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Editor’s key points | fatigue | RECRUITMENT |
Anxiolysis for children undergoing short day-case surgical procedures is an important intervention.The findings of this randomised trial suggest melatonin is less effective than midazolam for preoperative anxiolysis in children.However, the trial was terminated early because of recruitment fatigue, which makes the findings more susceptible to bias.Each year, ∼487,000 children undergo general anaesthesia in the UK.Midazolam is a benzodiazepine and remains the most commonly prescribed oral premedication in the UK for anxious children before general anaesthetic.The aim of the MAGIC trial was to evaluate the effectiveness of melatonin compared with midazolam in the premedication of anxious children before general anaesthesia with non-inferiority methodology. The rationale for completing this comparison on a non-inferiority basis is represented by the improved AE profile of melatonin. Secondary trial objectives include the comparison of side-effects observed with each drug and the time to discharge. | PMC10797512 |
Methods | PMC10797512 | |||
Study design and participants | learning disabilities, throat, anxiety | BLIND | This multicentre, parallel-group, double blind, individual participant-randomised trial took place across 20 UK NHS Hospital Trusts. Delegated research staff identified, assented, and randomised paediatric participants identified as anxious on the day of surgery. Trial information was given via age-specific patient information sheets and short video animation. Eligible participants were anxious children aged 3–14 yr, scheduled for elective dental, ear, nose, and throat (ENT), ophthalmology, gastroenterology, radiology, plastic, orthopaedic, urology, or general surgery under general anaesthetic. As a pragmatic trial, preoperative anxiety as eligibility for inclusion was left to clinical judgement of the responsible anaesthetist, as per local standard of care. This reflects normal practice in the UK. There is no clinically validated objective measure or universal guidance on the selection of children for premedication in the UK, where the decision is based on anaesthetists' judgement. Therefore, prescribing practice can vary from clinician to clinician. Decision-making for premedication is undertaken at preassessment clinics, on the morning of surgery when the anaesthetist assesses the child, or both. Participants were American Society of Anesthesiologists (ASA) physical status 1 or 2 and required written caregiver’s consent for entry into the trial.Exclusion criteria were: children deemed non-anxious by the responsible anaesthetist; surgery requiring inpatient admission (non-day-case); premedication required for reasons other than anxiety; current prescription of melatonin, midazolam, or drug that contraindicated the co-prescription of either trial medication; presence of severe learning disabilities rendering verbal and written communication difficult; ASA physical status 3, 4, or 5; and caregiver not consenting to participation in the trial. This population was similar to that of trials which assessed the efficacy of midazolam. | PMC10797512 |
Randomisation and blinding | ’s taste reaction, head and neck, gastroenterology and MRI | Participants were randomly assigned in a 1:1 ratio to either control (midazolam) or treatment (melatonin) arms. Randomisation was computer-generated and completed using minimisation based on centre, surgical speciality (head and neck, gastroenterology and MRI, and other) and sex (male/female). All hospitals involved in the trial were assessed before inclusion by a pre-trial audit and feasibility assessment to ensure comparability, including case lists, anaesthetic teams, use of paediatric wards/recovery facilities, and midazolam prescribing practices. Hospitals were similar in that they were either teaching hospitals or large district general hospitals serving comparable general populations, with appropriate dedicated paediatric lists from which patients were further carefully specified by means of the trial’s inclusion/exclusion criteria.The trial was double-blind, with the participant, clinical care team, and assessor (research nurse or trained member of clinical staff) all blinded to treatment allocation. Allocation concealment was achieved using a centralised web-based randomisation system, with treatment allocation revealed solely to an unblinded trial pharmacist for drug dispensation. Trial medication for both arms was supplied in matching single-use plastic bottles of identical dosage strengths, raspberry flavourant, and volume. There was a risk that the staff member administering the Investigational Medicinal Product (IMP) may become unblinded; either through observing the child’s taste reaction as a result of midazolam being associated with unfavourable taste/rejection | PMC10797512 | |
Data collection | anxiety | A series of anxiety and recovery measures, for both child participants and their caregivers, were administered on the day of surgery (pre- and post-surgery) and 14 days post-discharge. | PMC10797512 | |
Interventions | Participants were allocated to receive either melatonin or midazolam 0.5 mg kg | PMC10797512 | ||
Primary outcome measure—modified Yale Preoperative Anxiety Scale-Short Form | Anxiety, anxiety | The primary endpoint was modified Yale Preoperative Anxiety Scale-Short Form (mYPAS-SF) score (adjusted for baseline) measured over the three consecutive, standard preoperative time points recommended for the scale: start of transfer to theatre, entry into anaesthetic room, and administration of anaesthesia. The mYPAS-SF is the current gold standard for assessing child anxiety during induction of anaesthesia. | PMC10797512 | |
Secondary outcome measures | anxiety | SECONDARY | A selection of secondary outcome measures were recorded to further assess participant and caregiver preoperative anxiety and postoperative child recovery, including; anaesthetic failure, Cooperation Score, FPS-R observer and participant reported, caregiver STAI questionnaire, VSRS, and PAED index. At 2 weeks post-surgery, longer-term measures of anaesthetic impact were assessed using the PHBQ-AS and QoL CHU9D. | PMC10797512 |
Sample size | The sample size, based on mYPAS-SF over all three time points whilst adjusting for baseline (assumed correlation 0.5), | PMC10797512 | ||
Statistical analysis | All of the statistical analysis was performed according to the MAGIC Statistical Analysis Plan | PMC10797512 | ||
Approvals | The full MAGIC trial protocol is available via the University of Sheffield data repository, ORDA. | PMC10797512 | ||
Results | PMC10797512 | |||
Early closure | RECRUITMENT | The MAGIC trial opened to recruitment in July 2019. In early 2020, the COVID-19 pandemic severely disrupted the trial, which was halted and then reopened to recruitment in October 2020, closed again in February 2021, and re-opened again in June 2022. However, the ongoing pandemic led to challenges in drug supply, paediatric elective surgery list recovery (post-COVID), and therefore trial recruitment. With agreement from the trial steering committee and the trial funders, the trial was terminated early in November 2022, on the grounds of recruitment futility. A total of 110 participants were recruited to the trial; the original sample size was 624. Barriers to the recruitment of anxious children undergoing day-case surgery are discussed elsewhere. | PMC10797512 | |
Recruitment, randomisation, and withdrawal | throat, Anxiety | Between July 30, 2019 and November 9, 2022, 110 participants were randomised across 17 centres; 55 to receive melatonin and 55 to receive midazolam (CONSORT flow diagram. mYPAS-SF, modified Yale Preoperative Anxiety Scale-Short Form; PI, principal investigator; RN, research nurse.Baseline characteristics of randomised participants. Select percentages may not sum to 100 because of rounding. Assessed numbers are given where data were not available for the whole population. ENT, ear, nose, and throat; IQR, inter-quartile range; mYPAS-SF, modified Yale Preoperative Anxiety Scale-Short Form; STAI, State Trait Anxiety Inventory.Boxplots of mYPAS-SF scores at each time point by treatment group. mYPAS-SF, modified Yale Preoperative Anxiety Scale-Short Form. | PMC10797512 | |
Primary outcome measure (mYPAS-SF) | The primary outcome measure, mYPAS-SF, was completed at baseline and at least one follow-up time point for 94 participants (86%), with all data included in the ITT analysis. Six participants (6%) were excluded from the PP analysis. The adjusted mean difference in mYPAS-SF scores for melatonin Adjusted mean difference in mYPAS-SF of melatonin compared with midazolam from the primary analysis models. (Mean [standard deviation]) mYPAS-SF scores and adjusted mean differences from the primary analysis model for each analysis population located in | PMC10797512 | ||
Secondary outcome measures | SECONDARY | Full results from all of the secondary outcomes can be found in Post-surgery, PAED index decreased over time from a mean score of 11.6 (VSRS scores increased over time from a mean score of 13.7 ( | PMC10797512 | |
Adverse events | ADVERSE EVENTS, ADVERSE EVENT | Of the participants receiving the IMP (99/110, 90%), 22 (22%) had at least one AE (Number of adverse events and proportion of participants with at least one adverse event. | PMC10797512 | |
Discussion | delirium, Delirium | SECONDARY, RECRUITMENT | Here we report the first multicentre, randomised trial of melatonin The magnitude of difference in adjusted mYPAS-SF observed in the midazolam group compared with melatonin was a consistent finding throughout all three time points (transfer, entry into anaesthetic room, and anaesthetic induction). Consequently, both ITT and PP analyses delivered 95% CI heavily skewed in favour of midazolam (The MAGIC trial gathered a number of secondary outcomes to assist with triangulation of those properties of a favourable premedication that may not be directly linked to anxiolytic efficacy. Regarding all secondary outcome measures, our findings are underpowered and so care should be taken with their interpretation. Midazolam’s clinical profile led to a pre-trial assumption that postoperative recovery would be more impaired in comparison to the melatonin group, although trial measures of sedation recovery (VSRS) and emergence delirium (PAED index) demonstrated no such difference between groups (Mean post-surgery PAED and VSRS scores (with 95% CI) by treatment group. CI, confidence interval; PAED, Paediatric Anaesthesia Emergence Delirium scale; VSRS, Vancouver Sedation Recovery Scale.A number of barriers to recruitment were noted during a formal qualitative analysis, undertaken as part of the internal pilot of the trial | PMC10797512 |
Future studies | anxiety | The trial showed that using melatonin as a premedication was less effective at reducing preoperative anxiety than midazolam, further adding to the knowledge base within the perioperative anaesthetic field of effective anxiolytic paediatric premedications. However, given the findings of the MAGIC trial, there still remains a clinical need to develop or repurpose another premedication with a more favourable side-effects profile. A recent 2022 systematic review evaluated the sedative effects of various commonly used premedications, including: dexmedetomidine, midazolam, clonidine, ketamine, and melatonin, in managing preoperative anxiety in children (aged <7 yr). | PMC10797512 | |
Conclusions | anxiety | The trial did not reach the required sample size and therefore is prone to bias. Within the population studied, melatonin is less effective than midazolam at reducing preoperative anxiety in children and young people before general anaesthesia. The current standard of care, midazolam, was better by a clinically meaningful margin. | PMC10797512 | |
Authors' contributions | RS | CD (chief investigator), RB (co-investigator), MCH (trial manager), EH (statistician), DP (CTRU lead), NT (statistician) and MW (co-investigator) together produced the first draft of the manuscript. All members of the authorship group, provided in Conceived of or designed the work: RB, DP, CD, NT, MW, ZM, JC, SoA, SA, MB, JB, JCC, AE, FG, JR, HR, GW, JY, TY on behalf of the MAGIC collaborative.Involved in the acquisition of data for the work: MCH, ES, AL, RS, JH, KH, AT, KM, SW and CD on behalf of the MAGIC collaborative.Involved in the analysis of data: EH, NT, MB, AL, RS, RB, DP, CD, MW, MCH on behalf of the MAGIC collaborative.Responsible for statistical analysis and modelling: EH, NT, MB on behalf of the MAGIC collaborative (Responsible for project level steering, national coordination, and data collection: the trial steering committee and data monitoring and ethics committee.Responsible for ensuring adherence to hospital-level governance protocols and regional data collection: local leads.Revised the work critically for important intellectual content: all authors.Involved in the final approval of the version to be published: all authors. | PMC10797512 | |
Declaration of interest | The authors declare that they have no conflicts of interest. | PMC10797512 | ||
Funding | The MAGIC trial was funded by the NIHR Health Technology Assessment programme (NIHR HTA 16/80/08). Further information available at: | PMC10797512 | ||
References | PMC10797512 | |||
Supplementary data | The following are the Supplementary data to this article: | PMC10797512 | ||
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Acknowledgements | SCHILDER | We gratefully acknowledge the hard work, support, and advice from the following: the MAGIC study teams, research nurses; research support staff and clinical teams within the participating NHS trusts for participant screening, delivering the intervention, data collection, and patient follow up. We also offer thanks to Alessia Dunn and Erica Wallis (research managers as research sponsor) for support of the trial. We specially thank the 110 patients who took part in the study, and their families for supporting their choice and also contributing.We thank and acknowledge advice and oversight from members of the trial steering committee: Anne Schilder (chair), Paul Brady, Justine Heard, Nia Goulden, and John Rouse (PPI) and data monitoring and ethics committee: Ivor Chestnutt (chair), Lee Middleton, James Armstrong, and Glyn Williams.This report presents independent research commissioned by the NIHR. The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the National Institute for Health and Care Research (NIHR), NIHR Evaluation, Trials and Studies Coordinating Centre (NETSCC), the HTA programme, or the Department of Health.For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising from this submission.Supplementary data to this article can be found online at | PMC10797512 | |
Subject terms | infection, cardiac dysfunction | INFECTION, SARS-COV-2 INFECTION, CARDIOVASCULAR DISORDERS | Post-COVID-19 condition refers to a range of persisting physical, neurocognitive, and neuropsychological symptoms following SARS-CoV-2 infection. Recent evidence revealed that post-COVID-19 syndrome patients may suffer from cardiac dysfunction and are at increased risk for a broad range of cardiovascular disorders. This randomized, sham-control, double-blind trial evaluated the effect of hyperbaric oxygen therapy (HBOT) on the cardiac function of post-COVID-19 patients with ongoing symptoms for at least three months after confirmed infection. Sixty patients were randomized to receive 40 daily HBOT or sham sessions. They underwent echocardiography at baseline and 1–3 weeks after the last protocol session. Twenty-nine (48.3%) patients had reduced global longitudinal strain (GLS) at baseline. Of them, 13 (43.3%) and 16 (53.3%) were allocated to the sham and HBOT groups, respectively. Compared to the sham group, GLS significantly increased following HBOT (− 17.8 ± 1.1 to − 20.2 ± 1.0, This study was registered with ClinicalTrials.gov, number NCT04647656 on 01/12/2020. | PMC10257166 |
Introduction | cardiac injury, COVID-19 syndrome, cardiac abnormalities, myocardial inflammation | CORONAVIRUS, MYOCARDIAL INFLAMMATION, SEVERE ACUTE RESPIRATORY SYNDROME | The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has resulted in more than 541 million infected cases, as of June 2022. Even though most infected patients recover, around 10–30% remain with persistent symptoms that can significantly affect their quality of lifeThe long-term impact of COVID-19 associated cardiac injury has recently been revealed. A radiological study of 100 discharged COVID-19 patients found cardiac abnormalities and myocardial inflammation in 78% and 60% of participants, respectively, which were not associated with the initial COVID-19 severityCurrently, treatment options for post-COVID-19 condition include targeted anti-inflammatory molecules and specific diets. However, none have been determined effectiveIn recent years, evidence has accumulated about hyperbaric oxygen therapy’s (HBOT) efficacyThe aim of the current study was to evaluate the effects of HBOT on cardiac function in patients suffering from the post COVID-19 syndrome in a randomized, sham-control, double-blind clinical trial. | PMC10257166 |
Methods | PMC10257166 | |||
Patients | cognitive decline, traumatic brain injury | ASYMPTOMATIC SARS-COV-2 INFECTION, BRAIN PATHOLOGY | Included patients were over 18 years old with a reported post-COVID-19 cognitive symptoms that affected their quality of life and persisted for more than three months after an RT-PCR confirmed mild-moderate symptomatic SARS-CoV-2 infection. Patients were excluded if they had a history of pathological cognitive decline, traumatic brain injury, or any other known non-COVID-19 brain pathology. | PMC10257166 |
Design | SECONDARY | The current study is part of phase II exploratory clinical trial. A prospective randomized, double-blind, sham-controlled study was conducted from December 14, 2020, to December 27, 2021, at Shamir Medical Center (SMC), Israel. After signing informed consent, patients were randomized to either HBOT or sham-control groups in a 1:1 ratio according to a computerized randomization table, performed using an in-house software written in MATLAB R2021b (MathWorks, Natick, MA), supervised by a blinded researcher.Patients were questioned after the first session on their perception regarding the treatment they received to evaluate masking. The evaluation procedure was done at baseline and 1–3 weeks after the last HBOT/sham session. All evaluators were blinded to the patients’ group allocations. The study was approved by SMC’s Institutional Review Board (IRB) (No. 332–20-ASF) and all participants signed informed consent before their inclusion. All research was performed according to the relevant guidelines and regulations. This study was registered with ClinicalTrials.gov, number NCT04647656 on 01/12/2020. The primary end point of this clinical trial was cognitive function which was reported in the first publication along with secondary endpoints of the associated related symptoms brain MRI features. This article focused on the cardiac functions evaluated on the same study population. | PMC10257166 | |
Intervention | Both HBOT and sham protocols were administrated in a multi-place Starmed-2700 chamber (HAUX, Germany). The protocol comprised of 40 daily sessions, five sessions per week within a two-month period. The HBOT protocol included breathing 100% oxygen by mask at 2ATA for 90 min with five-minute air breaks every 20 min. Compression/decompression rates were 1.0 m/minute. The sham protocol included breathing 21% oxygen by mask at 1.03 ATA for 90 min. To mask the controls, the chamber pressure was raised to 1.2 ATA during the first five minutes of the session along with circulating air noise followed by decompression (0.4 m/minute) to 1.03 ATA during the next five minutes.All the patients underwent an echocardiography examination twice, at baseline (before the first intervention session) and 1–3 weeks post the last protocol session. | PMC10257166 | ||
Primary and secondary outcomes | PMC10257166 | |||
Primary outcomes—Global Longitudinal Strain | Secondary outcomes: myocardial work index parameters: Global Work Index, Global Constructive Work. Global Wasted Work, Global Work Efficacy. | PMC10257166 | ||
Echocardiography examination | All echocardiography exams were performed using Vivid E95, (General Electric; Horten, Norway) with a standard transducer of 1.7–4 Hz. The frame rate during echocardiography examinations was greater than or equal to 40 frames per second. Comprehensive transthoracic echocardiography examinations were performed according to the latest recommendations on chamber quantificationBiplane left atrial volume index (LAVi) was calculated according to the following formula:Left ventricular mass index (LVMi) was calculated according to the following formula:All echocardiography examinations were then transferred to the EchoPAC workstation (Version 204), for further off-line speckle-tracking imaging analysis. Speckle tracking imaging analysis was done according to the original recommendations from the apical views | PMC10257166 | ||
Statistical analysis | Continuous data were expressed as means ± standard deviations (SD). Normality assumption was evaluated according to a Kolmogorov–Smirnov test. A paired t-test and a two-sample Student’s t-test were used to compare means as appropriate. A Welch's | PMC10257166 | ||
Results | intercurrent illness, traumatic | WASTED, EVENT | Out of 91 patients eligible to participate in the study, 11 patients did not complete the baseline evaluation and one patient did not meet inclusion criteria. Thus, 79 patients were randomized to either HBOT or sham arms. Two patients from the sham group withdrew their consent during treatment, and two patients did not complete the post-protocol assessments due to poor compliance. From the HBOT group, three patients did not complete post-protocol assessments due to intercurrent illness, a personal traumatic event, and withdrawal of consent. Accordingly, 37 patients from the HBOT group and 35 patients from the sham group completed the protocol and underwent post-treatment assessments. Six echocardiography examinations from the HBOT group and 4 from the sham group were not transferred appropriately and saved for analysis. One exam from each group was not suitable for speckle tracking imaging analysis due to suboptimal quality. Figure Patient flowchart.Patient baseline characteristics are detailed in Table Patient characteristics.BMI, body mass index; BSA, body surface area; PCI, percutaneous coronary interventions; ACE, angiotensin converting enzyme.Conventional echocardiography parameters including ejection fraction (EF), LAVi, LVMi, diastolic function, and pulmonary artery pressure were similar between both groups (Baseline echocardiography and hemodynamic parameters.HR, heart rate; SBP, systolic blood pressure; DBP, diastolic blood pressure; LAVi, left atrial volume index; PAP, pulmonary artery pressure.Speckle tracking imaging parameters are presented in Table Myocardial work index changes.GLS, global longitudinal strain; GWI, global work index; GCW, global constructive work; GWW, global wasted work; GWE, global work efficacy.*p—the significance of baseline differences.Significant values are in bold.Post-hoc analysis was performed on the subgroup of patients with reduced GLS at baseline defined as lower than − 20% (Table Myocardial work index parameter changes in patients with reduced GLS.GLS, global longitudinal strain; GWI, global work index; GCW, global constructive work; GWW, global wasted work; GWE, global work efficacy.Significant values are in bold.Global longitudinal strain in the group of patients with reduced strain at baseline. GLS improved in both groups of patients with reduced strain at baseline. In patients that underwent HBOT, GLS improved significantly.Global longitudinal strain and myocardial work index parameters before and after the HBOT in a 45-year-old patient. (The data were analyzed by ML blindly. Interobserver and intraobserver variabilities (ML and VT) were done on 20 random study patients and were both found to range up to 5%. | PMC10257166 |
Discussion | myocardial damage, fatigue, early-stage myocardial fibrosis, COVID-19 infection, myocardial dysfunction, systolic dysfunction, cardiac abnormalities | VIRUS, NEUROLOGICAL DISEASE, LEFT VENTRICULAR DYSFUNCTION, POST-ACUTE COVID-19 SYNDROME, COVID-19 INFECTION, CARDIAC COMPLICATIONS, MYOCARDIAL DYSFUNCTION, SYSTOLIC DYSFUNCTION | The current randomized controlled trial demonstrates a subtle systolic dysfunction of GLS lower than − 20%, in about half (48.3%) of the post-COVID-19 syndrome patients, which was significantly improved by HBOT. This recovery in GLS by HBOT exceeded the natural recovery rate observed in the sham group.Previous studies have documented cardiac abnormalities in post-acute COVID-19 syndrome with transthoracic echocardiography (TTE). In 80% of patients who underwent echocardiography examination during hospitalization with COVID-19, GLS was reducedGLS has also been shown to allow the detection of subclinical myocardial dysfunction due to its ability to predict early-stage myocardial fibrosis in correlation with CMRThe principal pathophysiological mechanisms considered responsible for the myocardial damage caused by COVID-19 infection are related mostly to direct virus-induced injury due to a high distribution of ACE2 receptors on cardiac myocytes which are binding sites for virus particlesIn the past decade, novel HBOT protocols have been shown to induce both regenerative and anti-inflammatory effectsIn the current study, GLS significantly improved following HBOT, compared to the sham protocol. However, the significant mixed model interaction was significant in the post-hoc analysis for patients with reduced GLS. In other words, the regenerative effect of HBOT was beneficial in dysfunctional cardiac tissue, compared to supposedly healthy functional cardiac tissue. This finding has been validated in studies of non-healing wounds using HBOT, as well as recently in neurological diseases with dysfunctional (but non-necrotic) brain tissue. Recently, Robbins et al. reported a significant improvement in fatigue following HBOT sessions in post-COVID-19 patientsThe study has several strengths and limitations. The primary strength of this study is the sham protocol for the control arm. The main limitation lies in the relatively small sample size. A second limitation is that echocardiographic evaluation is operator-dependent. However, all the echocardiography examinations were performed by experienced sonographers and evaluated by the same senior cardiologists, who were blinded to the patient's allocation. Third, although the HBOT protocol included 40 sessions, an optimal number of sessions for maximal therapeutic effect has yet to be determined. Fourth, the SARS-CoV-2 different variants are not routinely tested in clinical practice, and therefore the data were unavailable as a possible co-factor. Lastly, results were collected 1–3 weeks after the last HBOT session. Long-term results as well as possible long-term clinical cardiac complications remain to be collected.In conclusion, in post-COVID-19 patients, slightly reduced GLS despite normal EF is a frequent finding and can indicate subclinical left ventricular dysfunction. HBOT promotes cardiac systolic function recovery in patients suffering from the post-COVID-19 condition. Further studies are needed to optimize patient selection and to evaluate long-term outcomes. | PMC10257166 |
Author contributions | M.L.—writing of the manuscript, data analysis; S.F.—a critical review, intellectual input; V.T.—data analysis, intellectual input; critical review; A.H.—a critical review, intellectual input; S.Z.-Y.—a critical review; S.E.—sudy design, intellectual input, critical review, final approval. All authors reviewed the manuscript. | PMC10257166 | ||
Data availability | The datasets analyzed during the current study available from the corresponding author on reasonable request. | PMC10257166 | ||
Competing interests | The authors declare no competing interests. | PMC10257166 | ||
References | PMC10257166 | |||
Background | COLORECTAL CANCER, SOLID TUMORS | NEO201 is a humanized IgG1 monoclonal antibody (mAb) generated against tumor-associated antigens from patients with colorectal cancer. NEO-201 binds to core 1 or extended core 1 O-glycans expressed by its target cells. Here, we present outcomes from a phase I trial of NEO-201 in patients with advanced solid tumors that have not responded to standard treatments. | PMC10053355 | |
Methods | toxicity | DISEASE PROGRESSION, SECONDARY, DISEASE | This was a single site, open label 3 + 3 dose escalation clinical trial. NEO-201 was administered intravenously every two weeks in a 28-day cycle at dose level (DL) 1 (1 mg/kg), DL 1.5 (1.5 mg/kg) and DL 2 (2 mg/kg) until dose limiting toxicity (DLT), disease progression, or patient withdrawal. Disease evaluations were conducted after every 2 cycles. The primary objective was to assess the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of NEO-201. The secondary objective was to assess the antitumor activity by RECIST v1.1. The exploratory objectives assessed pharmacokinetics and the effect of NEO-201 administration on immunologic parameters and their impact on clinical response. | PMC10053355 |
Results | toxicities, SD, neutropenia, febrile neutropenia | DISEASE PROGRESSION, COLORECTAL CANCER, NEUTROPENIA, BREAST CANCERS, FEBRILE NEUTROPENIA, DISEASE | Seventeen patients (11 colorectal, 4 pancreatic and 2 breast cancers) were enrolled; 2 patients withdrew after the first dose and were not evaluable for DLT. Twelve of the 15 patients evaluable for safety discontinued due to disease progression and 3 patients discontinued due to DLT (grade 4 febrile neutropenia [1 patient] and prolonged neutropenia [1 patient] at DL 2, and grade 3 prolonged (> 72 h) febrile neutropenia [1 patient] at DL 1.5). A total of 69 doses of NEO-201 were administered (range 1–15, median 4). Common (> 10%) grade 3/4 toxicities occurred as follows: neutropenia (26/69 doses, 17/17 patients), white blood cell decrease (16/69 doses, 12/17 patients), lymphocyte decrease (8/69 doses, 6/17 patients). Thirteen patients were evaluable for disease response; the best response was stable disease (SD) in 4 patients with colorectal cancer. Analysis of soluble factors in serum revealed that a high level of soluble MICA at baseline was correlated with a downregulation of NK cell activation markers and progressive disease. Unexpectedly, flow cytometry showed that NEO-201 also binds to circulating regulatory T cells and reduction of the quantities of these cells was observed especially in patients with SD. | PMC10053355 |
Conclusions | treatment-resistant solid tumors, neutropenia | ADVERSE EVENT, NEUTROPENIA | NEO-201 was safe and well tolerated at the MTD of 1.5 mg/kg, with neutropenia being the most common adverse event. Furthermore, a reduction in the percentage of regulatory T cells following NEO-201 treatment supports our ongoing phase II clinical trial evaluating the efficiency of the combination of NEO-201 with the immune checkpoint inhibitor pembrolizumab in adults with treatment-resistant solid tumors. | PMC10053355 |
Graphical Abstract | PMC10053355 | |||
Supplementary Information | The online version contains supplementary material available at 10.1186/s13046-023-02649-6. | PMC10053355 | ||
Keywords | PMC10053355 | |||
Background | colorectal cancer, tumor, neutropenia, toxicity, cancer, NEO-201, toxicities, tumors | TUMOR, COLORECTAL CANCER, NEUTROPENIA, CARCINOGENESIS, CANCER, DISEASE, SOLID TUMORS, ADVERSE EFFECT, TUMORS, CYTOTOXICITY | Recent efforts in cancer therapeutics have focused on the development of drugs that activate the immune system against cancer cells to achieve durable disease control. In recent decades, cancer immunotherapies have emerged as promising treatment options for many cancer patients and have increasingly been employed in specific disease settings as either an alternative to traditional chemotherapy and radiotherapy or as adjunctive therapy to these traditional modalities providing additive or even synergistic activity. Most cancer immunotherapies, including immune checkpoint inhibitors, vaccines, and engineered chimeric T-cell receptors, have focused on boosting the adaptive immune system in its activities of immunosurveillance, allowing it to recognize and mount immune responses against tumors [Concurrently with the development of immune checkpoint inhibitors, other mAbs, capable of recognizing tumor-associated antigens and directly eliciting tumor cell killing via antibody-dependent cellular cytotoxicity (ADCC) and/or complement-dependent cytotoxicity (CDC), have been developed [NEO-201 is a humanized IgG1 mAb generated against tumor-associated antigens from patients with colorectal cancer [NEO-201 binding specificity for tumor-associated proteins could be due to the presence of glycan patterns (i.e. O-glycans) attached to the protein carriers during post-translational modifications made during the process of carcinogenesis [The specificity of NEO-201 for a tumor associated antigen suggests a minimal risk of off-target, off-tumor toxicities on surrounding healthy tissue, which has been an important source of toxicity for many mAbs. NEO-201 demonstrated exceptional safety/tolerability in non-human primates, with transient neutropenia, due to high levels of expression of the antigen on mature neutrophils, being the only adverse effect observed [This study reports results from the first-in-human phase I trial designed to determine the MTD and RP2D of NEO-201 in patients with advanced solid tumors which have progressed on or not responded to standard treatments. Additional correlative data are presented related to NEO-201 pharmacokinetics and pharmacodynamics, specifically, for the effects on immune profile and correlation with treatment toxicity and response. | PMC10053355 |
Methods | PMC10053355 | |||
Study design and patient selection | tumor, DLTs, bleeding, neutropenia, febrile neutropenia, toxicity, toxicities, thrombocytopenia, signet cell ovarian cancer, anemia, pancreatic cancer, Cancer | TUMOR, BLEEDING, FEBRILE NEUTROPENIA, ADENOCARCINOMA OF THE LUNG, CANCER, BREAST CANCER, THROMBOCYTOPENIA, SQUAMOUS CELL LUNG CANCER, NEUTROPENIC FEVER, COLON CANCER, ANEMIA, METASTATIC CANCER, PANCREATIC CANCER, CARCINOMATOSIS, DISEASE PROGRESSION, NEUTROPENIA, EVENT, DISEASE, SECONDARY, PLEURAL EFFUSIONS, INFUSION REACTION | This is a Phase I first-in-human, single center, open label, dose escalation clinical trial (NCT03476681) using a standard 3 + 3 design. The primary objective was to determine the RP2D of NEO-201. The secondary objective was to assess the preliminary antitumor activity of NEO-201 and exploratory aims characterized the tumor expression of NEO-201 target antigen in archival tumor tissue, pharmacokinetics (PK), immunogenicity and effects of NEO-201 on immunologic correlates, including functional and phenotypic immune response and serum cytokines, chemokines, and soluble factors. All patients in this open-label study were treated at the National Cancer Institute (NCI), National Institutes of Health (NIH), USA. At each dose level, groups of 3–6 patients received NEO-201 intravenously at doses ranging from 1.0 to 2.0 mg/kg every 2 weeks until unacceptable toxicity, patient withdrawal or disease progression. Cycles were 28 days in length.Dose-limiting toxicities (DLTs) were defined as neutropenic fever, grade 4 neutropenia or thrombocytopenia lasting > 7 days, grade 3 thrombocytopenia with bleeding, or any grade 3 or higher NEO-201–related event occurring during the first cycle. As discussed below, the study was subsequently amended to recognize neutropenia as an expected toxicity, and grade 3 neutropenia improving to grade ≤ 2 with supportive growth factor therapy by the next scheduled dose or grade 3 febrile neutropenia improving within 72 h with or without interventions were not considered DLTs. Other exceptions that were not considered DLTs included transient infusion reactions resolving to grade 1 or better in less than 8 h, and grade 3 anemia less than 2 mg/dL below baseline or resolving to grade 1 or baseline by next scheduled dose. Full DLT definition is provided in the protocol in the supplementary materials. The MTD was defined as the highest dose at which fewer than two of six patients experienced a DLT. At the conclusion of the 2Based on previously conducted tissue reactivity studies described above, the dose escalation phase of this trial was opened to tumor types in which reactivity occurred in the majority of samples, including colon cancer, pancreatic cancer, adenocarcinoma of the lung, squamous cell lung cancer, breast cancer, and mucinous and signet cell ovarian cancer. Additional key eligibility criteria included locally advanced or metastatic cancer not eligible for standard therapy known to confer clinical benefit, disease that was measurable by RECIST v1.1 criteria or otherwise evaluable (e.g. bone scan, peritoneal or pleural effusions, carcinomatosis), and adequate performance status (e.g. ECOG ≤ 2 or Karnofsky ≥ 50%). There was no limit on number of prior therapies, including immunotherapies. | PMC10053355 |
Safety assessments | toxicity, DLTs | ADVERSE EVENTS, ADVERSE EVENT, ADVERSE EVENT | All patients who received at least two doses of NEO-201 were evaluable for safety and toxicity unless they were removed from study therapy for DLT. Safety evaluations were conducted at every treatment cycle, including determination of adverse events, DLTs during the dose-escalation stage, clinical laboratory measurements, vital signs, and physical examinations. Adverse events were assessed according to the NCI-Common Terminology Criteria for Adverse Events Version 5.0 and were monitored until 30 days after the last dose of study drug. | PMC10053355 |
Efficacy assessments | tumor | DISEASE PROGRESSION, DISEASE, PROGRESSION, TUMOR | Patients were considered evaluable for clinical response if they had measurable disease present at baseline, received at least one cycle of therapy, developed objective disease progression prior to the end of cycle 1, or had their disease re-evaluated by imaging at the conclusion of cycle 1. Radiologic assessment, including CT, MRI, or PET-CT as appropriate, was performed within 28 days prior to initial infusion and was repeated thereafter every 2 cycles. CEA levels and other tumor marker evaluations if appropriate were performed at these time points as well. Response was determined by a blinded central reviewer. Preliminary evidence of efficacy was determined by RECIST v1.1 guideline and reported as Objective Response Rate (ORR) (ORR = complete response (CR), partial response (PR), SD) and Progression Free Survival (PFS). | PMC10053355 |
Pharmacokinetic (PK) analyses | cancer | BLOOD, CANCER | Blood samples for PK analysis were obtained at pre-dose prior to the first infusion dose on cycle 1 day 1 (C1D1), end-of-infusion (EOI), then at 1 h (hr) post EOI, 4 h post EOI, 24 h post EOI, 72 h post EOI, 7 days post EOI and 14 days post EOI. Spare sampling (pre/trough and end of infusion) was performed on cycle 1 day 15 (C1D15), cycle 2 day 1 (C2D1), cycle 2 day 15 (C2D15), cycle 3 day 1 (C3D1) and samples were used to assess accumulation with biweekly dosing. Assessment into saturable elimination was also made. Blood samples were collected into Serum Separator Tubes (SST®), left to sit at room temperature for 30 min to allow clotting, then centrifuged to obtain serum. The serum was aliquoted into cryovials and frozen at -80 °C until bioanalysis. The first dose (starting from cycle 1, day 1 [C1D1]) exposure metrics of the maximum serum concentration (Cmax), minimum serum concentration (Cmin), area under the serum concentration vs time curve (AUC), half-life, clearance and volume of distribution through dense PK sampling were assessed.NEO-201 concentration in serum of cancer patients was determined by a fully-validated enzyme-linked immunosorbent assay (ELISA) method with a linear range of 0.25 – 2.0 mg/L (250 – 2000 ng/mL) performed by the NCI Clinical Pharmacology Program. NEO-201 was stable through 2 freeze/thaw cycles in serum at -80 °C, allowing for sample re-analysis. All data on serum NEO-201 concentrations met FDA guidelines for bioanalytical testing.Specifics of the ELISA and PK analysis are described in Supplementary materials and methods. | PMC10053355 |
Immunohistochemistry (IHC) | colon carcinoma, cancer, tumor, Cancer | COLON CARCINOMA, CANCER, TUMOR, CANCER | Archival tumor tissue samples were collected from all patients enrolling in the study, but expression of NEO-201 target antigen was not an eligibility criterion. A qualitative IHC staining system was used to identify the expression of the antigen recognized by NEO-201 in formalin-fixed, paraffin-embedded (FFPE) neoplastic tissues from cancer patients. For accuracy and reproducibility in conducting IHC, automated immunohistochemical staining was run and analyzed using the Leica Bond Max Automated Immunohistochemical Staining Procedure (Leica Biosystem, Buffalo Grove, IL, USA). A minimum of 10% of tumor cells in cancer tissues stained at a minimum of 2 + or 3 + intensity of staining with m16C3 reagent antibody (murine version of NEO-201) was considered positive for the expression of the antigen recognized by the clinical NEO-201 mAb. Cancer tissue with 0 or 1 + staining with m16C3 and underlying stromal tissue with 0 intensity of staining with m16C3 were considered negative for the expression of the antigen recognized by NEO-201. In this study, colon carcinoma with 3 + intensity of staining and adjacent colonic mucosa stained at background level of 1 + intensity were used as positive controls for m16C3 antibody in each run.Additional details about IHC staining procedure are reported in Supplementary materials and methods. | PMC10053355 |
Correlative assays | PMC10053355 | |||
Cytokines | toxicity, CRS | BLOOD, CLOT, CYTOKINE RELEASE SYNDROME | Blood samples (10 mL) were drawn for cytokine analysis in 10 mL red-top tubes to evaluate the toxicity risk of cytokine release syndrome (CRS). Blood samples were drawn prior to the first infusion dose on C1D1, 24 h post EOI, 72 h post EOI, 14 days post EOI and prior to C3D1. After drawing, blood was allowed to clot at room temperature for a minimum of 2 h and then red-top tubes were centrifuged for 10 min at the 2000 rpm with full brake.After centrifugation, the serum layer was aliquoted into cryovials designated for immune-monitoring research samples. Cryovials were frozen and stored at -80˚C until assays were performed. Cytokines (IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, TNF-α, IFN-γ) were evaluated using the V-PLEX Proinflammatory Panel 1 Human Kit (Meso Scale Discovery, Rockville, MD, USA), according to manufacturer’s instructions. | PMC10053355 |
Soluble factors | BLOOD | Blood samples (10 mL) were drawn in 10 mL red-top tubes to evaluate the serum levels of soluble CEACAM-5, CEACAM-6 and MICA. Blood samples were drawn prior to the first infusion dose on C1D1, 72 h post EOI, 14 days post EOI and prior to C3D1. After drawing, blood was processed with the same procedure described for cytokines analysis. The day of the assay, an aliquot of serum for each time point was defrosted and used at 1:3 dilution. Serum levels of soluble factors were detected through ELISA using the following kits and following manufacturer’s instructions: soluble CEACAM-5: Human Carcinoembryonic Antigen ELISA Kit (Abcam, Cambridge, MA, USA); soluble CEACAM-6: Human CD66c / CEACAM6 (Sandwich ELISA) ELISA Kit (LSBio, Seattle, WA, USA); soluble MICA: MICA Human ELISA Kit (Thermo Fisher Scientific, Waltham, MA, USA). | PMC10053355 | |
NK cells and regulatory T cells (Tregs) phenotype analysis | cancer | CANCER, COLD, APC | Analysis of the expression of cell-surface and intracellular proteins in peripheral blood mononuclear cells (PBMCs) from cancer patients was performed by flow cytometry to evaluate NK cells and Tregs phenotype. PBMCs from cancer patients were utilized under the appropriate NCI Institutional Review Board approval (protocol code NCT03476681, first approved 03/26/2018; latest update 01/08/2020). To isolate PBMCs, blood from cancer patients was collected in Heparin Green Top tubes.For NK phenotype analysis, blood samples were drawn prior to the first infusion dose on C1D1, 72 h post EOI, 14 days post EOI and prior to C3D1. For Tregs phenotype analysis blood samples were drawn prior to the first infusion dose on C1D1, 14 days post EOI and prior to C3D1. Isolated PBMCs were cryopreserved in cryovials containing 95% human AB serum + 10% DMSO in liquid nitrogen. The day of the flow cytometry PBMCs were thawed and stained with primary anti-human mAbs in 1X PBS + 1% BSA (Teknova, Hollister, CA, USA) for 30 min at 4 °C.To detect the NK surface markers PBMCs were labeled with following antibodies: CD56 PE (clone 5.1H11), CD16 PerCP-Cy5.5 (clone 3G8), NKG2D BV421 (clone 1D11), NKp46 FITC (clone 9E2) (BioLegend, San Diego, CA, USA), CD107a APC-H7 (clone H4A3) (BD Biosciences, San Jose, CA, USA), CEACAM-1 APC (clone 283340) (VWR, Radnor, PA, USA). To detect surface Tregs markers and to evaluate the reactivity of NEO-201 to human Tregs, PBMCs were labeled with the following anti-human mAbs: CD4 FITC (clone OKT4), CD127 APC (clone A019D5), CD15s PE (clone FH6), NEO-201 Pacific Blue (BioLegend, San Diego, CA, USA), CD25 APC-H7 (clone M-A251) (BD Biosciences, San Jose, CA, USA).For Tregs analysis, after staining surface markers, cells were permeabilized with Fix/Perm Solution (eBioscience™ Foxp3 / Transcription Factor Staining Buffer Set, Thermo Fisher Scientific) for 1 h at 4 °C to allow detection of intracellular transcription factors, and then stained in 100 uL of 1X Permeabilization Buffer for 1 h at room temperature in the dark with 2-4µL/sample of the anti-human Foxp3 PerCP-Cy5.5 mAb (clone 236A/E7, BD Biosciences, San Jose, CA, USA).After staining, cells were washed twice with cold 1X PBS and examined using a FACSVerse flow cytometer (BD Biosciences, San Jose, CA, USA). Analysis of cellular fluorescence was performed using BD FACSuite software (BD Biosciences, San Jose, CA, USA) and FlowJo 10.8.1. Positivity was determined by using fluorescence-minus-one controls.Complete staining procedure is reported in Supplementary materials and methods. | PMC10053355 |
Statistical analysis | Student’s t-test, 1-way ANOVA, and 2-way ANOVA with Bonferroni post-test analysis were performed where indicated. The number of samples chosen for each comparison was determined based on past similar experiments or by performing pilot experiments to assess the expected magnitude of differences. The number of experiments performed is indicated in the figure legends. Biological assays were performed in triplicate, with separate donors before statistical analysis was performed. | PMC10053355 | ||
Results | PMC10053355 | |||
Study population and disposition | colorectal cancer, pancreatic cancer, breast cancer | COLORECTAL CANCER, PANCREATIC CANCER, BREAST CANCER | Between January 8, 2019 and December 8, 2020, a total of 17 patients received one or more doses of NEO-201. The demographics of patients enrolled are listed in Table Patient demographics and baseline characteristicsPrior to treatment with NEO-201, ten and six patients with colorectal cancer had received anti-VEGF and anti-EGFR directed therapy respectively, and one patient had previously received an immune checkpoint inhibitor (pembrolizumab). Almost all (10/11) patients with colorectal cancer were microsatellite stable. Of the patients with pancreatic cancer, two had received immune checkpoint inhibitors (one pembrolizumab and one ipilimumab + nivolumab) prior to receiving NEO-201. Both patients with breast cancer were treated with anti-estrogen therapy (fulvestrant) and one with ipilimumab + nivolumab prior to receiving NEO-201. One patient with pancreatic cancer and four patients with colorectal cancer showed mutations in the KRAS gene. TMB status was known in only 4 patients: one patient with pancreatic cancer, one patient with breast cancer and one patient with colorectal cancer had intermediate TMB status, while one patient with colorectal cancer showed low TMB status. All patients tested (one with colorectal, one with breast, one with pancreatic cancer) were negative for PDL-1. A panel of all gene alterations recorded for each patient is provided in Supplementary Table | PMC10053355 |
Toxicity | neutropenia, febrile neutropenia, necrotic tumor, toxicity, infection | NEUTROPENIA, FEBRILE NEUTROPENIA, NECROTIC TUMOR, ADVERSE EVENTS, INFECTION | Among the 17 patients enrolled, 4 patients received NEO-201 at DL 1 (1 mg/kg), 7 patients received NEO-201 at DL 2 (2 mg/kg) and 6 patients received NEO-201 at DL 1.5 (1.5 mg/kg) (Table Most common grade 3 (Gr3) and grade 4 (Gr4) adverse events (AEs) in all patientsSee Supplementary Table Due to the ability of NEO-201 to kill neutrophils expressing core 1 O-glycans through ADCC [Three patients received NEO-201 at DL 1 for two doses without experiencing a DLT. After completion of 2 doses in three patients at DL 2, one patient experienced a DLT of prolonged neutropenia. DL 2 was subsequently expanded to 6 patients (1 patient withdrew consent after the first dose and was therefore not evaluable for DLT and was replaced in the enrollment). A second patient at DL 2 developed grade 4 febrile neutropenia (DLT). On further review of baseline imaging, this patient was noted to have necrotic tumor in close proximity to bowel, that was considered high risk for infection.After completion of the first 3 patients in DL 2, the protocol was amended to recognize severe neutropenia as an expected toxicity and to allow for administration of filgrastim to shorten the duration of the neutropenia and to reduce the risk of infection. Patients who developed neutrophil decrease after NEO-201 infusion were treated with filgrastim until the absolute neutrophil count (ANC) exceeded 1000/mm | PMC10053355 |
Activity | colorectal cancer, SD | DISEASE, COLORECTAL CANCER | Thirteen patients were able to undergo assessment for disease response. The best response observed was SD (> 56 days) in 4 patients, all of whom had colorectal cancer (Fig. RECIST response and time on study All 4 patients with SD after at least 4 doses of NEO-201 elected to continue receiving therapy, range of 1–11 additional doses (Fig. | PMC10053355 |
Pharmacokinetic analyses | All 17 patients were evaluable for first dose noncompartmental pharmacokinetic analysis. First dose NEO-201 serum concentration–time profiles were measured for all 17 patients across the three different dose levels (Fig. Clinical Pharmacokinetics of NEO-201 Relevant PK parameters during dense PK sampling were calculated following the first dose given on C1D1 (Fig. | PMC10053355 | ||
Time of administration of filgrastim affects NEO-201 PK | neutropenia | NEUTROPENIA | Ten of 17 patients (4 in DL 2 and 6 in DL 1.5) received filgrastim to shorten the duration of the neutropenia.In the DL 2 cohort, time of administration of filgrastim to mitigate neutropenia had an impact on NEO-201 concentration in the serum of some patients (Supplementary Fig. | PMC10053355 |
Pharmacodynamic analyses | PMC10053355 | |||
Immunohistochemistry (IHC) | tumor, breast cancer | TUMOR, BREAST CANCER | Baseline tissue samples from all patients enrolled in the study were tested for NEO-201 expression by IHC. Fifteen of 17 patients had tissue evaluable for IHC, and of these 14/15 had more than 90% tissue stain positive for the NEO-201 antigen with 3 + intensity. One breast cancer patient had 3 + staining in about 20% of the tumor section analyzed (Supplementary Table | PMC10053355 |
Cytokine analysis | TNF-α | PANCREATIC CANCER | To evaluate modulation of cytokines by NEO-201, serum samples were collected at timepoints before and after treatment and analyzed by ELISA-based cytokine array. At 24 h from infusion, serum IL-10 and TNF-α levels were increased in all patients at all dose levels. IL-10 increased to median fourfold higher in all patients compared to pre-infusion, and TNF-α to median 4- to sixfold higher in all patients (Fig. Serum cytokines modulation after NEO-201 infusion. Serum cytokines were evaluated using the V-PLEX Proinflammatory Panel 1 Human Kit. The figure depicts modulation of serum levels of cytokines statistically significant after NEO-201 treatments at different time points compared to baseline levels before treatment (C1PRE). No change in IL-12p70, IL-13, IL-1β, IL-2, IL-4 levels were observed in these patients after NEO-201infusion at all time points in all cohorts (data not shown). Effects on IL-6 were variable, with elevated median serum IL-6 levels detected in 3 patients (2 from 1.0 mg/kg, 1 from 2.0 mg/kg) at 24 h post-infusion. IL-6 levels returned to baseline levels at 72 h post-infusion, except for in one patient with pancreatic cancer in the 2.0 mg/kg cohort in which IL-6 levels remained elevated until C1D15 (Fig. | PMC10053355 |
Soluble MICA affects NK cell phenotype | cancer | CANCER, CYTOTOXICITY | The release of soluble factors from cancer cells constitutes an immune escape mechanism that systemically impairs efficacy of immunotherapy [Correlation between soluble factors and immune cells anti-cancer activity Since it has been demonstrated that tumor-derived soluble MICA can negatively impact NK cell cytotoxicity by modulating the NKG2D pathway [ | PMC10053355 |
NEO-201 binds to circulating Tregs | In a previous study, flow cytometry analysis of hematopoietic cells for NEO-201 binding revealed that approximately 4.6% of CD4One marker used to characterize a subset of highly immunosuppressive Tregs is CD15s [ | PMC10053355 | ||
Discussion | NSCLC, tumor, colorectal cancer, TNF-α, neutropenia, toxicity, cancer, inflammation, Head and Neck Squamous Cell Carcinoma, SD, uterine carcinoma, PD, NRAS, HNSCC, tumors | TUMOR, METASTASIS, COLORECTAL CANCER, NEUTROPENIA, ONCOGENESIS, CANCER, INFLAMMATION, EVENT, SOLID TUMORS, ADVERSE EFFECT, NON-SMALL CELL LUNG CANCER, UTERINE CARCINOMA, OVARIAN CARCINOMA, CERVICAL CANCER, NSCLC, TUMORS, COMPLICATIONS | One of the mechanisms involved in cancer development, progression and metastasis is the disruption of post-translational modifications of proteins and lipids, such as glycosylation. One glycosylation pattern altered in cancer cells is the O-glycosylation. During oncogenesis, truncated O-glycans can be expressed. This occurs when N-acetyl galactosamine (O-GalNAc) is added to the amino acids serine and threonine on cancer cells’ carrier proteins [In contrast to many antitumor antibodies, which were developed against a normal human protein, NEO-201 was raised against immunogenic tumor extracts as part of an allogenic colorectal cancer vaccine program [A recent study showed that NEO-201 recognizes specifically core 1 and/or extended core 1 O-glycans, and that NEO-201 binds and kills target cells expressing core 1 and/or extended core 1 O-glycans, through ADCC [This manuscript reports the results of the first-in-human, phase I dose escalation study of anti-core 1 O-glycans mAb NEO-201 in patients with solid tumors. Pre-clinical toxicity studies performed in cynomolgus monkeys showed exceptional safety/tolerability of NEO-201, with a transient decrease in neutrophils being the only adverse effect observed [Aside from the expected complications of neutropenia, NEO-201 was otherwise well tolerated. As expected from the binding profile of NEO-201 in animal studies and in vitro [Correlative studies revealed that NEO-201 infusion resulted in an upregulation of serum IL-10 and TNF-α levels, with more variable effects on other proinflammatory cytokines such as IL-8 and IFNγ. These cytokines are all classically considered proinflammatory and are elevated during acute inflammation. If inflammation becomes chronic, IL-10 and TNF-α could also have effects that block antitumor immunity by promoting the expansion of immunosuppressive cells such as Tregs and myeloid-derived suppressor cells (MDSCs) [In this study, we observed only a transient elevation of TNF-α and IL-10 levels following NEO-201 administration. Levels of these cytokines decreased toward baseline by 72 h from infusion in all patients, suggesting that this elevation is an acute inflammatory event and that NEO-201 does not determine a prolonged elevation of these cytokines. In our ongoing Phase II study, we are performing further mechanistic studies to evaluate the modulation of these cytokines not only in the peripheral blood but also in the TMEWe did not observe a significant difference in serum levels of soluble CEACAM-5 and CEACAM-6 between patients with SD and PD. On the contrary, patients with SD showed much lower baseline and post treatment serum levels of MICA compared to patients with PD, although this difference was not statistically significant. Patients with PD, who had high soluble MICA levels, also showed an impairment of NK activation markers. Conversely, patients with SD, who had low soluble MICA levels, did not show an impairment of NK activation markers, suggesting that soluble MICA could be a factor involved in the impairment of NK antitumor activity. Our observations correlate with several studies that proved that high soluble MICA levels correlate with poor prognosis in cancer patients [Additional correlative immunophenotyping assays unexpectedly revealed that NEO-201 binds to a specific subset of highly immunosuppressive Tregs expressing the cell surface marker CD15s (sialyl-Lewis-X). CD15s is specifically expressed by activated, terminally differentiated and most suppressive FOXP3This first in human study confirms what was observed in pre-clinical studies. NEO-201 has a potent ADCC-mediated killing activity against its target cells (i.e. neutrophils), and its potency is correlated to the activation status of NK cells, as shown in patients with SD. However, this study presents some weaknesses that are being addressed in both ongoing and future planned clinical studies with NEO-201. One of the weaknesses of this study is that we enrolled mostly patients with colorectal cancer who, although had high expression of NEO-201 target antigen, may have some intrinsic resistance to the anti-tumor activity of NEO-201. These were heavily pretreated patients in whom standard therapies had failed. These patients had microsatellite stable status, for whom immunotherapy is not indicated. Several factors involved in the TME of patients with colorectal cancer, such as accumulation of Tregs, MDSCs, and immunosuppressive cytokines, have been reported to determine resistance to immunotherapy [In our study, we reported SD in 4 patients with colorectal cancer, and we observed that SD could be linked to the low baseline level of soluble MICA and reduction of circulating Tregs after treatment with NEO-201. It is possible that NEO-201 may have an effect in depleting Tregs in the TME. Unfortunately, in this study, we did not have the possibility to evaluate the antitumor effect of NEO-201 in the TME. In addition, due to small sample size and heterogeneous tumor types in this study, the interpretation of our correlative studies is limited.Moreover, we noticed that all patients with SD harbored mutations in KRAS and/or NRAS genes. Based on this observation we will continue to explore the impact of specific genetic alterations in several types of tumors on the efficacy of NEO-201 and to determine if there is a role in combining NEO-201 and precision cancer drugs based on specific genetic alterations.To overcome these issues, in our ongoing phase II clinical trial, we are a) enlarging sample size; b) including different types of tumors that could be more sensitive to the immunotherapy than colorectal cancer (metastatic Non-Small Cell Lung Cancer (NSCLC), cervical cancer, Head and Neck Squamous Cell Carcinoma (HNSCC), uterine carcinoma who have progressed during or after front-line standard of care treatment including chemotherapy, checkpoint therapy and/or targeted therapy; c) evaluating the antitumoral activity of NEO-201 in the TME, including its ability to deplete Tregs, and if Tregs depletion in the TME is correlated to the clinical response to NEO-201 in combination with pembrolizumab; d) using NEO-201 at the RP2D with better timing of administration of filgrastim; e) evaluating the correlation with low baseline levels of soluble MICA with the clinical response to treatment with NEO-201 with a bigger sample size. If this correlation will be linked to a statistically significant difference between responders and non-responders, low soluble MICA level will be included as one of the eligibility criteria to select a more specific population that may benefit from treatment with NEO-201.Another shortcoming is that neutrophils killed by NEO-201 through ADCC can act as a “sink”, removing NEO-201 from the bloodstream and reducing the amount of antibody available to kill tumor cells. To overcome this issue and maximize the level of NEO-201 available to the tumor we are planning to launch new studies to use NEO-201 with chemotherapy or other anti-cancer drugs during neutrophil nadir. This concept is reinforced by results obtained in animal models harboring human pancreatic and ovarian carcinoma, in which we tested the antitumor activity of NEO-201. In these animals, lacking circulating human neutrophils, NEO-201 showed a potent antitumor activity, resulting in a reduction of tumor volume and/or prolonged survival compared to controls [ | PMC10053355 |
Conclusions | NSCLC, pembrolizumab, HNSCC, uterine cancer, chemo-resistant solid tumors, SD, malignancies, tumors | SOLID TUMORS, MALIGNANCIES, CERVICAL CANCER, NSCLC, TUMOR GROWTH, TUMORS | This first-in-human study of NEO-201 in solid tumors demonstrated that NEO-201 was well-tolerated and the RP2D was established at 1.5 mg/kg. Exploratory studies in serum suggested a correlation between maintenance of SD and lower baseline levels of soluble serum MICA, while serum levels of CEACAM-5 and CEACAM-6 were not related to the outcome of the treatment. In this study we also reported the ability of NEO-201 to bind to circulating Tregs. The reduction in circulating Tregs after NEO-201 infusion in patients with SD was one of the rationales to combine NEO-201 with pembrolizumab in the ongoing phase II clinical trial in adults with chemo-resistant solid tumors [Patients with malignancies for which checkpoint inhibitors are clinically indicated, including NSCLC, HNSCC, uterine cancer, and cervical cancer, often do not respond to initial treatment and eventually become resistant to many therapies. Resistance to immunotherapy is a great challenge from a therapeutic standpoint and necessitates the development of novel approaches to circumvent resistance, including combination therapies. Combining NEO-201 with pembrolizumab in our ongoing phase II clinical trial could be a promising strategy to enhance immune system mediated anti-tumor activity for two reasons: 1) NEO-201 may overcome resistance to checkpoint inhibitors, by depleting Tregs involved in the immunosuppression of immune cells that play a role in the control of tumor growth; 2) NEO-201 can kill via ADCC and/or CDC, tumors expressing its target antigen in subjects for whom pembrolizumab is currently indicated. | PMC10053355 |
Acknowledgements | Authors want to thank Seth Steinberg, head of Biostatistics and Data Management Section at NCI, for his biostatistical help. | PMC10053355 | ||
Authors’ contributions | MPM | RECRUITMENT | Conceptualization and design of clinical trial: CBC, MPM, MF, SAM, KYT, CMA; Recruitment of patients: CBC, MPM, NH, AMC, CMA; methodology, data interpretation and validation (pharmacokinetics): CP, WDF,TY; methodology, data interpretation and validation (IHC): MM, PF; methodology, data interpretation, and validation (correlative studies): CBC, MPM, MF, MF | PMC10053355 |
Funding | The study has been funded by Precision Biologics, Inc. and by NCI. | PMC10053355 | ||
Declarations | PMC10053355 | |||
Ethics approval and consent to participate | The study was approved by NCI, NIH, Institutional Review Board (protocol code NCT03476681, first approved 03/26/2018; latest update 01/08/2020) and all participants signed a written informed consent. | PMC10053355 | ||
Availability of data and materials | All data generated or analyzed during this study are included in this published article [and its supplementary information files].Data not shown in the manuscript are available from the corresponding author on reasonable request. | PMC10053355 | ||
Consent for publication | All patients gave written informed consent.All authors have read and approved of its submission to this journal. | PMC10053355 | ||
Competing interests | MF, SAM, AZ, KYT and PMA are employees of Precision Biologics, Inc. PMA has an ownership interest in Precision Biologics, Inc. PMA had no role in the design of the study, in the collection, analyses or interpretation of the data, in the writing of the manuscript or in the decision to publish the results. All other authors have no conflicts of interest to declare. | PMC10053355 | ||
References | PMC10053355 | |||
Key Points | PMC10308298 | |||
Question | psychosis | What are the optimal type, timing, and sequence of interventions for individuals at ultrahigh risk of psychosis? | PMC10308298 | |
Findings | REMISSION, RELAPSE | In this sequential multiple assignment randomized trial including 342 individuals, a specialized psychological intervention (cognitive-behavioral case management [CBCM]) and a psychopharmacological intervention (CBCM and antidepressant medication) were not more efficacious than control conditions in improving remission and functional recovery. Relapse rates among individuals who remitted were high. | PMC10308298 | |
Meaning | psychosis | The findings of this study show that addition of sequentially more specialized psychosocial and antidepressant treatment for individuals who did not remit did not lead to superior outcomes, underscoring the need for further adaptive trials, treatment innovation, and an extended duration of care for relapse prevention.This sequential multiple assignment randomized trial evaluates the efficacy of an intervention strategy for individuals at ultrahigh risk of psychosis. | PMC10308298 | |
Importance | psychosis | Clinical trials have not established the optimal type, sequence, and duration of interventions for people at ultrahigh risk of psychosis. | PMC10308298 | |
Objective | psychosis | To determine the effectiveness of a sequential and adaptive intervention strategy for individuals at ultrahigh risk of psychosis. | PMC10308298 | |
Design, Setting, and Participants | Psychosis, psychosis | The Staged Treatment in Early Psychosis (STEP) sequential multiple assignment randomized trial took place within the clinical program at Orygen, Melbourne, Australia. Individuals aged 12 to 25 years who were seeking treatment and met criteria for ultrahigh risk of psychosis according to the Comprehensive Assessment of At-Risk Mental States were recruited between April 2016 and January 2019. Of 1343 individuals considered, 342 were recruited. | PMC10308298 | |
Interventions | ω-3 fatty acids | Step 1: 6 weeks of support and problem solving (SPS); step 2: 20 weeks of cognitive-behavioral case management (CBCM) vs SPS; and step 3: 26 weeks of CBCM with fluoxetine vs CBCM with placebo with an embedded fast-fail option of ω-3 fatty acids or low-dose antipsychotic medication. Individuals who did not remit progressed through these steps; those who remitted received SPS or monitoring for up to 12 months. | PMC10308298 | |
Main Outcomes and Measures | Depression, psychosis | REMISSION | Global Functioning: Social and Role scales (primary outcome), Brief Psychiatric Rating Scale, Scale for the Assessment of Negative Symptoms, Montgomery-Åsberg Depression Rating Scale, quality of life, transition to psychosis, and remission and relapse rates. | PMC10308298 |
Results | psychosis | REMISSION, RELAPSE | The sample comprised 342 participants (198 female; mean [SD] age, 17.7 [3.1] years). Remission rates, reflecting sustained symptomatic and functional improvement, were 8.5%, 10.3%, and 11.4% at steps 1, 2, and 3, respectively. A total of 27.2% met remission criteria at any step. Relapse rates among those who remitted did not significantly differ between SPS and monitoring (step 1: 65.1% vs 58.3%; step 2: 37.7% vs 47.5%). There was no significant difference in functioning, symptoms, and transition rates between SPS and CBCM and between CBCM with fluoxetine and CBCM with placebo. Twelve-month transition rates to psychosis were 13.5% (entire sample), 3.3% (those who ever remitted), and 17.4% (those with no remission). | PMC10308298 |
Conclusions and Relevance | psychosis | REMISSION | In this sequential multiple assignment randomized trial, transition rates to psychosis were moderate, and remission rates were lower than expected, partly reflecting the ambitious criteria set and challenges with real-world treatment fidelity and adherence. While all groups showed mild to moderate functional and symptomatic improvement, this was typically short of remission. While further adaptive trials that address these challenges are needed, findings confirm substantial and sustained morbidity and reveal relatively poor responsiveness to existing treatments. | PMC10308298 |
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