a Strict IL-7Rα Antagonist, Non-Cytotoxic Monoclonal Antibody

Abstract Background Key transcripts of the IL-7R pathway were shown to accumulate in inflamed colon tissues of severe IBD patients not responding to conventional or biologics therapies. Furthermore, high expression of both IL7R and IL-7R signaling signature in the colon before treatment is strongly associated with non-responsiveness to anti-TNF therapy. We have designed a humanized monoclonal antibody targeting the IL-7Rα chain, named OSE-127 (lusvertikimab), which displays strict antagonist activity without cytotoxicity nor internalizing properties. In an ex vivo culture system using colon biopsies from UC patients, OSE-127 altered synthesis of interferon γ by Teff. In addition, IL-7R blockade by OSE-127 in humanized mouse models reduced human T cell homing to the gut and colonic inflammation (Belarif L et al, 2019). Methods A first-in-human, phase I, randomized, double-blind, placebo-controlled, single-center study was carried out to determine the safety, pharmacokinetics and pharmacodynamics of OSE-127 administration. Results Sixty-three healthy subjects were randomly assigned to OSE-127 or placebo with 45 of them exposed to the active product in 9 groups: 6 single ascending dose groups with intravenous (IV) administration (0.002-10 mg/kg), 1 subcutaneous treatment group (1 mg/kg) and 2 double IV infusion groups (6 or 10 mg/kg). OSE-127 was well tolerated, with no evidence of cytokine-release syndrome and no significant alteration of blood lymphocyte counts or subset populations. OSE-127’s pharmacokinetic half-life after a single dose increased from 4.6 days (1mg/kg) to 11.7 days (10 mg/kg) and, after a second dose, from 12.5 days (6 mg/kg) to 16.25 days (10 mg/kg). Receptor occupancy was ≥ 95% at doses ≥ 0.02 mg/kg and this saturation level was maintained up to >100 days after 2 IV infusions at 10 mg/kg. Furthermore, a differential gene expression signature performed in peripheral leukocytes, pre- and post-OSE-127 administration, identified six IL-7 pathway-related genes (BCL2, CISH, PTGER2, DPP4, SOCS2 and FLT3LG). Interestingly, decreased expression of this signature was sustained overtime in accordance with the systemic drug exposure. The differential expression of 4 of these 6 genes (BCL2, CISH, PTGER2, DPP4) has been individually validated by quantitative RT-qPCR, and this novel 4-gene signature appears to follow a dose-dependent expression. Conclusion Our data provide evidence that IL-7 receptor can be blocked in humans without inducing serious adverse events. The signature identified in the peripheral leukocytes of subjects having received OSE-127 represents a robust and simple means to monitor target engagement in the clinical setting. OSE-127 is currently being evaluated in a Phase 2b study in UC patients (CoTikiS study: NCT04882007).

CTIM-27. LOCOREGIONAL B7-H3-SPECIFIC CAR T CELLS FOR CHILDREN AND YOUNG ADULTS WITH DIPG: INTERIM REPORT OF BRAINCHILD-03 ARM C

Abstract Following preclinical optimization of B7-H3-specific CAR T cells against pediatric brain tumor models, we opened BrainChild-03 (NCT04185038), a phase 1 clinical trial of repeatedly dosed, outpatient, locoregional B7-H3-specific CAR T cells for children with recurrent/refractory central nervous system (CNS) tumors or diffuse intrinsic pontine glioma (DIPG). Here, we report the interim findings from patients enrolled on Arm C, dedicated to DIPG. The primary endpoints are feasibility and safety, with secondary endpoints of disease response. We utilize second-generation CAR T cells with a 4-1BB costimulatory domain and a methotrexate-resistant human DHFR mutein (huDHFRFS; L22F,F31S), allowing for methotrexate selection. We do not deliver conditioning chemotherapy. The first three evaluable patients with DIPG all met feasibility for generating a balanced CD4:CD8 CAR T cell product, with 3.85x109 CAR T cells generated for S005, 4.29x109 for S008, and 2.45x109 for S012, allowing for greater than 6 months of biweekly dosing for each patient. All subjects were treated at Dose Level 1 (1x107 CAR T cells). S005 received 10 doses before clinical progression greater than 2 years from diagnosis, S008 has received 10 doses and continues on therapy with decreased tumor volume, and S012 has received 5 doses and continues on study with stable disease. There have been no dose limiting toxicities (DLT). 3/3 patients exhibited post infusion fever, headache, and elevated serum CRP but no evidence of cytokine release syndrome (CRS) or systemic CAR T cells. 0/3 patients required PICU admissions. In the cerebrospinal fluid (CSF), 2/3 patients have had elevations of cytokines such as CXCL10 and CCL2, as well as circulating CSF CAR T cells. Advanced serial patient CSF proteomic and transcriptomic profiling are underway. Ultimately, this report provides preliminary evidence that outpatient locoregional B7-H3 CAR T cells for children with DIPG may be feasible and tolerable.

Neurological Consequences of Cytokine Release Syndrome Following Subcutaneous Recombinant IL-15 and Haploidentical Donor Natural Killer Cell Therapy for Advanced Acute Myeloid Leukemia

Abstract Cytokine Release Syndrome (CRS) is associated with elevated cytokine levels, macrophage activation, and IL-6 production after antibody or cell-based immunotherapy. We have observed over 200 patients with no CRS following adoptively transferred haploidentical donor natural killer (haplo-NK) cell products after lymphodepleting chemotherapy plus IL-2; and achieved complete remission in 30-50% of patients with refractory AML. To promote NK cell expansion without stimulation of Treg that may compromise NK function, we tested the substitution of IL-2 with the NCI manufactured rIL-15. Using the same lymphodepleting preparative regimen (Fludarabine 25 mg/m2IV for 5 days and Cyclophosphamide 60 mg/kg IV for 2 days) we infused CD3- and CD19-depleted haplo-NK incubated overnight with rIL-15 (10 ng/mL) prior to infusion. Two cohorts received rIL-15; either intravenously x 12 daily doses (at the Phase I MTD of 0.75 mcg/kg) or subcutaneously x 10 doses (5 days on, 2 days off, 5 days on at 2 mcg/kg SQ, the MTD when used as monotherapy in solid tumor patients). CRS was defined by modified CRS grading criteria (Lee et al. Blood, 2014). Results: Forty patients with relapsed/refractory AML were treated with haplo-NK plus IV rIL-15 (n=24) or SQ rIL-15 (n=16). Patients received an average of 11.6 IV doses [9-12, 96% of planned doses] or 7.5 SQ doses [1-10, 75% of planned doses]. Dosing was stopped for toxicity. No CRS events were observed after IV dosing. However, after SQ dosing, 9 of 16 patients [56%] had grade 1-4 CRS; [4 (25%) with grade 3-4 CRS) (Table 1). The median time from NK infusion to onset of CRS was 8 days [2-44]. Six of the 9 CRS patients (66%) had neurological events. Neurological toxicities included grade 1-2 encephalopathy (n=2), intracranial hemorrhage (ICH) (n=2, grade 1 and grade 5), and grade 4 seizures (n=2). One additional event (a patient with a fall resulting in ICH due to pre-existing gait abnormality) without evidence of CRS was not considered as IL-15 associated neurotoxicity CRS. Symptoms resolved in 4 of 5 patients who received treatment for neurologic CRS (3 received both steroids and Tocilizumab, 1 received steroids only, 1 patient did not require treatment as symptoms resolved with stopping IL-15). Non-neurologic toxicity included hypoxia (n=2) and hypotension (n=3). No significant correlations were found between development of CRS and absolute lymphocyte or monocyte count, presence or absence of haplo-NK expansion at day 14, number of rIL-15 doses received, or disease burden at baseline as measured by blast percentage in bone marrow. In the IV rIL-15 cohort, only 2 of 14 patients at the MTD (14%) cleared leukemia and underwent transplantation. In contrast, 8 of 16 patients (50%, P=0.04) in the SQ rIL-15 cohort achieved CR (n=7) or CRp (n=1), with 6 patients proceeding to alloHCT consolidation. CRS did not limit the clinical benefit in the SQ cohort as 4 of 9 [44%] patients with CRS achieved CR/PR compared to 4 of 7 [57%] patients without CRS. Pharmacokinetic data showed slower clearance of rIL-15 in SQ compared to IV dosing, as shown by higher trough levels prior to dose 2 (501 vs. 233 pg/mL, p Download : Download high-res image (163KB) Download : Download full-size image Disclosures Bachanova: Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Seattle-Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Zymogen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oxis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Miller: Celegene: Consultancy; Oxis Biotech: Consultancy; Fate Therapeutics: Consultancy, Research Funding.

Covid-19: A Pharmacotherapeutic Perspective

Introduction: COVID-19 disease has been difficult to tackle owing to the lack of typical therapeutic options. Many antivirals, antimalarial, and biologics are being carefully evaluated for treatment. This literature analysis aims to shed light to the ongoing studies concerning treatment possibilities for COVID-19 and assist as a reserve for health experts.
 Objectives: This literature review was done to underline the efficacy and safety of existing treatment alternatives for COVID-19 and the cautious use of non-steroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.
 Methods: PubMed, Medline, Embase and SCOPUS were meticulously browsed utilizing an amalgamation of the keywords "COVID 19," "SARS-CoV-2," and "treatment." All categories of articles together with clinical guidelines, case-studies and systematic reviews were assessed.
 Conclusions: Treatments that unswervingly target SARS-CoV-2 are not present so far; however, several antivirals (Remdesivir) and antimalarials (Hydroxychloroquine) have appeared as valuable treatment possibilities. Remdesivir and convalescent plasma may be expected to play a beneficial role in serious patients with respiratory failure. Interleukin-6 (IL-6) antagonists could also be utilized in patients who progress and display evidence of cytokine release syndrome. Corticosteroids need to be avoided lest there is a gripping indication for their usage. Available evidence for prevention and treatment of COVID-19 must be utilized till recognized treatments are derived into reality.

564. Tocilizumab Induces Rapid, Sustained Improvement of Inflammatory Markers in COVID-19

BackgroundFrequent observation of increasing fever and rising inflammatory markers late after onset of COVID-19 suggests Cytokine Release Syndrome (CRS, “Cytokine Storm”) may contribute to pathophysiology. Tocilizumab (TCZ), a monoclonal antibody targeting the receptor for the pro-inflammatory cytokine, IL-6, is effective in suppressing pathological inflammation in several rheumatological diseases. After administering TCZ to COVID-19 patients with suspected CRS, we observed a sharp fall in inflammatory indices. We analyzed this effect using results from the first 19 COVID-19 patients receiving TCZ at our hospital.MethodsData for all patients with confirmed COVID-19 who received TCZ at our center, a 200 bed community hospital in New England, were extracted from the Electronic Medical Record, including demographics, body temperature, C-Reactive Protein (CRP), IL-6 levels, clinical severity on the Ordinal Scale for Clinical Improvement (OSCI), and clinical outcome (recovery/discharge home, partial recovery/discharge rehab, death). Results were tabulated and statistical significance of changes in indices pre- and post- TCZ assessed by Wilcoxon Signed-Rank Test.Results19 patients received TCZ: 16 got 400mg x1, 2 got 400 mg x2, 1 got 660 mg x1. Median age was 64 years (range: 44–94), 68% male. Mean interval from symptom onset to receiving TCZ was 11.5 days. Mean IL-6 was 145 pg/mL. Demographics, OSCI scores, and discharge status are shown in Table 1. Average daily peak temperatures (Tmax) pre- and post- TCZ were 100.7 and 98.9°F, p< 0.001. Mean CRP pre- and post- were 234 and 84.6 mg/L, p=0.001 (Fig.1). Decrease in Tmax and CRP was rapid and sustained (Fig. 2, 1st 8 patients shown for clarity.). 58% had improved clinical improvement by OSCI by day 7, 68% by day 14. 7 of 19 of patients were discharged home, 6 to rehab or acute care facility, and 6 died.Table 1: Patient Demographics, Clinical Severity Score, and Discharge Status ConclusionIn this cohort of patients with moderate-to-severe COVID-19 and evidence of Cytokine Release Syndrome, tocilizumab was associated with rapid resolution of fever and marked decline in CRP. Most patients showed improvement in clinical severity scores and no adverse reactions were noted. Tocilizumab may be useful in control of pathological inflammation in COVID-19. Controlled trials will be needed to assess overall clinical benefit.Disclosures All Authors: No reported disclosures

Filgrastim associations with CAR T-cell therapy.

Little is known about the benefits and risks of myeloid growth factor administration after chimeric antigen receptor (CAR) T‐cell therapy for diffuse large B‐cell lymphoma (DLBCL). We present a retrospective analysis among 22 relapsed/refractory DLBCL patients who received CAR T‐cell therapy with axicabtagene ciloleucel. Filgrastim was administered by physician discretion to seven patients (31.8%), and the median duration of neutropenia after lymphodepleting therapy was significantly shorter for those patients who received filgrastim (5 vs 15 days, P = .016). Five patients (22.7%) developed infection in the 30 days post‐CAR T‐cell therapy with three patients being Grade 3 or higher. There was no difference in the incidence and severity of infection based on filgrastim use (P = .274, P = .138). Among the seven patients that received filgrastim, six patients (85.7%) and four patients (57.1%) had evidence of cytokine release syndrome (CRS) and immune effector cell‐associated neurotoxicity syndrome (ICANS), respectively. Among the 15 patients that did not receive filgrastim, 8 patients (53.3%) and 7 patients (46.7%) had evidence of CRS and ICANS, respectively. There was no significant difference in the incidence of developing CRS or ICANS between the group of patients that received filgrastim and those that did not (P = .193, P = .647). However, there was a significant increase in the severity of CRS for patients that received filgrastim compared to those that did not (P = .042). Filgrastim administration after CAR T‐cell therapy may lead to an increase in severity of CRS without decreasing infection rates.

Granulocyte Colony-Stimulating Factor (G-CSF) Interactions with Chimeric Antigen Receptor (CAR) T-Cell Therapy for Diffuse Large B-Cell Lymphoma

Introduction Chimeric Antigen Receptor (CAR) T-cell therapy is an innovative therapy for relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Prior to CAR T-cell infusion, patients receive lymphodepleting chemotherapy and may receive granulocyte colony-stimulating factor (G-CSF) to decrease the duration of neutropenia and risk of infection. However, G-CSF also has the potential to increase the incidence and/or severity of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) by promoting antigen-presenting cell function (Mehta HM, J Immunol, 2015). More data is required to guide clinicians on the benefits and risks of G-CSF use in CAR T-cell treatment. Methods A retrospective analysis was performed among 22 DLBCL patients who received CAR T-cell therapy with Axicabtagene ciloleucel at the University of California Los Angeles from March 2018 to May 2019. All patients received standard lymphodepleting therapy with fludarabine 30 mg/m2/day and cyclophosphamide 500 mg/m2/day on days -5 through -3, except one patient who received reduced dosages for renal disease. Prophylactic tocilizumab 8 mg/kg was given to all patients at 36 hours after CAR T-cell infusion, with additional doses of tocilizumab and/or steroids given for evidence of CRS/ICANS based on the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading system. G-CSF was administered by physician discretion following CAR T-cell infusion at a weight-based dosage of either 300 or 480 mcg and cumulative G-CSF dose recorded within the first 30 days. Results Patient and disease characteristics are shown in Table 1. Seven of the 22 patients (31.8%) received G-CSF at a median cumulative dosage of 2880 mcg (IQR 900-8640), with the majority (4 patients, 57.1%) receiving G-CSF in the first 5 days post CAR T-cell infusion (Table 2). The median duration of neutropenia following lymphodepleting therapy was 5 days (IQR 4.5-8.5) for those patients treated with G-CSF compared to 15 days (IQR 8.0-30.0) for those who did not receive G-CSF (p = 0.0157). Seven patients (31.8%) developed infection in the 30 days post CAR T-cell therapy with 4 infections being grade 3 or higher. There was no difference in the incidence and severity of infection between those patients who received G-CSF and those that did not (p = 0.630, p = 0.424, Figure 1). CRS was noted in 14 patients overall (63.6%), 4 of which were grade 3 or higher. ICANS was noted in 11 patients overall (50.0%), 9 of which were grade 3 or higher. Among the 7 patients that received G-CSF, 6 patients (85.7%) and 4 patients (57.1%) had evidence of CRS and ICANS, respectively. Among the 15 patients that did not receive G-CSF, 8 patients (53.3%) and 7 patients (46.7%) had evidence of CRS and ICANS, respectively. There was no significant difference in the incidence of developing CRS (any grade) or ICANS (any grade) between the group of patients that received G-CSF and those that did not (p = 0.193, p = 0.647). However, there was a significant increase in the severity of CRS for patients that received G-CSF compared to those that did not (p = 0.0418, Figure 1), but no increase in the severity of ICANS based on G-CSF use (p = 0.660, Figure 1). Thirteen patients (59.1%) received corticosteroids following CAR T-cell treatment at a median cumulative dosage of 666.7 mg prednisone equivalents (IQR 445.0-933.3), with the majority (9 patients, 69.2%) receiving steroids in the first 5 days post CAR T-cell infusion (Table 2). More than half of the cohort (14 patients, 63.6%) required more than 1 dose of tocilizumab (Table 2). There was no association between G-CSF use and steroid use or administration of more than 1 dose of tocilizumab (p = 0.648, p = 0.074). Conclusions Our data demonstrates a significant increase in severity without an increase in incidence of CRS with G-CSF use within 30 days of Axicabtagene ciloleucel administration for relapsed/refractory DLBCL. There was no association of G-CSF with severity or incidence of ICANS and no difference in infection rates with G-CSF in this setting. *Both Daria Gaut and Kevin Tang contributed equally to this work. Disclosures No relevant conflicts of interest to declare.

Pilot Study of Non-Viral, RNA-Redirected Autologous Anti-CD19 Chimeric Antigen Receptor Modified T-Cells in Patients with Refractory/Relapsed Hodgkin Lymphoma (HL)

Pilot Study of Non-Viral, RNA-Redirected Autologous Anti-CD19 Chimeric Antigen Receptor Modified T-Cells in Patients with Refractory/Relapsed Hodgkin Lymphoma (HL)

A First-in-Human Study of Autologous T Lymphocytes with Antibody-Dependent Cell Cytotoxicity (ADCC) in Patients with B-Cell Non-Hodgkin Lymphoma (NHL)

Recent trials in patients with B-cell malignancies have demonstrated the clinical potential of chimeric antigen receptor (CAR)-directed T cells. We developed a chimeric receptor (antibody-coupled T-cell receptor, ACTR) consisting of high affinity CD16 V158, CD8α transmembrane domain, 4-1BB and CD3ζ (Kudo et al. Cancer Res 2014). Expression of ACTR conferred ADCC capacity to T cells. In vitro and in immunodeficient mice, ACTR T cells specifically killed B-NHL and chronic lymphocytic leukemia cells tagged with the anti-CD20 antibody rituximab. Trastuzumab induced ACTR-mediated T cell killing of breast and gastric cancer cells, and anti-GD2 of neuroblastoma and osteosarcoma cells. Thus, infusion of ACTR T cells might significantly augment the anti-tumor potential of immunotherapeutic antibodies, and expand options for cell therapy of cancer.To assess the safety of this strategy and explore its efficacy, we began a pilot study in patients with relapsed/refractory CD20+ B-NHL (ATTCK20; ClinicalTrials.gov No. NCT02315118). In this first-in-human study, ACTR expression is achieved by mRNA electroporation and, hence, is transient. In Phase 1a, 3 subjects receive one dose of autologous ACTR T cells (0.5 x 106/kg) 2 days after rituximab (500 mg/m2); a second dose of ACTR T cells at 0.5 x 107/kg 28 days later is allowed if there is no toxicity and evidence of response. Interleukin-2 (IL-2) is given subcutaneously at 1 million IU/m2/d x 3 during the first week after infusion. Phase 1b plans up to 4 infusions of ACTR T cells (0.5 x 107/kg) at 10 day intervals, each preceded by rituximab at 375 mg/m2; IL-2 (as in Phase1a) is given after the first 2 infusions only.Six subjects have been enrolled to date (3 in Phase 1a, 3 in Phase 1b) and received a total of 14 ACTR T cell infusions. All had advanced CD20+ B-NHL (2 diffuse large B cell lymphoma, 2 primary mediastinal B cell lymphoma, 1 mantle cell lymphoma, and 1 mediastinal grey zone lymphoma) and had failed multiple lines of therapy. As a lymphodepleting regimen prior to the first ACTR T cell infusion, 5 of the 6 patients received fludarabine (25 mg/m2/d x 5) plus cyclophosphamide (60 mg/kg/d x 1, n=3; 900 mg/m2/d x 1, n=2); the remaining patient received bendamustine (90 mg/m2/d x 2).After leukapheresis, T cells were cultured under cGMP conditions with anti-CD3 and -CD28 antibodies, and IL-2. After 10 days, cells were electroporated with ACTR mRNA using the MaxCyte GT system. The next day, median ACTR expression in T cells, as shown by flow cytometry, was 95.8% (range, 82.8%-99.3%; n=14). With Rituximab, this produced a median cytotoxicity of 77.5% (67.6%-97.6%; n=14) against CD20+ Daudi cells at a 4:1 effector : target ratio in 4 hours. As expected, ACTR expression in vitro remained high for the first 3-4 days, declining thereafter.We met or exceeded the estimated minimum target levels of CD3+ ACTR+ cells in 13 of the 14 infused cell products. CD3+ ACTR+ cells (mostly CD8+) were detectable in peripheral blood 1 day after infusion and reached their peak on day 3-4 when they represented 0.43-11.20 (median, 1.27) cells per µL. They became undetectable after day 6, reflecting the kinetics of ACTR expression in vitro.As of July 2016, 5 of the 6 patients are evaluable, with a median follow-up of 60 weeks (range, 6-83) after the last ACTR-T cell infusion; the remaining patient has received 3 of the 4 scheduled cycles. The main toxicities were grade 3-4 cytopenias: these were observed in all patients and likely due to the lymphodepleting regimen. There was no non-hematologic toxicity, nor evidence of cytokine release syndrome. In Phase 1a, 2 patients had progressive disease (PD) and 1 had stable disease (SD) on CT scan following the first and second infusions, with PET-CT showing reduced FDG avidity and central areas of photopenia suggestive of necrosis. Of the 2 Phase 1b patients evaluable for response, 1 had PD after the third infusion and was taken off study; the other had SD 1 month after 4 ACTR-T infusions; the 2nd month assessment was interpreted as PD.The initial results of this ongoing trial using autologous T cells with transient ACTR expression are encouraging and warrant additional studies with more potent formulations of this technology. To this end, a clinical trial for patients with relapsed/refractory CD20+ B-NHL in which ACTR is permanently expressed in autologous T cells via viral vector transduction is planned (ClinicalTrials.gov No. NCT02776813). DisclosuresCampana:Unum Therapeutics: Consultancy, Equity Ownership, Patents & Royalties; Juno Therapeutics: Patents & Royalties; Nkarta Therapeutics: Consultancy, Equity Ownership, Patents & Royalties.

T-Cell Replete Peripheral Blood Haploidentical Donor Transplant Is Frequently Associated with Cytokine Release Syndrome Which Responds to Anti-IL-6 Therapy

Introduction: Allogeneic hematopoietic cell transplantation is a cornerstone of therapy for hematologic malignancies and often a patient's only curative intent treatment. Traditionally reserved for patients with an HLA-matched donor, advances in graft versus host disease (GVHD) prophylaxis utilizing post-transplant cyclophosphamide (PTCy) have expanded the use of haploidentical hematopoietic cell transplantation (haplo-HCT). While overall outcomes for haplo-HCT appear to be excellent, its novel approach brings toxicities that are particular to its biological and clinical milieu.The immediate post-transplant course in T cell replete haplo-HCT is often complicated by symptoms including fever, hypoxia, hypotension and organ dysfunction resembling the cytokine release syndrome (CRS) previously described in recipients of targeted cellular therapeutics such as CAR T-Cells. IL-6 is thought to be a key mediator of CRS in patients receiving novel T-cell engaging therapies, and tocilizumab has been used with success in this setting.Here we aim to describe the nature and incidence of CRS in haplo-HCT recipients, as well as its potential implications on clinical outcomes. Additionally, prospective analysis of cytokine profiles of haplo-HCT recipients and clinical responses to tocilizumab therapy are presented.Patients and Methods: We performed a retrospective review of patients who underwent haplo-HCT transplantation at our institution from July 2009 through April 2015. Patients were scored for symptoms of CRS based on established grading criteria (Lee et al, Blood 2014). Patients were stratified into three categories by grade of CRS experienced: none (grade 0), mild (grade 1-2) and severe (grade 3-4). Outcomes were assessed.A total of 84 patients were identified, 55% (46) were male, with a median age at transplant of 49 (19-73), and 49% (41) had active disease at the time of transplant. The most common diagnosis was AML (55 pts), followed by ALL (9 pts), MDS (5 pts) and NHL (2 pts). Among the patients, 26% (22 pts) had undergone prior transplant.In addition to the retrospective review, baseline and post- transplant cytokine levels were prospectively drawn in 10 patients who underwent haplo-HCT. A total of 7 additional patients who met criteria for CRS were treated prospectively with tocilizumab (dose: 4mg/kg-bw) and clinical responses were recorded. We recorded CRP levels in selected patients as part of clinical monitoring.Results: We found a high incidence, 85%, of CRS in our haplo-HCT patients. Among a total of 84 patients, 12 (14%) experienced severe CRS, 60 (72%) had mild CRS, and 12 (14%) patients had no evidence of CRS. The most common manifestations of severe CRS included: fever (100%), respiratory failure (75%), hypotension (83.3%), hepatic failure (25%) and renal failure (33.3%). The median maximum CRP (during post-transplant days 0 to 8) in all patients suffering from CRS was 155 mg/L.Of the twelve patients who suffered from severe CRS, nine (75%) died. Predicted median survival was 0.72 months for severe CRS, 12.7 months for patients with no CRS and was not reached for patients with mild CRS (fig 1). Rates of acute and chronic graft-versus-host disease did not differ by CRS status. The incidence of mild and severe CRS did not differ by ABO mismatch, age, CMV status, donor sex, T-cell or CD34 cell dose. There was no difference in rates of CRS for patients in remission versus active disease at time of transplant. There were no differences in engraftment.Cytokine profiles in haplo-HCT recipients showed significant elevation in serum IL-6 levels, most significant in patients who suffered from severe CRS (fig 2). We administered tocilizumab to 7 patients with severe CRS symptoms early after haplo-HCT (median day of treatment was day +3) resulting in the resolution of their CRS symptoms within 48-72 hours. Over the same time period CRP levels dropped below 50% of the peak value.Summary:CRS is common after T-cell replete haplo-HCT and severe CRS is potentially associated with high risk of early mortality after transplant. Cytokine profiles suggest IL-6 is a key mediator of CRS in haplo-HCT patients. Tocilizumab appears to be an effective treatment for patients who develop severe CRS early after T-cell replete haplo-HCT. Future prospective studies are warranted in studying the role of tocilizumab in the treatment and potentially prevention of severe CRS in haplo-HCT patients. [Display omitted] [Display omitted] DisclosuresFehniger:Celgene: Research Funding. Uy:Novartis: Research Funding. Abboud:Teva Pharmaceuticals: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Pfizer: Research Funding; Merck: Research Funding; Gerson Lehman Group: Consultancy.

NK-92 Therapy Is Well Tolerated, Has Minimal Toxicity and Shows Efficacy in a Phase I Trial of Patients with Relapsed/Refractory Hematological Malignancies Relapsing after Autologous Stem Cell Transplantation

BackgroundAutologous NK cell adoptive immunotherapy has potential to treat a variety of malignancies, but is limited by patient-specific variations in numbers and quality of expanded cells. In contrast, allogeneic NK cell lines can overcome many of these limitations. The NK line, NK-92 can be manufactured under Good Manufacturing Practice (GMP) compliant conditions, and infused into patients, as demonstrated in two prior phase I trials for solid tumours. Here, we report the findings of a phase I trial of NK-92 with the highest cell dosing regimen tested to date, in patients with relapsed/refractory hematological malignancies.MethodsWe conducted a single-center, non-randomized, non-blinded, open-label, Phase I dose-escalation trial of irradiated NK-92 cells in adults with refractory hematological malignancies who relapsed after autologous stem cell transplantation. The objectives were to determine, safety, feasibility and evidence of activity against refractory hematological malignancies. Inclusion criteria included measurable disease, adequate organ function and ECOG performance status of < 2. Exclusion criteria were pregnancy, concurrent treatment within 28 days with other experimental therapy, known HIV, HBV or HCV infection and malignant CNS disease. Patients were treated at one of three dose levels (1x109 cells/m2, 3x109 cells/m2 and 5x109 cells/m2), given on day 1, 3 and 5 for a planned total of six monthly cycles. NK-92 cells were obtained from Conkwest, and a frozen working cell bank was established at Princess Margaret Cancer Centre and stored in liquid nitrogen. Clinical-grade NK-92 cells were then manufactured under GMP conditions by expanding a cryopreserved vial of NK-92 in Vuelife culture bags using GM1 medium. Release criteria of NK-92 for infusion included negative mycoplasma testing, day 7 culture sterility, endotoxin <0.05 EU/mL, and additionally, a negative stat gram stain and cell viability of >70%. The final NK-92 cell product was resuspended in GM2 medium (Plasma-Lyte-A medium), irradiated with 10 Gy and infused fresh intravenously over one hour.ResultsTwelve patients with hematological malignancies who relapsed after undergoing stem cell transplantation for relapsed/refractory disease were enrolled with the following diagnoses: multiple myeloma (5), diffuse large B-cell lymphoma (4), Hodgkin lymphoma (2) and mantle cell lymphoma (1). There were 9 males and 3 females and median age was 60 (range: 42-67) years. Patients had received 2-5 chemotherapy regimens before autologous stem cell transplantation and some also received additional chemotherapy after autotransplant and prior to receiving NK-92 infusions. The number of cycles of NK-92 administered ranged from 1-6, with 10 patients coming off study because of disease progression, and one patient proceeding to allogeneic stem cell transplantation. The only toxicity was infusion-related fever and chills (grade II) in one patient, and none had evidence of cytokine release syndrome. A patient with relapsed, refractory Hodgkin lymphoma had a complete response and remains in remission more than five years after NK-92 therapy. An additional three patients experienced transient responses. There were no significant alterations in hemoglobin, platelets, white cell count, creatinine or liver function tests in patients receiving NK-92 infusions. While six patients developed anti-HLA antibodies, none developed a T-cell immune response as determined by the mixed lymphocyte response of patient lymphocytes against NK-92.ConclusionNK-92 can be administered after autologous stem cell transplantation at very high doses with virtually no toxicity to patients with relapsed/refractory hematological malignancies. This is the first trial of NK-92 which includes patients with multiple myeloma. Surprisingly, most patients did not mount cellular immune responses against NK-92, despite receiving very large numbers of NK cells, up to a total of 150x109 cells. We conclude that high dose NK-92 therapy is safe and has the potential to induce long term survival in select patients. We propose that NK-92 can serve as a standardized off-the-shelf cellular treatment for malignancies and could provide a platform for gene-modified targeted cell therapy. DisclosuresKeating:Conkwest: Other: Research funding unrelated to clinical trial.

Chimeric T Cells for Therapy of CD30+ Hodgkin and Non-Hodgkin Lymphomas

Adoptive cellular immunotherapy for Hodgkin lymphoma (HL) associated with EBV infection has had considerable success, inducing >50% complete and sustained remission rates in patients with relapsed/resistant disease. However, only 40% of HL patients express EBV-associated antigens. By contrast, almost all HL and some non-Hodgkin lymphomas (NHL), such as anaplastic large cell lymphoma (ALCL), express the CD30 antigen both at diagnosis and relapse, and monoclonal antibodies targeting CD30 produce objective antitumor responses. Monoclonal antibodies (mAb), however, have limited bio-distribution and their effects may be limited in duration. We therefore expressed the antigen binding domain of a CD30 mAb as part of a chimeric antigen receptor (CAR) on T cells, coupled to the CD28 and ζ chain endodomains, in an effort to ensure prolonged persistence, active penetration of tumors and activation of multiple lytic components of the immune system. We report here an initial analysis of our phase I dose escalation study of activated autologous CD30.CAR-T cells (CD30.CARTs) infused in patients with relapsed/refractory EBV-negative CD30+ HL or NHL.We manufactured CD30.CARTs for 18 patients using retroviral transduction. Starting from a median of 2.4×107 PBMCs (range 3.6×106 to 4.9×107), we obtained 9.0×108 CD30.CARTs (range 2.8×108 to 2.9×109) in 15±3 days of culture, with a transduction efficiency of 89%±1%. The cell products comprised >99% T cells and phenotypic analysis showed 58%±29% CD8+ T cells, with a majority of them being effector T cells (CD45RO+ 94%±7%). 51 Cr-release cytotoxicity assays confirmed that patients' CD30.CARTs lysed a CD30+ tumor line, HDLM-2 (60%±13% killing at a 20:1 effector:target ratio), with negligible effects on CD30− target cells (<5% killing). During cell manufacture, 3 patients became ineligible due to rapid worsening of their performance status and 1 patient was not infused because his tumor was subsequently shown to be CD30-negative.Nine patients (7 with HL and 2 ALCL) have received CD30.CARTs. Eight of these had relapsed or progressed after treatment with the CD30 mAb brentuximab. Two patients were treated on dose level (DL) 1 (2×107 CD30.CAR+ T cells/m2), 2 patients on DL2 (1×108) and 5 patients on DL3 (2×108). None of the patients received any conditioning regimen before CART infusion. CART infusions produced no attributable adverse events; in particular, no patient had evidence of cytokine release syndrome. As CD30 can be transiently expressed by activated T cells, for example during infection with viruses, we monitored antiviral immunity in CART recipients. The frequency of T cells responding to CMV, adenovirus, influenza virus and EBV (assessed using stimulation with viral peptides in IFNγ ELIspot assays) remained unchanged by treatment. The molecular signal from CARTs, assessed by Q-PCR in peripheral blood, peaked at 1 week following infusion, but decreased to near background by 4 weeks post infusion. The signal level was dose dependent, with an mean of 7020 copies/μg DNA in patients treated on DL3, in whom CAR-T cells were detectable by flow cytometry in the peripheral blood (~5% of PBMCs), versus 60 copies/μg for DL1.At 6 weeks after treatment, 1 patient had a CR, 1 patient had a very good PR, and 4 patients had stable disease (persisting for 1½ to 8 months), while 3 patients had disease progression. Having completed the dose escalation and found that DL3 is safe and associated with significant in vivo expansion, we will now explore the use of these cells after autologous stem cell transplantation in patients at high risk of relapse. DisclosuresOff Label Use: Adoptively transferred T cells administered under an IND. Rooney:Celgene: Other: Collaborative research agreement; Cell Medica: Other: Licensing Agreement. Brenner:Bluebird Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Cell Medica: Other: Licensing Agreement; Celgene: Other: Collaborative Research Agreement. Heslop:Celgene: Other: Collaborative research agreement; Cell Medica: Other: Licensing Agreement.

IMCT-15PILOT STUDY OF T CELLS REDIRECTED TO EGFRvIII WITH A CHIMERIC ANTIGEN RECEPTOR IN PATIENTS WITH EGFRvIII+ GLIOBLASTOMA

We have initiated a first-in-human pilot study of intravenous delivery of autologous T cells re-directed to the EGFR variant III mutation by means of a lentiviral vector encoding a chimeric antigen receptor (CAR). Patients with recurrent or incompletely resected glioblastoma (GBM) have their tumors screened for the presence of the EGFRvIII mutation by a next-generation sequencing based assay. Eligible patients undergo leukapheresis for collection of autologous T cells, which are then manufactured to form CART-EGFRvIII T cell products. We report preliminary results on the first six patients we have treated. We targeted a challenging subset of GBM patients, with multi-focal recurrent, residual, progressive disease refractory to standard and experimental therapies, including chemotherapy, radiation, bevacizumab and prior immunotherapy. To date, we have found that infusion of CART-EGFRvIII cells is safe, without evidence of off-tumor toxicity such as cross-reactivity to wild type EGFR. No clinical or laboratory signs of systemic cytokine release syndrome have been observed. One patient developed a seizure and non-convulsive status epilepticus nine days after CART-EGFRvIII infusion. Seizures resolved with anti-epileptic medications, and the patient was treated with steroids and anti-IL6 cytokine therapy. All patients have had significant expansion of CART-EGFRvIII cells as measured by flow cytometry and quantitative PCR in peripheral blood samples, despite the use of steroids in two patients. In one of two patients who had operative resection of presumed residual tumor, pathologic evaluation demonstrated inflammation, T cell infiltration, and EGFRvIII antigen loss. In total, two of six heavily pretreated patients are clinically stable three months post-CART infusion. These findings provide preliminary evidence that CART-EGFRvIII cells are safe, without evidence of off-target toxicity and without evidence of cytokine release syndrome, and that these are active T cell products that expand in the blood.

A Phase 1, Randomized Ascending Single-Dose Study of Antagonist Anti-Human CD40 ASKP1240 in Healthy Subjects

This first-in-human, phase I study evaluated the safety, tolerability, pharmacokinetic and pharmacodynamic profile of ASKP1240 in healthy subjects. Twelve sequential groups (each 6 active and 3 placebo) were randomly assigned to placebo or single ascending doses of intravenous ASKP1240 (0.00003-10 mg/kg). ASKP1240 exhibited nonlinear pharmacokinetics, with mean maximal serum concentrations and area under the serum concentration-time curves ranging from 0.7 to 251.6 μg/mL and 6.5 to 55409.6 h·μg/mL following doses 0.1 mg/kg-10 mg/kg, respectively. CD40 receptor occupancy by ASKP1240, which was dose-dependent, reached a maximum at doses above 0.01 mg/kg. ASKP1240 was well tolerated, with no evidence of cytokine release syndrome or thromboembolic events. Treatment emergent antibodies to ASKP1240 were detected in 5/70 (7.1%) ASKP1240 recipients. In conclusion, antagonism of the CD40/CD154 interaction with ASKP1240 was safe and well tolerated at the doses tested.

Randomised trial of basiliximab versus placebo for control of acute cellular rejection in renal allograft recipients

Currently available immunosuppressive regimens for cadaver-kidney recipients are far from ideal because acute-rejection episodes occur in about 30% to 50% of these patients. In the phase III study described here we assessed the ability of basiliximab, a chimeric interleukin (IL)-2 receptor monoclonal antibody, to prevent acute-rejection episodes in renal allograft recipients. 380 adult recipients of a primary cadaveric kidney transplant were randomly allocated, in this double-blind trial, to receive a 20 mg infusion of basiliximab on day 0 (day of surgery) and on day 4, to provide IL-2-receptor suppression for 4-6 weeks (n=193), or to receive placebo (n=187). Both groups received baseline dual immunosuppressive therapy with cyclosporin and steroids throughout the study. The primary outcome measure was incidence of acute-rejection episodes during the 6 months after transplantation. Safety and tolerability were monitored over the 12 months of the study. 376 patients were eligible for intention-to-treat analysis (basiliximab, n=190; placebo, n=186). No significant differences in patient characteristics were apparent. The incidence of biopsy-confirmed acute rejection 6 months after transplantation was 51 (29.8%) of 171 in the basiliximab group compared with 73 (44.0%) of 166 in the placebo group (32% reduction; 14.2% difference [95% Kaplan-Meier CIs 3% to 24%], p=0.012). The incidence of steroid-resistant first rejection episodes that required antibody therapy was significantly lower in the basiliximab group (10% vs 23.1%, 13.1% difference [5.4% to 20.8%], p<0.001). At weeks 2 and 4 post-transplantation, the mean daily dose of steroids was significantly higher in the placebo group (p<0.001 with one-way analysis of variance). The incidence of graft loss at 12 months post-transplantation was 23 (12.1%) of 190 in the basiliximab group and 25 (13.4%) of 186 in the placebo group (1.3% difference [-5% to 9%], p=0.591). The incidence of infection and other adverse events was similar in the two treatment groups. The acute tolerability of basiliximab was excellent, with no evidence of cytokine-release syndrome. 14 deaths (basiliximab n=9; placebo n=5; -2.0% difference [-6% to 2%], p=0.293) occurred during the 12-month study and a further three deaths (basiliximab n=1; placebo n=2) occurred within the 380-day cut-off period. One post-transplantation lymphoproliferative disorder was recorded in each group. Prophylaxis with 40 mg basiliximab reduces the incidence of acute rejection episodes significantly, with no clinically relevant safety or tolerability concerns.