28 results on '"Cameron Durrant"'
Search Results
2. Lenzilumab in hospitalised patients with COVID-19 pneumonia (LIVE-AIR): a phase 3, randomised, placebo-controlled trial
- Author
-
Juan Pulido, Michael Boger, John Hollingsworth, Homero Paniagua, Lucas GuimarÃes, Lisa Davidson, Victor Matheus Rolim de Souzafrom, Ana Elizabeth G. Maldonado, Colleen F. Kelley, Ricardo Diaz, Caitlin Moran, Jennifer Fulton, Ana Carolina M. Beheregaray, Valeria Telles, Khang Vo, Cameron Durrant, Omar Ahmed, Alpesh Amin, Daniel Barbaro, EstevÃo Figueiredo, David Weinrib, Noah Wald-Dickler, Daniel Wagner de Castro Lima Santos, Rebeca C. Lacerda Garcia, Brian Metzger, Paulo Ferreira, Andrew Miller, Marina Andrade Lima, Wilfred Onyia, William S Aronstein, Chrisoula Politis, Maqsood Alam, Celso Silva, Ana Maria T. Ortiz, Julia Minghini, Gualter CanÇado, Charles D. Burger, Mindy Sampson, Martin Cearras, Anne Frosch, Maysa B. Alves, Roy Poblete, Felipe Dal Pizzol, Carmen Polito, TÁcito do Nascimento JÁcome, Adilson Joaquim Westheimer Cavalcante, John Burk, Camila Anton, Eveline Pipolo Milan, Cristiane Ritter, Vincent C. Marconi, Dale Chappell, Loni Dorigo, Ricardo Albaneze, Renata Bezerra Onofre, Carlos del Rio, Miki Watanabe, Joshua Berg, Claudia R. Libertin, Janine Soares de Castro, Seife Yohannes, Juvencio José Duailibe Furtado, Linda Sher, May M. Lee, Robert Orenstein, Obinna Okoye, Linh Ngo, Jeffrey Lennox, Richard Zuckerman, Stephanie Strollo, Lakshmi Sambathkumar, Jason Sniffen, Paula Pietrobom, Kiran Gajurel, Lewis McCurdy, Matheus José Barbosa Moreira, Subarna Biswas, Valeria Cantos, Ana Caroline Iglessias, Jason Baker, Leopoldo T. Trevelin, John Gharbin, Victor Barreto Garcia, Marcelo B. Vinhas, Kleber Luz, Henrikki Antila, Fernando Carvalho Neuenschwander, Zelalem Temesgen, Cheryl McDonald, Sara Zulfigar, Michael Leonard, Fabiano Ramos, Gabrielle Chappell, William Gill, Martti Anton Antila, Anandi Sheth, Meghan Lewis, Sheetal Kandiah, Michael Bowdish, Lanny Hsieh, Paulina Rebolledo, Francini Correa, Chaitanya Mandapakala, Stuart McDonald, Natalia Bacellar, Zainab Shahid, Victoria M Catterson, Matthew Robinson, Rebeca Brugnolli, Richard Lee, Marina de A. R. Da Silva, Amay Parikh, Anup Patel, Gustavo Araujo, Andrew D. Badley, Caroline Uber Ghisi, Roberto Patron, Douglass Hutcheon, Marianna M. Lago, Christopher Polk, Nestor Quezada, Lionel Lewis, Marina Salgado Miranda, and Lydia Lam
- Subjects
Adult ,Male ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,medicine.medical_treatment ,Population ,Placebo-controlled study ,Antibodies, Monoclonal, Humanized ,Placebo ,Double-Blind Method ,Internal medicine ,Clinical endpoint ,Humans ,Medicine ,Adverse effect ,education ,Mechanical ventilation ,education.field_of_study ,SARS-CoV-2 ,business.industry ,Hazard ratio ,COVID-19 ,Granulocyte-Macrophage Colony-Stimulating Factor ,Articles ,Middle Aged ,COVID-19 Drug Treatment ,Treatment Outcome ,Respiratory failure ,business - Abstract
Summary Background The pathophysiology of COVID-19 includes immune-mediated hyperinflammation, which could potentially lead to respiratory failure and death. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is among cytokines that contribute to the inflammatory processes. Lenzilumab, a GM-CSF neutralising monoclonal antibody, was investigated in the LIVE-AIR trial to assess its efficacy and safety in treating COVID-19 beyond available treatments. Methods In LIVE-AIR, a phase 3, randomised, double-blind, placebo-controlled trial, hospitalised adult patients with COVID-19 pneumonia not requiring invasive mechanical ventilation were recruited from 29 sites in the USA and Brazil and were randomly assigned (1:1) to receive three intravenous doses of lenzilumab (600 mg per dose) or placebo delivered 8 h apart. All patients received standard supportive care, including the use of remdesivir and corticosteroids. Patients were stratified at randomisation by age and disease severity. The primary endpoint was survival without invasive mechanical ventilation to day 28 in the modified intention-to-treat population (mITT), comprising all randomised participants who received at least one dose of study drug under the documented supervision of the principal investigator or sub-investigator. Adverse events were assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov , NCT04351152 , and is completed. Findings Patients were enrolled from May 5, 2020, until Jan 27, 2021. 528 patients were screened, of whom 520 were randomly assigned and included in the intention-to-treat population. 479 of these patients (n=236, lenzilumab; n=243, placebo) were included in the mITT analysis for the primary outcome. Baseline demographics were similar between groups. 311 (65%) participants were males, mean age was 61 (SD 14) years at baseline, and median C-reactive protein concentration was 79 (IQR 41–137) mg/L. Steroids were administered to 449 (94%) patients and remdesivir to 347 (72%) patients; 331 (69%) patients received both treatments. Survival without invasive mechanical ventilation to day 28 was achieved in 198 (84%; 95% CI 79–89) participants in the lenzilumab group and in 190 (78%; 72–83) patients in the placebo group, and the likelihood of survival was greater with lenzilumab than placebo (hazard ratio 1·54; 95% CI 1·02–2·32; p=0·040). 68 (27%) of 255 patients in the lenzilumab group and 84 (33%) of 257 patients in the placebo group experienced at least one adverse event that was at least grade 3 in severity based on CTCAE criteria. The most common treatment-emergent adverse events of grade 3 or higher were related to respiratory disorders (26%) and cardiac disorders (6%) and none led to death. Interpretation Lenzilumab significantly improved survival without invasive mechanical ventilation in hospitalised patients with COVID-19, with a safety profile similar to that of placebo. The added value of lenzilumab beyond other immunomodulators used to treat COVID-19 alongside steroids remains unknown. Funding Humanigen.
- Published
- 2022
3. 1134. Lenzilumab Treatment in COVID-19 Pneumonia Reduces Circulating Cytokines and Markers of Systemic Inflammation
- Author
-
Dale Chappell, Adrian Kilcoyne, Frank Cerasoli, John Lukas, Cameron Durrant, Zelalem Temesgen, Christopher Polk, Jason Baker, and Vincent Marconi
- Subjects
Infectious Diseases ,Oncology - Abstract
Background Coronavirus disease 2019 (COVID-19) results from SARS-CoV-2-induced hyperinflammatory immune response, orchestrated by granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF increases interleukin-6 (IL-6) levels, ultimately leading to increased C-reactive protein (CRP). The LIVE-AIR trial demonstrated that lenzilumab, the GM-CSF neutralizing antibody, improved the likelihood of survival without invasive mechanical ventilation (IMV) in hospitalized COVID-19 patients requiring supplemental oxygen but not IMV. This sub-analysis correlated levels of cytokines before and after lenzilumab treatment. Methods LIVE-AIR was a phase 3, randomized, double-blind, placebo-controlled trial (NCT04351152). Patients hospitalized with COVID-19 pneumonia, requiring only supplemental oxygen, were randomized to receive lenzilumab (1800 mg in three equally divided doses of 600 mg, q8h) or placebo IV infusion, in addition to standard of care which included remdesivir and corticosteroids. Blood taken at baseline (BL) and subsequent to treatment through day 10 (D10) were obtained and analyzed by high sensitivity enzyme immunoassay for GM-CSF, IL-6, and CRP. Results Baseline IL-6 levels (Loge-transformed for all cytokines and biomarkers) were linearly correlated with higher baseline GM-CSF levels (slope=0.60, p< 0.001). Baseline CRP levels were linearly correlated with higher baseline IL-6 levels (slope=0.29, p < 0.001). GM-CSF levels decreased with lenzilumab treatment on day 1 (D1) which persisted through D10 (Table). In contrast, GM-CSF increased with placebo treatment. IL-6 levels decreased only with lenzilumab treatment. CRP following lenzilumab or placebo treatment decreased on D1 to similar levels and further decreased on D10 only with lenzilumab treatment. Cytokine Levels Associated with Lenzilumab Treatment Conclusion Lenzilumab decreased GM-CSF as well as downstream cytokines and systemic biomarkers of inflammation during the hyperinflammatory immune response of COVD-19. Disclosures Dale Chappell, MD, MBA, Humanigen, Inc: Employee|Humanigen, Inc: Ownership Interest Adrian Kilcoyne, MD, Humanigen, Inc: Employee Frank Cerasoli, PhD, Humanigen, Inc: Advisor/Consultant John Lukas, PhD, Humanigen, Inc: Advisor/Consultant Cameron Durrant, MD, Humanigen, Inc: Employee|Humanigen, Inc: Ownership Interest Zelalem Temesgen, MD, Gilead: unrestricted educational grant (to the institution)|Humanigen, Inc: Grant/Research Support|Merck: unrestricted educational grant (to the institution)|ViiV: Advisor/Consultant Christopher Polk, MD, Gilead: Advisor/Consultant Jason Baker, MD, Gilead: Grant/Research Support|Humanigen, Inc: Grant/Research Support Vincent Marconi, MD, Gilead: Grant/Research Support.
- Published
- 2022
4. LENZILUMAB OUTCOMES ACCORDING TO RACE OF COVID-19 PARTICIPANTS IN THE LIVE-AIR PHASE 3 TRIAL
- Author
-
Vincent C. Marconi, Adrian Kilcoyne, Franklin Cerasoli, Christopher Polk, Meghan Lewis, Charles D. Burger, Edward Jordan, Cameron Durrant, Dale Chappell, and Zelalem Temesgen
- Abstract
RATIONALEThe hyperinflammatory immune response of COVID-19, in part orchestrated by granulocyte-macrophage colony-stimulating factor (GM-CSF) can lead to respiratory failure and death with disparities in outcomes between racial subgroups. In the LIVE-AIR trial, the GM-CSF neutralizing antibody lenzilumab improved survival without mechanical ventilation (SWOV) in COVID-19.OBJECTIVEAn analysis of outcomes was performed to determine differences between Black/African American (B/AA) and White participants in LIVE-AIR.METHODSLIVE-AIR was a phase 3, randomized, double-blind, placebo-controlled trial. Participants hospitalized with COVID-19 pneumonia were randomized 1:1 to receive lenzilumab (1800 mg total) or placebo in addition to standard of care, including remdesivir and/or corticosteroids.MEASUREMENTS AND MAIN RESULTSLenzilumab, compared to placebo, numerically improved the likelihood of SWOV (primary endpoint) in B/AA (n=71; 86.8% vs 70.9%; HR, 2.68; 95% confidence interval [CI], 0.88-8.11; p=0.0814) and White (n=343; 85.1% vs 80.8%; HR, 1.41; 95%CI, 0.85-2.35, p=0.182) participants. A statistically significant improvement in SWOV was observed in B/AA (HR: 8.9; 95%CI: 1.08, 73.09; p=0.0418) and White (HR: 2.32; 95%CI: 1.17, 4.61; p=0.0166) participants with baseline CRPCONCLUSIONLenzilumab significantly improved SWOV and some key secondary outcomes in B/AA COVID-19 participants with baseline CRPNCT04351152
- Published
- 2022
5. Abstract CT085: A phase 2/3, multicenter trial of lenzilumab and azacitidine in chronic myelomonocytic leukemia: The PREACH-M trial
- Author
-
Devendra Hiwase, David Ross, Steven Lane, Agnes Yong, Kirsty Sharplin, David Yeung, Lisa Butler, Dale Chappell, Cameron Durrant, Timothy Hughes, and Daniel Thomas
- Subjects
Cancer Research ,Oncology - Abstract
Background: Chronic myelomonocytic leukemia (CMML) is a rare, aggressive cancer for which no targeted therapy exists. Standard of care (SOC) includes azacitidine (A), with complete and partial response (CR and PR) rates ranging between 10-17%. The pro-inflammatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) plays a central role in stimulating leukemic monocyte proliferation. Lenzilumab (LENZ) is a proprietary Humaneered® first-in-class monoclonal antibody with best-in-class specificity and affinity that neutralizes GM-CSF to prevent signaling through its receptor. The PREcision Approach to CHronic Myelomonocytic Leukemia (PREACH-M) trial assesses the efficacy of LENZ in CMML (ACTRN12621000223831p) to improve outcomes beyond those afforded by SOC. Methods: PREACH-M is a Phase 2/3 non-randomized, open-label precision medicine trial in 72 adults aged at least 18 years, newly diagnosed with WHO 2016 criteria for CMML; cytopenia (hemoglobin < 100 g/L, platelets < 100 × 109/L or absolute neutrophil count < 1.8 × 109/L): white blood cell count ≥ 13 × 109/L; as well as TET2 and/or RAS pathway mutations (NRAS, KRAS, CBL). Key exclusion criteria include prior treatment with investigational agents; radiotherapy within 28 days before treatment; treatment with G-CSF within 7 days of screening; GM-CSF within 28 days of screening; and uncontrolled medical conditions. Subjects exhibiting RAS pathway mutations, with or without TET2 mutations, receive 24 cycles (28 days) of A (SC; 75 mg/m2 for 7 days) and LENZ (IV; 552 mg; d1 & d15 of cycle 1 and d1 only for all subsequent cycles); while those with non-RAS pathway mutations receive the same A regimen and sodium ascorbate (IV; 30 g for 7 days [15 g for 1st dose only, 30 g thereafter if no evidence of tumor lysis syndrome]; PO; 1.1g on all other days). Subjects who complete 24 cycles of treatment are followed every 6 months for 24 months for survival, disease status, and CMML-related therapy. The primary endpoint is the frequency of CR or PR at any time during the first 12 cycles according to Savona Criteria. Secondary endpoints include overall survival and progression-free survival at 2 years; proportion of subjects with clinical benefit at any point during the 24 cycles; impact on physical and functional capacity; social well-being according to Multidimensional Geriatric Assessment and quality of life; as well as hematological and non-hematologic safety. Results: As of December 31, 2022, eight subjects were treated with A and LENZ (5 females, mean age of 67 years; 3 males, mean age of 69 years); among them 6 were evaluable based on at least 3 months of follow-up. CR or objective responses were observed in all evaluable patients including 2 with high risk based on molecular profiling. 10 grade 3/4 Serious Adverse Events were observed of which 2 were assessed by the investigator as possibly related to LENZ. Conclusion: The ongoing PREACH-M trial evaluates GM-CSF neutralization with LENZ in addition to SOC, in the treatment of CMML with RAS pathway mutations. Citation Format: Devendra Hiwase, David Ross, Steven Lane, Agnes Yong, Kirsty Sharplin, David Yeung, Lisa Butler, Dale Chappell, Cameron Durrant, Timothy Hughes, Daniel Thomas. A phase 2/3, multicenter trial of lenzilumab and azacitidine in chronic myelomonocytic leukemia: The PREACH-M trial [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 CT085.
- Published
- 2023
6. C-REACTIVE PROTEIN AS A BIOMARKER FOR IMPROVED EFFICACY OF LENZILUMAB IN PATIENTS WITH COVID-19: RESULTS FROM THE LIVE-AIR TRIAL
- Author
-
Andrew D. Badley, Dale Chappell, Colleen F. Kelley, Gabrielle Chappell, Jason V. Baker, Victoria Catterson, Robert Orenstein, Omar J. Ahmed, Claudia R. Libertin, Vincent C. Marconi, Cameron Durrant, Charles D. Burger, Zelalem Temesgen, William Aronstein, and Christopher Polk
- Subjects
Pulmonary and Respiratory Medicine ,Oncology ,medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,biology ,business.industry ,C-reactive protein ,Late Breaking ,Critical Care and Intensive Care Medicine ,LENZILUMAB ,Internal medicine ,medicine ,biology.protein ,Biomarker (medicine) ,In patient ,Cardiology and Cardiovascular Medicine ,business - Published
- 2021
7. C reactive protein utilisation, a biomarker for early COVID-19 treatment, improves lenzilumab efficacy: results from the randomised phase 3 'LIVE-AIR' trial
- Author
-
Zelalem, Temesgen, Colleen F, Kelley, Frank, Cerasoli, Adrian, Kilcoyne, Dale, Chappell, Cameron, Durrant, Omar, Ahmed, Gabrielle, Chappell, Victoria, Catterson, Christopher, Polk, Andrew, Badley, Vincent C, Marconi, and Henrikki, Antila
- Subjects
Pulmonary and Respiratory Medicine - Abstract
ObjectiveCOVID-19 severity is correlated with granulocyte macrophage colony-stimulating factor (GM-CSF) and C reactive protein (CRP) levels. In the phase three LIVE-AIR trial, lenzilumab an anti-GM-CSF monoclonal antibody, improved the likelihood of survival without ventilation (SWOV) in COVID-19, with the greatest effect in participants having baseline CRP below a median of 79 mg/L. Herein, the utility of baseline CRP to guide lenzilumab treatment was assessed.DesignA subanalysis of the randomised, blinded, controlled, LIVE-AIR trial in which lenzilumab or placebo was administered on day 0 and participants were followed through Day 28.ParticipantsHospitalised COVID-19 participants (N=520) with SpO2 ≤94% on room air or requiring supplemental oxygen but not invasive mechanical ventilation.InterventionsLenzilumab (1800 mg; three divided doses, q8h, within 24 hours) or placebo infusion alongside corticosteroid and remdesivir treatments.Main outcome measuresThe primary endpoint was the time-to-event analysis difference in SWOV through day 28 between lenzilumab and placebo treatments, stratified by baseline CRP.ResultsSWOV was achieved in 152 (90%; 95% CI 85 to 94) lenzilumab and 144 (79%; 72 to 84) placebo-treated participants with baseline CRP ConclusionHospitalised hypoxemic patients with COVID-19 with baseline CRP Trial registration numberNCT04351152
- Published
- 2022
8. S51 Evaluation of treatment approaches for hospitalized Covid-19 patients
- Author
-
A. Kilcoyne, Cameron Durrant, E. Jordan, Omar J. Ahmed, and Dale Chappell
- Subjects
medicine.medical_specialty ,Immune Modulators ,Emergency Use Authorization ,Coronavirus disease 2019 (COVID-19) ,business.industry ,Concomitant ,Emergency medicine ,medicine ,Absolute risk reduction ,Number needed to treat ,Adverse effect ,business ,Viral load - Abstract
BackgroundCOVID-19 has driven innovation leading to emergency use authorization of treatments that address its urgent healthcare needs. However, physicians, payers and healthcare systems are challenged to select among these novel treatments for both effectiveness and value. Reliance on change in relative, rather than absolute, risk often makes discrimination of treatment effects between medications impractical, with potentially misleading conclusions. Number Needed to Treat (NNT), the reciprocal of the Absolute Risk Reduction, can be a valuable alternative in assessing benefit:risk. The objective of the current analysis was to calculate NNT for reported endpoints of COVID-19 treatments.MethodsClinical information was captured from published literature and pre-prints from investigations of COVID-19 treatments. NNTs were calculated for reported endpoints. Outpatient treatments to reduce viral load included neutralizing antibody ‘cocktails’ REGN-COV21 and bamlanivimab/etesevimab.2 Inpatient treatments included the anti-viral: remdesivir 3,4;and immune modulators: baricitinib5, and lenzilumab.6ResultsREGN-COV2 reduced the number of medically attended visits with NNT of 33.3. The NNT for hospitalization or death was 20 for bamlanivimab/etesevimab. NNTs for 28-day mortality with inpatient treatment were 37 for baricitinib, 26.3 for remdesivir alone, and 22.7 for lenzilumab. Additional analyses of lenzilumab resulted in NNT of 14.7 when combined with remdesivir and corticosteroids, 15.4 when combined with remdesivir, and 13.9 in patients with baseline CRP
- Published
- 2021
9. S49 C-reactive protein as a biomarker for improved efficacy of lenzilumab in Covid-19 patients: results from the LIVE-AIR trial
- Author
-
Andrew D. Badley, Cameron Durrant, Charles D. Burger, Robert Orenstein, V. M. Catterson, Jason V. Baker, Vincent C. Marconi, Omar J. Ahmed, Claudia R. Libertin, Gabrielle Chappell, Colleen F. Kelley, Christopher Polk, Dale Chappell, Zelalem Temesgen, and W. S. Aronstein
- Subjects
Mechanical ventilation ,medicine.medical_specialty ,biology ,business.industry ,medicine.medical_treatment ,Incidence (epidemiology) ,C-reactive protein ,Placebo ,Systemic inflammation ,Gastroenterology ,Internal medicine ,medicine ,Breathing ,biology.protein ,Clinical endpoint ,Biomarker (medicine) ,medicine.symptom ,business - Abstract
BackgroundThe hyperinflammatory cytokine storm (CS) of COVID-19 is mediated by GM-CSF leading to release of downstream inflammatory chemokines, cytokines, and markers of systemic inflammation (C-reactive protein, CRP). The LIVE-AIR study demonstrated that lenzilumab, an anti-GM-CSF monoclonal antibody in patients hospitalized with COVID-19, safely improved the likelihood of achieving the primary endpoint, survival without ventilation (SWOV) by 1.54-fold (HR: 1.54;95%CI: 1.02–2.32, p=0.0403) compared with placebo. An exploratory analysis in patients with CRP 18 years, and ≤94% oxygen saturation on room air and/or requiring supplemental oxygen, but not invasive mechanical ventilation (IMV), were randomized to receive lenzilumab (600 mg, n=261) or placebo (n=259) via three intravenous infusions administered 8 hours apart. Participants were followed through Day 28 following treatment.ResultsOverall, baseline demographics were comparable between treatment groups: male, 64.7%;mean age, 60.5 years;mean BMI, 32.5 kg/m2;median CRP, 79 mg/L;CRP was 137 mg/L, HR: 1.17). The incidence of IMV, ECMO, or death was reduced (OR: 0.31;95%CI: 0.15–0.63, p=0.002) and mortality was improved by 2.22-fold (OR: 2.22;95%CI: 1.07–4.67, p=0.034). In these participants, lenzilumab decreased CRP as early as Day 2 following treatment, compared with placebo which was further decreased by 38% on Day 28 compared with placebo (24.4±3.4 mg/L vs 39.1±4.9 mg/L).ConclusionLenzilumab significantly improved SWOV in hospitalized, hypoxic participants with COVID-19 pneumonia with the greatest benefits in SWOV and survival in patients with CRP
- Published
- 2021
10. Optimized Inhibition of GM-CSF in Preclinical Models of Anti-CD19 Chimeric Antigen Receptor T Cell Therapy
- Author
-
Evandro D. Bezerra, Reona Sakemura, James H. Girsch, Carli M. Stewart, Kun Yun, Olivia L. Sirpilla, Claudia Manriquez Roman, Kendall J. Schick, Ismail Can, Ekene J. Ogbodo, Erin E. Tapper, Elizabeth L. Siegler, Mohamad M. Adada, Lionel Aurelien Kankeu Fonkoua, Mehrdad Hefazi, Michael W. Ruff, Susan L. Slager, Sameer A. Parikh, Neil E. Kay, Cameron Durrant, Omar Ahmed, Dale Chappell, Michelle J. Cox, and Saad S. Kenderian
- Subjects
Transplantation ,Molecular Medicine ,Immunology and Allergy ,Cell Biology ,Hematology - Published
- 2022
11. LENZILUMAB EFFICACY AND SAFETY IN NEWLY HOSPITALIZED COVID-19 SUBJECTS: RESULTS FROM THE LIVE-AIR PHASE 3 RANDOMIZED DOUBLE-BLIND PLACEBO-CONTROLLED TRIAL
- Author
-
Zelalem Temesgen, Andrew D. Badley, Colleen F. Kelley, Cameron Durrant, Charles D. Burger, Robert Orenstein, Gabrielle Chappell, Dale Chappell, Claudia R. Libertin, Christopher Polk, Jason V. Baker, Omar H. Ahmed, and Vincent C. Marconi
- Subjects
Mechanical ventilation ,medicine.medical_specialty ,education.field_of_study ,Randomization ,business.industry ,medicine.medical_treatment ,Population ,Placebo-controlled study ,medicine.disease ,Placebo ,Gastroenterology ,Article ,Respiratory failure ,Internal medicine ,medicine ,Coagulopathy ,business ,education ,Kidney disease - Abstract
BACKGROUNDSevere COVID-19 pneumonia results from a hyperinflammatory immune response (cytokine storm, CS), characterized by GM-CSF mediated activation and trafficking of myeloid cells, leading to elevation of downstream inflammatory chemokines (MCP-1, IL-8, IP-10), cytokines (IL-6, IL-1), and other markers of systemic inflammation (CRP, D-dimer, ferritin). CS leads to fever, hypotension, coagulopathy, respiratory failure, ARDS, and death. Lenzilumab is a novel Humaneered® anti-human GM-CSF monoclonal antibody that directly binds GM-CSF and prevents signaling through its receptor. The LIVE-AIR Phase 3 randomized, double-blind, placebo-controlled trial investigated the efficacy and safety of lenzilumab to assess the potential for lenzilumab to improve the likelihood of ventilator-free survival (referred to herein as survival without ventilation, SWOV), beyond standard supportive care, in hospitalized subjects with severe COVID-19.METHODSSubjects with COVID-19 (n=520), ≥18 years, and ≤94% oxygen saturation on room air and/or requiring supplemental oxygen, but not invasive mechanical ventilation, were randomized to receive lenzilumab (600 mg, n=261) or placebo (n=259) via three intravenous infusions administered 8 hours apart. Subjects were followed through Day 28 following treatment.RESULTSBaseline demographics were comparable between the two treatment groups: male, 64.7%; mean age, 60.5 years; mean BMI, 32.5 kg/m2; mean CRP, 98.36 mg/L; CRP was CONCLUSIONLenzilumab significantly improved SWOV in hospitalized, hypoxic subjects with COVID-19 pneumonia over and above treatment with remdesivir and/or corticosteroids. Subjects with CRPNCT04351152
- Published
- 2021
12. GM-CSF disruption in cart cells ameliorates cart cell activation and reduces activation-induced cell death
- Author
-
Omar J. Ahmed, Mehrdad Hefazi, Ismail Can, Reona Sakemura, Saad S. Kenderian, Sameer A. Parikh, Paulina Horvei, Sutapa Sinha, C. Manriquez Roman, Elizabeth L. Siegler, Neil E. Kay, Erin E. Tapper, Cameron Durrant, Dale Chappell, Kendall J. Schick, Mohamad M. Adada, Michelle J. Cox, Michael W. Ruff, Evandro D. Bezerra, and L. Kankeu Fonkoua
- Subjects
Cart ,Cancer Research ,Transplantation ,Oncology ,Chemistry ,Immunology ,Immunology and Allergy ,Cell Biology ,Activation-induced cell death ,Cell activation ,Genetics (clinical) ,Cell biology - Published
- 2021
13. COVID-19 associated chronic ARDS successfully treated with lenzilumab
- Author
-
Juan D Pulido, Omar Ahmed, Rida Rasool, Gabrielle Chappell, Cameron Durrant, and Dale Chappell
- Abstract
Background:Myeloid hyperinflammation leading to T-cell immune suppression and lymphocytopenia is a hallmark of severe COVID-19. Granulocyte macrophage-colony stimulating factor (GM-CSF) neutralization may prevent myeloid driven T-cell suppression leading to increased lymphocyte counts in patients with COVID-19. Given the dual mechanism of action, lenzilumab (anti-human GM-CSF monoclonal antibody) may reduce myeloid driven hyperinflammation and improve CD8+ antiviral T-cell responses directed at SARS-Cov-2 reducing the morbidity, mortality, need for invasive mechanical ventilation (IMV) and duration of hospitalization.Methods:Hospitalized subject with confirmed COVID-19 pneumonia and established risk factors for poor outcomes was treated in the ICU for 12 weeks using standard supportive care for chronic acute respiratory distress syndrome (ARDS). An emergency single-use investigational new drug application (IND) was approved for lenzilumab 600 mg, administered intravenously every eight hours for a total of three doses. Patient characteristics, clinical and laboratory outcomes, and adverse events were recorded through duration of hospitalization.Results:77-year-old Caucasian male with past medical history of severe chronic obstructive pulmonary disease (COPD) with emphysema, coronary artery disease, type II diabetes, and obstructive sleep apnea admitted to ICU with fever, shortness of breath and confirmed SARS-CoV-2 infection. Patient was treated with standard supportive care including corticosteroids. Over the course of his ICU stay, the patient developed ARDS and on week 13, and after several unsuccessful attempts at oxygen weaning, lenzilumab was administered via emergency single use IND. One-week post lenzulimab therapy, oxygen demands decreased, lymphopenia appeared to improve and sixteen days post lenzulimab therapy, the patient was discharged home on 4L nasal cannula. No infusion-related or systemic side effects were noted.Conclusion:In a case of COVID-19 with multiple co-morbidities, refractory to corticosteroids, and deteriorating for several months, GM-CSF neutralization with lenzilumab appeared to reduce oxygen requirements, improve lymphopenia and accelerate time to recovery/discharge in a COVID-19 subject. A randomized, double-blind, placebo-controlled phase 3 clinical trial is ongoing to validate these findings (NCT04351152).
- Published
- 2020
14. First Clinical Use of Lenzilumab to Neutralize GM-CSF in Patients with Severe and Critical COVID-19 Pneumonia
- Author
-
Reona Sakemura, Bharath Raj Palraj, Mariam Assi, Cameron Durrant, Charles D. Burger, Brian Pickering, Hugo E. Vargas, Robert Orenstein, Zelalem Temesgen, Claudia R. Libertin, Saad S. Kenderian, Ala S. Dababneh, Raymund R. Razonable, Gabrielle Chappell, Dale Chappell, Philippe R. Bauer, Paschalis Vergidis, Omar J. Ahmed, Stacey A. Rizza, and Andrew D. Badley
- Subjects
medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,business.industry ,Oxygenation ,Granulocyte ,medicine.disease ,Pneumonia ,LENZILUMAB ,medicine.anatomical_structure ,Respiratory failure ,Internal medicine ,medicine ,Adverse effect ,Cytokine storm ,business - Abstract
BackgroundIn COVID-19, high levels of granulocyte macrophage-colony stimulating factor (GM-CSF) and inflammatory myeloid cells correlate with disease severity, cytokine storm, and respiratory failure. With this rationale, we used lenzilumab, an anti-human GM-CSF monoclonal antibody, to treat patients with severe and critical COVID-19 pneumonia.MethodsHospitalized patients with COVID-19 pneumonia and risk factors for poor outcomes were treated with lenzilumab 600 mg intravenously for three doses through an emergency single-use IND application. Patient characteristics, clinical and laboratory outcomes, and adverse events were recorded. All patients receiving lenzilumab through May 1, 2020 were included in this report.ResultsTwelve patients were treated with lenzilumab. Clinical improvement was observed in 11 out of 12 (92%), with a median time to discharge of 5 days. There was a significant improvement in oxygenation: The proportion of patients with SpO2/FiO2 < 315 at the end of observation was 8% vs. compared to 67% at baseline (p=0.00015). A significant improvement in mean CRP and IL-6 values on day 3 following lenzilumab administration was also observed (137.3 mg/L vs 51.2 mg/L, p = 0.040; 26.8 pg/mL vs 16.1 pg/mL, p = 0.035; respectively). Cytokine analysis showed a reduction in inflammatory myeloid cells two days after lenzilumab treatment. There were no treatment-emergent adverse events attributable to lenzilumab, and no mortality in this cohort of patients with severe and critical COVID-19 pneumonia.ConclusionsIn high-risk COVID-19 patients with severe and critical pneumonia, GM-CSF neutralization with lenzilumab was safe and associated with improved clinical outcomes, oxygen requirement, and cytokine storm.
- Published
- 2020
15. Phase 1 study of lenzilumab, a recombinant anti-human GM-CSF antibody, for chronic myelomonocytic leukemia
- Author
-
Traci Kruer, Naseema Gangat, Darci Zblewski, Moritz Binder, Ayalew Tefferi, Rami S. Komrokji, Aref Al-Kali, Hannah Newman, Mrinal M. Patnaik, Cameron Durrant, Abhishek A. Mangaonkar, David A. Sallman, Christopher Letson, Eric Padron, Alan F. List, Maria E. Balasis, Ted Shih, Rachel Heuer, Jeffery Hirvela, and Adrian Lo
- Subjects
0301 basic medicine ,Male ,Drug-Related Side Effects and Adverse Reactions ,Maximum Tolerated Dose ,medicine.medical_treatment ,Immunology ,Chronic myelomonocytic leukemia ,Antibodies, Monoclonal, Humanized ,Biochemistry ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Antineoplastic Agents, Immunological ,law ,hemic and lymphatic diseases ,medicine ,Humans ,Letter to Blood ,Aged ,Aged, 80 and over ,Chemotherapy ,biology ,Dose-Response Relationship, Drug ,business.industry ,Antibodies, Monoclonal ,Granulocyte-Macrophage Colony-Stimulating Factor ,Leukemia, Myelomonocytic, Chronic ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,Recombinant Proteins ,Leukemia ,030104 developmental biology ,Granulocyte macrophage colony-stimulating factor ,LENZILUMAB ,Treatment Outcome ,Chemotherapy, Adjuvant ,030220 oncology & carcinogenesis ,Monoclonal ,biology.protein ,Recombinant DNA ,Female ,Antibody ,business ,medicine.drug - Abstract
In this phase 1 trial, inhibition of granulocyte-macrophage colony-stimulating factor (GM-CSF) was associated with clinically meaningful responses in 5 of 15 patients with relapsed or refractory chronic myelomonocytic leukemia (CMML). Preliminary data suggest that this approach may be tractable in CMML bearing activating NRAS mutations.
- Published
- 2020
16. 23: LENZILUMAB IN HOSPITALIZED BLACK/AFRICAN-AMERICAN COVID-19 PATIENTS: LIVE-AIR PHASE 3 STUDY RESULTS
- Author
-
Zelalem Temesgen, Charles Burger, Claudia Libertin, Cameron Durrant, Dale Chappell, Omar Ahmed, Adrian Kilcoyne, Gabrielle Chappell, Edward Jordan, and Andrew Badley
- Subjects
Critical Care and Intensive Care Medicine - Published
- 2021
17. A Phase 2/3 Randomized, Placebo-Controlled, Open-Label, Multi-Center Trial of Lenzilumab to Improve the Safety and Efficacy of CAR-T Cell Therapy in Adults with Relapsed or Refractory Large B-Cell Lymphoma (The SHIELD Study)
- Author
-
Adrian Kilcoyne, Omar J. Ahmed, Saad S. Kenderian, Dale Chappell, and Cameron Durrant
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Placebo ,Biochemistry ,LENZILUMAB ,Refractory ,Internal medicine ,medicine ,CAR T-cell therapy ,Center (algebra and category theory) ,Open label ,B-cell lymphoma ,business - Abstract
Background: Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive sub-type of non-Hodgkin's lymphoma(Liu, et al. Am J Hematol 2019). All three approved CD19-directed CAR-T therapies (axicabtagene ciloleucel, tisagenlecleucel, lisocabtagene maraleucel) are associated with toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) that can be severe, resulting in non-relapse mortality, ICU admission, and significant non-drug related health resource utilization which represent barriers to access and adoption (Nabhan, et al. J Clin. Pathway 2017). Studies have shown that early elevation of granulocyte-macrophage colony-stimulating factor (GM-CSF) levels 1-day post CAR-T infusion correlates with severe ICANS (Rossi, et al. EMA Workshop 2016), which is a negative prognostic factor for overall survival (Karschnia, et al. Blood 2019). It has been proposed that upon contact with the tumor, CAR-Ts produce GM-CSF, which serves as a communication conduit between the specific immune response of CAR-T and the off-target inflammatory cascade produced by myeloid lineage cells, causing myeloid cells to expand and promote the production of other downstream proinflammatory chemokines (MCP-1, IL-8, IP-10), cytokines (IL-1, IL-6), and other markers of systemic inflammation (CRP, Ferritin) (Sterner, et al. Blood 2019). Moreover, IL-6 is predominately released by tumor cells in a contact-independent manner (Barrett et al. Blood 2016), which helps explain why the prophylactic administration of tocilizumab is not effective in reducing the overall incidence of CRS or ICANS, as this cytokine is downstream in the inflammatory cascade. Further, the prophylactic use of tocilizumab has been shown to increase the incidence of all-grades and grade >3 ICANS (Locke, et al. Blood 2017). Lenzilumab is a novel Humaneered ® monoclonal antibody that neutralizes GM-CSF and has demonstrated potential to reduce the hyper-immune mediated cytokine storm induced by SARS-CoV-2 infection and significantly improve the likelihood of survival without ventilation in hospitalized COVID-19 patients, as reported in the LIVE-AIR phase 3 study (Temesgen, et al. medRxiv 2021). Methods: Eligible patients are adults (≥ 18 y) with relapsed or refractory DLBCL or are chemorefractory. Prior therapy must have included an anti-CD20 monoclonal antibody and an anthracycline-containing regimen. Patients will undergo leukapheresis and may receive optional corticosteroid bridging therapy. Patients will then receive lymphodepleting chemotherapy on Days ‒3 to ‒5 followed by infusion of lenzilumab on Day 0, 6-hrs prior to CAR-T infusion. Approximately 40 accredited sites across the U.S. certified to administer the three commercially available CAR-Ts have been engaged to participate in this 2-part study. In Part 1, all patients will receive lenzilumab 1800mg via a single 2-hour infusion prior to CAR-T administration. The objective of Part 1 is to evaluate the optimal regimen and assess whether a second dose of lenzilumab post-CAR-T infusion is required. A translational assessment of GM-CSF axis suppression, levels of CAR-T cells in blood, other inflammatory markers and lenzilumab PK/PD will be evaluated, along with the incidence and severity of CRS and ICANS, objective response rates (ORR) and rates of complete response (CR) by Day 28 to select the optimal regimen to carry forward into Part 2. The objective of Part 2 is to confirm whether lenzilumab can improve the toxicity and tolerance of CAR-T while maintaining or improving efficacy and durability of response. Up to 250 patients will be randomized 1:1 to receive lenzilumab or placebo with CAR-T per standard of care. The primary endpoint of the study is incidence of grade >2 CRS and/or ICANS by Day 28, with a key secondary endpoint of CR at 6-months in patients without grade ≥ 2 CRS and/or ICANS at Day 28 (Toxicity-free CR). This design and sample size yields 90% power to detect a 50% reduction in the primary outcome measure. Secondary endpoints include incidence of all grades and grade >3 CRS and/or ICANS, respectively; ORR and CR at 1, 3, 6, 12 months; durability of CR; progression-free survival, overall survival and health related quality of life using validated patient reported outcome measures. In addition, the study will explore the CRS and ICANS grading criteria that have been utilized with each of the approved CAR-Ts. Disclosures Kenderian: Humanigen, Inc.: Consultancy, Honoraria, Research Funding. Durrant: Humanigen, Inc.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Chappell: Humanigen Inc.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Ahmed: Humanigen Inc.: Current Employment, Current equity holder in publicly-traded company. Kilcoyne: Humanigen, Inc.: Current Employment, Current equity holder in publicly-traded company.
- Published
- 2021
18. Optimized Inhibition of GM-CSF in Preclinical Models of Anti-CD19 Chimeric Antigen Receptor T Cell Therapy
- Author
-
Erin E. Tapper, Cameron Durrant, Reona Sakemura, Ekene J. Ogbodo, Neil E. Kay, Lionel A. Kankeu Fonkoua, Michael W. Ruff, Gunjan A Awatramani, Susan L. Slager, Michelle J. Cox, Elizabeth L. Siegler, Ismail Can, Sameer A. Parikh, James Girsch, Kendall J. Schick, Omar J. Ahmed, Carli M. Stewart, Evandro D. Bezerra, Mehrdad Hefazi, Claudia Manriquez-Roman, Saad S. Kenderian, Mohamad M. Adada, and Dale Chappell
- Subjects
Chemistry ,Anti cd19 ,Immunology ,Cancer research ,Chimeric Antigen Receptor T-Cell Therapy ,Cell Biology ,Hematology ,Biochemistry ,health care economics and organizations - Abstract
Anti-CD19 chimeric antigen receptor T (CART19) cell therapy has resulted in unprecedented outcomes in patients with relapsed/refractory B-cell malignancies, which led to the FDA approval for several indications. However, CART19 cell therapy is limited by the development of severe life-threatening toxicities, as well as by the limited rates of durable response. It has become apparent that myeloid cells contribute to the development of both CART cell toxicity and also to the inhibitory tumor microenvironment. We and others have identified that granulocyte-monocyte-colony-stimulating factor (GM-CSF) depletion results in decreased myeloid activation, reduced toxicities, and enhancement of CART19 cell therapy efficacy in pre-clinical models. Furthermore, we observed that GM-CSF knockout (GM-CSF k/o) in CART19 cells resulted in the improvement of their functions (in vitro and in vivo). These findings suggest that there is also a direct effect of GM-CSF on CART19 cells, which is independent of the GM-CSF impact on myeloid cell activation. To further evaluate this, we first examined GM-CSF receptor alpha (GM-CSFRα) expression by flow cytometry on resting and activated CART19 cells (using FMC63-41BBζ). When CART19 cells were stimulated with either anti-CD3/CD28 beads or lethally irradiated (120 Gy) CD19 + Nalm6 cells (B cell acute lymphoblastic leukemia cancer cell line), GM-CSFRα expression was upregulated upon both T cell receptor (TCR) (data not shown) and CAR stimulation (Figure 1A). Having demonstrated that GM-CSFRα is significantly upregulated on stimulated CART19 cells, we aimed to determine the impact of GM-CSF neutralization (clinical-grade anti-GM-CSF antibody, lenzilumab, 10 µg/mL) versus GM-CSFRα blockade (research-grade antibody, 10 µg/mL) on CART19 cell function and CART cell-monocyte interactions. An IgG isotype antibody was used as a control antibody. Neither the GM-CSF neutralizing antibody, nor GM-CSFRα blocking antibody, had any impact on CART19 cell antigen-specific killing against the CD19 + JeKo-1 cells (mantle cell lymphoma cancer cell line), in the presence or absence of CD14 + monocytes (ratio 1:1:1) isolated by magnetic beads from healthy donors (Figures 1B-C). Next, we compared the effects of GM-CSF neutralization versus GM-CSFRα blockade on CART19 cell antigen-specific proliferation. Here, CART19 cells were co-cultured with lethally irradiated CD19 + cell line JeKo-1 at 1:1 ratio in the presence of 10 µg/mL of the GM-CSF neutralizing antibody, increasing doses of the GM-CSFRα blocking antibody (10-100 µg/mL), or an IgG control. The absolute number of CART cells was measured by flow cytometry on day 5. GM-CSF neutralization did not affect CART19 cell proliferation, but GM-CSFRα blocking antibody significantly inhibited CART19 cell proliferation in a dose-dependent manner. Then, we assessed the effects of GM-CSF neutralizing antibody (20 µg/mL) versus GM-CSFRα blocking antibody (20 µg/mL) on CART19 cell antigen-specific proliferation in the presence of healthy donor monocytes (ratio 1:1:0.5) on day 3. Flow cytometric analysis revealed that GM-CSF neutralization, but not GM-CSFRα blockade, mitigated monocyte-suppression of CART19 antigen-specific proliferation (Figure 1E). In summary, our findings indicate significant differences on CART cell functions and CART cell-monocyte interactions when a specific cytokine, GM-CSF, is neutralized compared to blocking its receptor. Further mechanistic studies are ongoing to assess the functions of GM-CSFRα k/o and GM-CSF k/o CART cells. Figure 1 Figure 1. Disclosures Sakemura: Humanigen: Patents & Royalties. Parikh: Pharmacyclics, MorphoSys, Janssen, AstraZeneca, TG Therapeutics, Bristol Myers Squibb, Merck, AbbVie, and Ascentage Pharma: Research Funding; Pharmacyclics, AstraZeneca, Genentech, Gilead, GlaxoSmithKline, Verastem Oncology, and AbbVie: Membership on an entity's Board of Directors or advisory committees. Kay: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Tolero Pharmaceuticals: Research Funding; CytomX Therapeutics: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Research Funding; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Research Funding; Acerta Pharma: Research Funding; Genentech: Research Funding; Rigel: Membership on an entity's Board of Directors or advisory committees; Behring: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Research Funding; Targeted Oncology: Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Agios Pharm: Membership on an entity's Board of Directors or advisory committees. Durrant: Humanigen Inc.: Current Employment. Ahmed: Humanigen Inc.: Current Employment, Current equity holder in publicly-traded company. Chappell: Humanigen Inc.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Cox: Humanigen: Patents & Royalties. Kenderian: Humanigen, Inc.: Consultancy, Honoraria, Research Funding.
- Published
- 2021
19. Abstract CT101: Phase I safety and bioimaging trial of ifabotuzumab in patients with glioblastoma
- Author
-
Graeme O'Keefe, Christian Wichmann, Lawrence Cher, Nancy Guo, Uwe Ackermann, Alex McDonald, Kate Fluck, Gel Bolarnos, Po Inglis, Andrew M. Scott, Kunthi Pathmaraj, Sze Ting Lee, Kirsten Remen, Hui K Gan, Andrew W. Boyd, Jodie Palmer, Omar J. Ahmed, Paul Thomas, Bryan W. Day, Cameron Durrant, Dale Chappell, Eddie Lau, Zarnie Lwin, Ashray Gunjur, Fiona Scott, and Sylvia J. Gong
- Subjects
Cancer Research ,medicine.medical_specialty ,business.industry ,Cancer ,Fluid-attenuated inversion recovery ,medicine.disease ,Rash ,Gastroenterology ,Leukemia ,Oncology ,Pharmacokinetics ,Internal medicine ,medicine ,Eye disorder ,medicine.symptom ,Headaches ,business ,Adverse effect - Abstract
Overview Glioblastoma multiforme (GBM) is the most frequent and lethal primary brain neoplasm, with only 10% of patients surviving 5 years.1 EphA3 is a tumor restricted antigen expressed in various solid tumors and the tumor vasculature of 100% of GBM.2,3 Ifabotuzumab is a non-fucosylated IgG1κ humaneered antibody targeting the EphA3 receptor.4 A Phase I study of ifabotuzumab in haematological malignancies showed it was well tolerated and clinically active.5 Here we report on a Phase I dose escalation and biodistribution study of ifabotuzumab in recurrent GBM. Study Design The primary objective is to determine the safety and recommended Phase II dose of ifabotuzumab in GBM patients (pts). Secondary objectives are to determine the biodistribution and pharmacokinetics (PK) of 89Zr- ifabotuzumab, the frequency of EphA3 positive GBM and response rates. On day 1, eligible pts with measurable tumors received a trace (5mg) dose of zirconium labelled ifabotuzumab (89Zr-ifab) followed by sequential PET imaging over 1 week to determine its biodistribution, frequency of in situ EphA3 expression and quantitative tumor uptake. Safety assessments and PK sampling were also undertaken. On day 8, pts commenced weekly ifabotuzumab infusions over 2 hours in one of two cohorts (3.5mg/kg, 5.25 mg/kg). On day 36, pts received both 89Zr-ifab and ifabotuzumab, allowing assessment of receptor occupancy. Response rate (RANO) and survival data were collected. Pts then continued on ifabotuzumab until progression. Results In total, 12 pts have been enrolled, including 6 in the 3.5mg/kg and 6 in the 5.25 mg/kg dose cohorts. Mean age was 51.6 years (±14.24) and 7/12 pts were male. Treatment emergent adverse events included infusion reactions in 4 pts, seizures in 3 pts, cerebral oedema in 1, rash in 1, headaches in 8, eye disorder in 1. Most were considered related to study drug except seizure in 2 pts, headaches and eye disorder. Seizures and infusion reactions were readily managed with increased premedications after the first occurrence. The best response was stable disease for 23 weeks. 89Zr-ifab-PET scans showed rapid, tumor-specific targeting at all known tumor sites and in all pts, but with no normal tissue uptake. MRI scans showed predominant T2/FLAIR changes, occasionally marked, which were consistent with treatment effect of ifabotuzumab on tumor vasculature. The mean ± SD (n=12) PK parameters for first infusion 89Zr-ifab were T½α= 9.03 ± 4.45 hr, T½β = 92.50 ± 65.65 hr, V1 = 3.75 ± 0.67 L, CL= 132.11 ± 70.16 mL/hr. Conclusions: Ifabotuzumab demonstrates highly sensitive, specific and reproducible targeting of the tumor and tumor microenvironment in all patients in this study. The imaging changes suggest direct modulation of the tumor vasculature. Additional studies are planned to evaluate ifabotuzumab as part of an antibody-drug conjugate in various solid tumor types. References: 1. Stupp R, et al, Lancet Oncology 10:459-66, 2009 2. Day BW, et al. Cancer Cell 23:238-48, 2013 3. Vail ME, et al. Cancer Research 74:4470-81, 2014 4. Tomasevic N, et al. Growth Factors 32:223-35, 2014 5. Swords RT, et al. Leukemia Research 50:123-131, 2016 Citation Format: Hui K. Gan, Lawrence Cher, Po Inglis, Zarnie Lwin, Eddie Lau, Christian Wichmann, Alex McDonald, Ashray Gunjur, Uwe Ackermann, Kirsten Remen, Kate Fluck, Gel Bolarnos, Nancy Guo, Sze Ting Lee, Sylvia Gong, Jodie B. Palmer, Kunthi Pathmaraj, Graeme J. O'Keefe, Fiona E. Scott, Bryan W. Day, Andrew W. Boyd, Paul Thomas, Omar Ahmed, Dale Chappell, Cameron Durrant, Andrew M. Scott. Phase I safety and bioimaging trial of ifabotuzumab in patients with glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT101.
- Published
- 2021
20. Improved Anti-Tumor Response of Chimeric Antigen Receptor T Cell (CART) Therapy after GM-CSF Inhibition Is Mechanistically Supported By a Novel Direct Interaction of GM-CSF with Activated Carts
- Author
-
Michael W. Ruff, Omar H. Ahmed, Reona Sakemura, Rosalie M. Sterner, Paulina Horvei, Dale Chappell, Neil E. Kay, Sameer A. Parikh, Mehrdad Hefazi, Michelle J. Cox, Charles J. Kuhlmann, Saad S. Kenderian, Claudia Manriquez Roman, Sutapa Sinha, Kendall J. Schick, Erin E. Tapper, and Cameron Durrant
- Subjects
Cart ,Transplantation ,biology ,business.industry ,medicine.medical_treatment ,T cell ,CD28 ,Hematology ,CD19 ,Cell biology ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Cytokine ,030220 oncology & carcinogenesis ,biology.protein ,Medicine ,business ,Receptor ,B cell ,030215 immunology - Abstract
Introduction Despite the remarkable activity of CD19 directed chimeric antigen receptor T cell (CART19) therapy in the treatment of B cell malignancies, limitations include neurotoxicity (NT) and cytokine release syndrome (CRS). Emerging literature suggests that inhibitory myeloid cells and their cytokines induce CAR-T cell toxicities and inhibit effector functions. GM-CSF was specifically identified as a critical cytokine in the development of NT and CRS. Neutralization of GM-CSF in preclinical models has been shown to prevent CRS, enhance CART anti-tumor activity, and reduce the presence of tumor associated macrophages. In addition, there appears to be a direct effect on CART19 cells. Objectives In this study, we aimed to evaluate the direct effect of GM-CSF on CART cells. Methods We used a guide RNA (gRNA) targeting exon 3 of GM-CSF in a CRISPR-Cas9 lentiviral vector to knock out GM-CSF during CART cell manufacturing. Edited and wildtype T cells and CART cells were sent for whole exome sequencing (WES) and RNA sequencing. We also used flow cytometry to assess the expression of GM-CSF receptors on CART cells, activated using CD3/CD28 beads or irradiated NALM6 cells. Results WES analysis revealed no significant difference in the single nucleotide variants or indel counts between GM-CSFk/o and GM-CSFwt CART19 (Fig 1A). WES was significant for only two alterations in the gene targeted by the gRNA (Fig 1B). This high efficiency and accuracy indicated that the improvement in CART function is unlikely related to an off-target effect of the gRNA and suggests a direct interaction between GM-CSF and CART cells as a potential mechanism behind the improved anti-tumor activity. Further investigation robustly indicates that while resting CART cells do not express any GM-CSF receptors, activated CART cells significantly upregulate both α and β subunits of the GM-CSF receptor. This finding was significant both when CART cells were activated through their T cell receptor (Fig 1C) or CAR (Fig 1D). This was also seen in GM-CSFk/o CART19 cells, indicating this is specifically induced by T cell stimulation. These data suggest a direct interaction between GM-CSF and upregulated GM-CSFR on activated CART cells. Finally, we sought to uncover the downstream changes resulting from this effect. Transcriptome interrogation of GM-CSFk/o CART19 revealed a distinct signature, including significant inhibition of the Fas death pathway (Fig 1E). This suggests a potential mechanism for enhanced CART19 activity following GM-CSF depletion. Conclusion Our results strongly indicate that CART cells increase expression of GM-CSF receptor subunits when activated, resulting in modulation of CART cell functions. Furthermore, GM-CSFk/o CART19 revealed a distinct transcriptome signature compared to GM-CSFwt CART19. These results illuminate a novel mechanism for a direct modulatory effect of GM-CSF on activated CART cells.
- Published
- 2020
21. GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts
- Author
-
Rosalie M. Sterner, Fang Jin, Omar H. Ahmed, Karen E. Hedin, Katayoun Ayasoufi, Denise K. Walters, Nan Yang, Cynthia L. Forsman, Tarek Sahmoud, Michelle J. Cox, Michael J. Hansen, Reona Sakemura, Dale Chappell, Aaron J. Johnson, Larry R. Pease, Wendy K. Nevala, Neil E. Kay, Mehrdad Hefazi, Mrinal M. Patnaik, Saad S. Kenderian, Kendall J. Schick, Roman H. Khadka, and Cameron Durrant
- Subjects
0301 basic medicine ,Immunobiology and Immunotherapy ,Immunology ,Cell ,Transplantation, Heterologous ,Receptors, Antigen, T-Cell ,Biochemistry ,Cell therapy ,03 medical and health sciences ,Mice ,0302 clinical medicine ,medicine ,Tumor Cells, Cultured ,Animals ,Humans ,Neuroinflammation ,Cell Proliferation ,Inflammation ,Receptors, Chimeric Antigen ,business.industry ,Cell growth ,Macrophages ,Neurotoxicity ,Granulocyte-Macrophage Colony-Stimulating Factor ,Cell Biology ,Hematology ,Syndrome ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Antibodies, Neutralizing ,Xenograft Model Antitumor Assays ,Chimeric antigen receptor ,Cytokine release syndrome ,030104 developmental biology ,medicine.anatomical_structure ,Granulocyte macrophage colony-stimulating factor ,Immune System Diseases ,030220 oncology & carcinogenesis ,Cancer research ,Cytokines ,business ,medicine.drug - Abstract
Chimeric antigen receptor T (CAR-T) cell therapy is a new pillar in cancer therapeutics; however, its application is limited by the associated toxicities. These include cytokine release syndrome (CRS) and neurotoxicity. Although the IL-6R antagonist tocilizumab is approved for treatment of CRS, there is no approved treatment of neurotoxicity associated with CD19-targeted CAR-T (CART19) cell therapy. Recent data suggest that monocytes and macrophages contribute to the development of CRS and neurotoxicity after CAR-T cell therapy. Therefore, we investigated neutralizing granulocyte-macrophage colony-stimulating factor (GM-CSF) as a potential strategy to manage CART19 cell–associated toxicities. In this study, we show that GM-CSF neutralization with lenzilumab does not inhibit CART19 cell function in vitro or in vivo. Moreover, CART19 cell proliferation was enhanced and durable control of leukemic disease was maintained better in patient-derived xenografts after GM-CSF neutralization with lenzilumab. In a patient acute lymphoblastic leukemia xenograft model of CRS and neuroinflammation (NI), GM-CSF neutralization resulted in a reduction of myeloid and T cell infiltration in the central nervous system and a significant reduction in NI and prevention of CRS. Finally, we generated GM-CSF–deficient CART19 cells through CRISPR/Cas9 disruption of GM-CSF during CAR-T cell manufacturing. These GM-CSFk/o CAR-T cells maintained normal functions and had enhanced antitumor activity in vivo, as well as improved overall survival, compared with CART19 cells. Together, these studies illuminate a novel approach to abrogate NI and CRS through GM-CSF neutralization, which may potentially enhance CAR-T cell function. Phase 2 studies with lenzilumab in combination with CART19 cell therapy are planned.
- Published
- 2019
22. Improved Anti-Tumor Response of Chimeric Antigen Receptor T Cell (CART) Therapy after GM-CSF Inhibition Is Mechanistically Supported By a Novel Direct Interaction of GM-CSF with Activated Carts
- Author
-
Omar H. Ahmed, Sameer A. Parikh, Claudia Manriquez Roman, Sutapa Sinha, Rosalie M. Sterner, Raphael Mwangi, Dale Chappell, Kendall J. Schick, Paulina Horvei, Reona Sakemura, Erin E. Tapper, Cameron Durrant, Neil E. Kay, Saad S. Kenderian, Nancy Scott, Michelle J. Cox, Mehrdad Hefazi, Charles J. Kuhlmann, and Michael W. Ruff
- Subjects
Cart ,Receptor expression ,medicine.medical_treatment ,T cell ,Immunology ,CD28 ,Cell Biology ,Hematology ,Biology ,Biochemistry ,Chimeric antigen receptor ,CD19 ,medicine.anatomical_structure ,Cytokine ,medicine ,Cancer research ,biology.protein ,B cell - Abstract
Despite the remarkable activity of CD19 directed chimeric antigen receptor T cell (CART19) therapy in the treatment of B cell malignancies, the therapy is limited by the development of severe life-threatening complications such as neurotoxicity (NT) and cytokine release syndrome (CRS). Additionally, durable efficacy following CART19 therapy is not optimal. Emerging literature suggests that inhibitory myeloid cells and their cytokines play an important role in inducing CAR-T cell toxicities and also contribute to the inhibition of their effector functions. Specifically, GM-CSF was identified as a critical cytokine in the development of NT and CRS after CART19 therapy. Neutralization of GM-CSF in preclinical models has been shown to prevent CRS and enhance CART anti-tumor activity through modulation of myeloid cell behavior, resulting in reduction of tumor associated macrophages. In addition to the predominant effect of GM-CSF on myeloid cells, there appears to be a direct effect on CART19 cells. In this study, we aimed to evaluate the direct effect of GM-CSF on CART cells. Our initial finding of enhanced anti-tumor activity of CART19 cells after GM-CSF inhibition suggested a direct effect of GM-CSF on CART cells (Sterner et al. 2019, Blood). In these experiments, a guide RNA (gRNA) targeting exon 3 of GM-CSF in a CRISPR-Cas9 lentiviral vector was used to knock out GM-CSF during CART cell manufacturing. This resulted in a disruption efficiency of approximately 70% of the GM-CSF gene. Using a high tumor burden xenograft model for relapsed acute lymphoblastic leukemia established through the engraftment of the CD19+ luciferase+ NALM6 cell line (1x106 cells intravenously) in immunocompromised NOD-SCID-γ-/- mice, treatment with low doses of GM-CSFk/o CART19 resulted in improved anti-tumor activity and overall survival compared to GM-CSFwt CART19. The lack of myeloid cells in this model pointed to an intrinsic effect of GM-CSF on CAR-T cells. To ensure that this was not related to an off-target effect of the gRNA, whole exome sequencing (WES) of the modified cells was performed. There was no difference in the single nucleotide variants or indel counts between GM-CSFk/o CART19 and GM-CSFwt CART19 (Figure 1A). WES was significant for only two alterations in the exon 3 targeted by the gRNA (Figure 1B). The high efficiency and accuracy of targeting exon 3 of GM-CSF indicated that the improvement in CART function is unlikely related to an off-target effect of the gRNA and suggested the possibility of a direct interaction between GM-CSF and CART cells as a potential mechanism behind the improved anti-tumor activity. To investigate this interaction, we first assessed the expression of GM-CSF receptors on CART cells. While resting CART cells do not express any GM-CSF receptors, our analysis robustly indicates that activated CART cells significantly upregulate both α and β subunits of the GM-CSF receptor. This finding was significant both when CART cells are activated through their T cell receptor with CD3/CD28 beads (Figure 1C) or through the CAR with irradiated NALM6 cells (Figure 1D). Additionally, activated GM-CSFk/o CART19 cells also upregulated GM-CSF receptors, indicating this upregulation is induced by T cell stimulation. These results suggest a direct interaction between GM-CSF and upregulated GM-CSFR on activated CART cells. Having demonstrated that 1) GM-CSF depletion enhances CART19 efficacy in xenograft models in the absence of monocytes and 2) T cell activation increases GM-CSF receptor expression, we sought to uncover the downstream changes resulting from this effect. Transcriptome interrogation of GM-CSFk/o CART19 revealed a distinct signature including a significant inhibition of the Fas death pathway, a known critical pathway in inducing CART cell apoptosis. This suggests a potential mechanism for enhanced CART19 activity following GM-CSF depletion (Figure 1E). In summary, our results strongly indicate that CART cells increase expression of GM-CSF receptor subunits when activated, resulting in modulation of CART cell functions. Furthermore, GM-CSFk/o CART19 revealed a distinct transcriptome signature compared to GM-CSFwt CART19. These results illuminate a novel mechanism for a direct modulatory effect of GM-CSF on activated CART cells. Disclosures Cox: Humanigen: Patents & Royalties. Sterner:Humanigen: Patents & Royalties. Sakemura:Humanigen: Patents & Royalties. Ahmed:Humanigen: Employment. Chappell:Humanigen: Employment. Durrant:Humanigen: Employment. Parikh:Acerta Pharma: Research Funding; MorphoSys: Research Funding; AbbVie: Honoraria, Research Funding; Genentech: Honoraria; Janssen: Research Funding; AstraZeneca: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Ascentage Pharma: Research Funding. Kay:MorphoSys: Other: Data Safety Monitoring Board; Infinity Pharmaceuticals: Other: DSMB; Celgene: Other: Data Safety Monitoring Board; Agios: Other: DSMB. Kenderian:Novartis: Patents & Royalties, Research Funding; Tolero: Research Funding; Lentigen: Research Funding; Humanigen: Other: Scientific advisory board , Patents & Royalties, Research Funding; Kite/Gilead: Research Funding; Morphosys: Research Funding.
- Published
- 2019
23. A Phase 1 Study of Lenzilumab, a humaneered recombinant Anti-Human Granulocyte-Macrophage Colony- Stimulating Factor (anti-hGM-CSF) Antibody, for Chronic Myelomonocytic Leukemia (CMML)
- Author
-
Abhishek A. Mangaonkar, Aref Al-Kali, Jeffery Hirvela, Adrian Lo, Rami S. Komrokji, Eric Padron, Darci Zblewski, Deanna Kanne, Mrinal M. Patnaik, Rachel Heuer, Dale Chappell, Alan F. List, David A. Sallman, Cameron Durrant, Omar J. Ahmed, Maria E. Balasis, and Rahil Ismail
- Subjects
biology ,medicine.drug_class ,business.industry ,Immunology ,Chronic myelomonocytic leukemia ,Cell Biology ,Hematology ,Colony-stimulating factor ,Monoclonal antibody ,medicine.disease ,Biochemistry ,Transplantation ,LENZILUMAB ,Granulocyte macrophage colony-stimulating factor ,medicine.anatomical_structure ,Cancer research ,biology.protein ,medicine ,Bone marrow ,Antibody ,business ,medicine.drug - Abstract
BACKGROUND: CMML is a myelodysplastic/myeloproliferative neoplasm with a median survival of 32 months and no therapies that improve its natural history. We have previously demonstrated that CMML bone marrow mononuclear cells (BMNCs) are hypersensitive to GM-CSF and that the GM-CSF axis is a viable therapeutic target (Padron et al., Blood 2013). Lenzilumab is a novel, humaneered IgG1κ monoclonal antibody, with high affinity for human GM-CSF that has activity in preclinical models of CMML. We report a Phase 1 clinical trial testing the safety and preliminary efficacy of this agent in CMML. METHODS: The study was approved by scientific and ethical review boards. This was a multicenter Phase 1 study designed to evaluate the safety and determine the recommended phase 2 dose of lenzilumab in subjects with CMML. Dose escalation proceeded using a standard 3+3 study design to determine the maximum tolerated dose (MTD). Three dose cohorts included 200 mg, 400 mg, and 600 mg, were given IV on day 1 and 15 of cycle 1 and then only on day 1 of subsequent 28-day cycles. Key inclusion criteria included a WHO-defined diagnosis of CMML and a platelet count greater than 20 x103 cells/dL. Response was evaluated utilizing the MDS/MPN International Working Group Criteria (Savona Blood 2015). Pharmacokinetic analysis and pharmacodynamics were evaluated by pSTAT5 by flow cytometry. RESULTS: Between July 2016 and June 2018, a total of 15 patients were enrolled. The median age at study entry was 74 years (range 52-85) and 80% were male. Nine patients were classified as CMML-0, 3 as CMML-1, and 3 as CMML-2. Seventy three percent of patients had normal cytogenetics or -Y. The most commonly mutated genes at screening included TET2 60%, ASXL1 53%, SRSF2 47%, and RAS pathway (i.e. NRAS or CBL) mutations 40%. Nine patients were previously treated with hypomethylating agents and/or experimental therapies, 3 were treated with hydroxyurea only, and 3 were untreated. The mean Hgb was 9.7g/dL (7.6-14g/dL), the mean platelet count was 147 x103 cells/dL (16-942 x103 cells/dL), and 66% of cases were MPN-CMML by the French-American-British classification at study entry. Three patients were enrolled at each dose level and an additional 6 patients were enrolled at 600mg as planned. Consistent with prior studies of lenzilumab, no dose limiting toxicities were identified and no treatment emergent grade 3 or 4 toxicities were reported. The mean duration on therapy was 221.8 days (14-787 days) and the majority of patients discontinued study drug because of disease progression or lack of response (69%). Five of 15 (33%) patients enrolled achieved clinical benefit by MDS/MPN IWG criteria with 3 platelet responses, 1 neutrophil response, and 1 spleen response. An additional patient had bone marrow myeloblast reduction from 6% to 1% which allowed that patient to undergo allogeneic stem cell transplantation. Clinical response was not statistically associated with somatic mutations or changes in pSTAT5 between screening and cycle 3. However, 3 of 4 patients with NRAS mutation achieved clinical benefit or had clinical meaningful bone marrow myeloblast reductions. CONCLUSION: Lenzilumab is well tolerated in patients with CMML, with no grade 3 or 4 treatment emergent adverse events or DLTs reported. Durable clinical benefit was achieved in 33% of patients and one patient was bridged to allogenic transplant, providing proof of concept that GM-CSF inhibition has activity in CMML. The favorable safety and activity profile of lenzilumab warrants future evaluation as part of a combination regimen targeted to specific subtypes more likely to respond, including patients with NRAS mutations. Disclosures Patnaik: Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees. Sallman:Celgene: Research Funding, Speakers Bureau; Celyad: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Abbvie: Speakers Bureau; Novartis: Speakers Bureau; Jazz: Research Funding. Al-Kali:Astex Pharmaceuticals, Inc.: Research Funding. Komrokji:celgene: Consultancy; Agios: Consultancy; JAZZ: Consultancy; Novartis: Speakers Bureau; JAZZ: Speakers Bureau; pfizer: Consultancy; DSI: Consultancy; Incyte: Consultancy. Lo:Humanigen: Employment. Durrant:Humanigen: Employment. Chappell:Humanigen: Employment. Ahmed:Humanigen: Employment. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.
- Published
- 2019
24. ATIM-23. PRELIMINARY FINDINGS OF A PHASE I SAFETY AND BIOIMAGING TRIAL OF KB004 (IFABOTUZUMAB) IN PATIENTS WITH GLIOBLASTOMA
- Author
-
Fiona Scott, Sylvia J. Gong, Lawrence Cher, Paul Thomas, Hui K Gan, Jodie Palmer, Cameron Durrant, Sze Ting Lee, Andrew W. Boyd, Nancy Guo, Uwe Ackermann, Graeme O'Keefe, Kirsten Remen, Nicole Coombs, Eddie Lau, Kunthi Pathmaraj, Po Inglis, Andrew M. Scott, Bryan W. Day, and Zarnie Lwin
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Adult Clinical Trials–Immunologic ,Hematologic Neoplasms ,Tumor vasculature ,medicine.disease ,Clinical neurology ,Internal medicine ,medicine ,In patient ,Neurology (clinical) ,business ,Glioblastoma - Abstract
Glioblastoma (GBM) is the most frequent and lethal primary brain neoplasm. EphA3 is a tumor restricted antigen expressed in 38–40% of GBM and 100% of the tumor vasculature. Ifabotuzumab is a non-fucosylated IgG1κ antibody targeting EphA3 receptor. A Phase 1 study of ifabotuzumab in haematological malignancies was well tolerated and clinically active. Here we report on a Phase I dose escalation and biodistribution study of ifabotuzumab in recurrent glioblastoma. DESIGN The primary objective is to determine the toxicity and recommended phase II dose of Ifabotuzumab in GBM patients (pts). Secondary objectives are to determine the biodistribution and pharmacokinetics (PK) of 89Zr-Ifabotuzumab, the frequency of EphA3 positive GBM and response rates. Eligible pts received a trace (5mg) dose of zirconium-89 labelled ifabotuzumab (89Zr-ifab) on day 1 followed by sequential PET imaging over 1 week to determine its biodistribution, frequency of in situ EphA3 expression and tumor uptake. Safety and PK assessments were undertaken. On Day 8, pts commenced weekly ifabotuzumab infusions until PD. Three cohorts are planned (3.5mg/kg, 5.25 mg/kg, 7.9 mg/kg). On day 36, pts received both 89Zr-ifab and Ifabotuzumab, to assess receptor occupancy. Response rate (RANO) and survival data were collected. RESULTS: To date, 7 of 12 pts have enrolled (6 at 3.5 mg/kg,1 at 5.25 mg/kg; Mean age: 55 years (±12.6), 4 are male). Treatment emergent AEs included infusion reactions, seizures, cerebral oedema, rash, pruritis, headaches, eye disorder. Most were considered related to study drug, seizures and infusion reactions were readily managed with increased premedications after the first occurrence. Best response in cohort 1 is SD for 23 weeks. 89Zr-ifab PET/CT scans showed rapid, specific targeting at all known tumor sites and in all pts, but no normal tissue uptake. MRI scans showed predominant T2/FLAIR changes, occasionally marked, which were consistent with treatment effect on tumor vasculature.
- Published
- 2019
25. Graded Microstructure of Additive Manufactured Ti-6Al-4V via Electron Beam Melting
- Author
-
Simon P. Ringer, Cameron Durrant, Hansheng Chen, S. Suresh Babu, Sophie Primig, Xiaozhou Liao, Yingluo Li, and Christopher Cooper
- Subjects
Materials science ,Cathode ray ,Ti 6al 4v ,Composite material ,Microstructure ,Instrumentation - Published
- 2019
26. Abstract CT063: Preliminary findings of a Phase I safety and bioimaging trial of KB004 (ifabotuzumab) in patients with glioblastoma
- Author
-
Sze Ting Lee, Nancy Guo, Uwe Ackermann, Jodie B. Palmer, Bryan W. Day, Kunthi Pathmaraj, Cameron Durrant, Fiona Scott, Po Inglis, Andrew M. Scott, Zarnie Lwin, Sylvia J. Gong, Hui K Gan, Christian Wichmann, Graeme O'Keefe, Paul Thomas, Lawrence M Cher, Kirsten Remen, Nicole Coombs, Eddie Lau, and Andrew W. Boyd
- Subjects
Cancer Research ,medicine.medical_specialty ,business.industry ,Cancer ,medicine.disease ,Gastroenterology ,Rash ,Leukemia ,Oncology ,Pharmacokinetics ,Internal medicine ,Toxicity ,medicine ,Eye disorder ,Headaches ,medicine.symptom ,Adverse effect ,business - Abstract
Overview: Glioblastoma (GBM) is the most frequent and lethal primary brain neoplasm, with only 10% of patients surviving 5 years (1). EphA3 is a tumor restricted antigen expressed in 38-40% of GBM and 100% of the tumor vasculature (2, 3). Ifabotuzumab is a non-fucosylated IgG1K antibody targeting EphA3 receptor (4). A Phase I study of ifabotuzumab in haematological malignancies showed it was well tolerated and clinically active (5). Here we report on a Phase I dose escalation and biodistribution study of ifabotuzumab in recurrent GBM. Study Design: The primary objective is to determine the toxicity and recommended phase II dose of Ifabotuzumab in GBM patients (pts). Secondary objectives are to determine the biodistribution and pharmacokinetics (PK) of 89Zr-Ifabotuzumab, the frequency of EphA3 positive GBM and response rates. Eligible pts had measurable tumors received a trace (5mg) dose of zirconium-89 labelled ifabotuzumab (89Zr-ifab) on day 1 followed by sequential PET imaging over 1 week to determine its biodistribution, frequency of in situ EphA3 expression and quantitative tumor uptake. Safety assessments and PK sampling was also undertaken. On Day 8, pts commenced weekly Ifabotuzumab infusions over 2 hours. Three cohorts are planned (3.5mg/kg, 5.25 mg/kg, 7.9 mg/kg). On day 36, pts received both 89Zr-ifab and Ifabotuzumab, allowing assessment of receptor occupancy. Response rate (RANO) and survival data were collected. Pts then continued on Ifabotuzumab until progression. Results: To date, 4 of 12 planned pts have enrolled. Their mean age is 53 years (±16.3) and 3 are male. Treatment emergent adverse events included infusion reactions in 4 patients, seizures in 3 pts, cerebral oedema in 1, rash in 1, headaches in 1, eye disorder in 1. Most were considered related to study drug except seizure in 2 pts, headaches and eye disorder. Seizures and infusion reactions were readily managed with increased premedications after the first occurrence. The best response was stable disease for 23 weeks. 89Zr-ifab PET/CT scans showed rapid, specific targeting at all known tumor sites and in all pts, but no normal tissue uptake. MRI scans showed predominant T2/FLAIR changes, occasionally marked, which were consistent with treatment effect on tumor vasculature. The mean ± SD (n=4) PK parameters for first infusion 89Zr-ifab were T½α= 10.63 ± 3.14 hr, T½β = 106.85 ± 40.60 hr, V1 = 3.88 ± 0.88 L, CL= 94.11 ± 36.54 mL/hr. Conclusions: 89Zr-Ifabotuzumab demonstrates sensitive, specific and reproducible targeting of the tumor microenvironment in GBM patients. The imaging changes suggest modulation of the tumor vasculature. Enrolment is on-going. References: 1. Stupp R, et al. Lancet Oncology 10:459-66, 2009 2. Day BW, et al. Cancer Cell 23:238-48, 2013 3. Vail ME, et al. Cancer Research 74:4470-81, 2014 4. Tomasevic N, et al. Growth Factors 32:223-35, 2014 5. Swords RT, et al. Leukemia Research 50:123-131, 2016 Citation Format: Hui Gan, Lawrence Cher, Po Inglis, Zarnie Lwin, Eddie Lau, Christian Wichmann, Uwe Ackermann, Nicole Coombs, Kirsten Remen, Nancy Guo, Sze Ting Lee, Sylvia Gong, Jodie B. Palmer, Kunthi Pathmaraj, Graeme O'Keefe, Fiona Scott, Bryan W. Day, Andrew W. Boyd, Paul Thomas, Cameron Durrant, Andrew M. Scott. Preliminary findings of a Phase I safety and bioimaging trial of KB004 (ifabotuzumab) in patients with glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT063.
- Published
- 2019
27. GM-CSF Blockade during Chimeric Antigen Receptor T-Cell (CART) Therapy Reduces Cytokine Release Syndrome and Neurotoxicity and May Enhance CART Effector Functions
- Author
-
Tarek Sahmoud, Omar H. Ahmed, Denise K. Walters, Reona Sakemura, Cynthia L. Forsman, German Martinez, Mrinal M. Patnaik, Katayoun Ayasoufi, Cameron Durrant, Michelle J. Cox, Wendy K. Nevala, Neil E. Kay, Stephen J. Russell, Fang Jin, Aaron J. Johnson, Larry R. Pease, Rosalie M. Sterner, Michael J. Hansen, Nan Yang, Karen E. Hedin, Saad S. Kenderian, Kendall J. Schick, Roman H. Khadka, Mehrdad Hefazi, and Baustin M. Welch
- Subjects
Cart ,Transplantation ,biology ,business.industry ,Monocyte ,T cell ,Hematology ,medicine.disease ,Chimeric antigen receptor ,CD19 ,Cell therapy ,Cytokine release syndrome ,medicine.anatomical_structure ,biology.protein ,medicine ,Cancer research ,Antibody ,business - Abstract
Chimeric antigen receptor T-cell therapy (CART) is limited by the development of cytokine release syndrome (CRS) and neurotoxicity (NT). CRS is related to extreme elevation of cytokines and massive T cell expansion. Preliminary studies suggest that NT might be mediated by myeloid cells that cross the blood brain barrier. This is supported by correlative analysis from CART19 pivotal trials where CD14+ cell numbers were increased in the cerebrospinal fluid of patients that developed severe NT (Locke et al, ASH 2017). Thus, we aimed to investigate the role of GM-CSF neutralization in preventing CRS and NT after CART cell therapy via monocyte control. The human GM-CSF neutralizing antibody lenzilumab (Humanigen, Burlingame, California), which has been shown to be safe in phase II clinical trials, does not impair CART cell function in vitro (10 ug/mL) when CART19 cells are stimulated with the CD19+ Luciferase+ acute lymphoblastic leukemia (ALL) cell line NALM6. Lenzilumab results in enhanced CART cell antigen specific proliferation in the presence of monocytes. In vivo, NOD-SCID-g−/− mice were engrafted with high disease burdens of NALM6 and treated with low doses of CART19 or control T cells, in combination with lenzilumab or isotype control antibody. The combination of CART19 and lenzilumab does not impair CART cell activity in vivo (Fig 1A). The impact of GM-CSF neutralization on CART toxicities in a novel patient derived xenograft model was explored. NOD-SCID-g−/− mice were engrafted with primary ALL blasts (1-3 × 106 cells). Mice were treated with high doses of CART19 cells (2-5 × 106 iv) and developed CART cell related toxicities. The combination of CART19, lenzilumab (to neutralize human GM-CSF), and murine GM-CSF blocking antibody (to neutralize mouse GM-CSF) resulted in prevention of weight loss (Fig 1B), decrease in critical myeloid cytokines (Fig 1C-D), reduction of cerebral edema (Fig 1E), enhanced leukemic disease control in the brain (Fig 1F), and reduction in brain macrophages (Fig 1G). As CRISPR/Cas9 gene editing of the GM-CSF gene during the process of CART cell manufacturing would result in CART cells with innately reduced secretion of GM-CSF, we designed guide RNA targeting exon 3 of the GM-CSF gene to generate GM-CSFk/o CART19 cells. These CARTs produce significantly less GM-CSF upon activation but other T cell cytokine production is not inhibited (Fig 1H). Using the NALM6 high tumor burden relapse xenograft model as described above, GM-CSFk/o CART19 cells resulted in slightly enhanced disease control compared to CART19 cells (Fig 1I). These studies illuminate a novel approach to abrogate NT and CRS through GM-CSF blockade that also potentially enhances CART cell functions. Based on these results, we have designed a phase II clinical trial using lenzilumab as a modality to prevent CART related toxicities in patients with diffuse large B cell lymphoma.
- Published
- 2019
28. GM-CSF Blockade during Chimeric Antigen Receptor T Cell Therapy Reduces Cytokine Release Syndrome and Neurotoxicity and May Enhance Their Effector Functions
- Author
-
Rosalie M. Sterner, Karen E. Hedin, Aaron J. Johnson, Cameron Durrant, Fang Jin, Stephen J. Russell, Larry R. Pease, Mrinal M. Patnaik, Nan Yang, Denise K. Walters, Cynthia L. Forsman, Wendy K. Nevala, Reona Sakemura, Katayoun Ayasoufi, Mehrdad Hefazi, Michelle J. Cox, Tarek Sahmoud, Omar H. Ahmed, Baustin M. Welch, Michael J. Hansen, German Martinez, Neil E. Kay, Kendall J. Schick, Roman H. Khadka, and Saad S. Kenderian
- Subjects
0301 basic medicine ,Myeloid ,medicine.medical_treatment ,T cell ,Immunology ,Biochemistry ,CD19 ,Cell therapy ,03 medical and health sciences ,0302 clinical medicine ,Medicine ,biology ,business.industry ,Cell Biology ,Hematology ,medicine.disease ,Chimeric antigen receptor ,Cytokine release syndrome ,030104 developmental biology ,medicine.anatomical_structure ,Cytokine ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Chimeric Antigen Receptor T-Cell Therapy ,business - Abstract
Despite its efficacy, chimeric antigen receptor T-cell therapy (CART) is limited by the development of cytokine release syndrome (CRS) and neurotoxicity (NT). While CRS is related to extreme elevation of cytokines and massive T cell expansion, the exact mechanisms for NT have not yet been elucidated. Preliminary studies suggest that NT might be mediated by myeloid cells that cross the blood brain barrier. This is supported by correlative analysis from CART19 pivotal trials where CD14+ cell numbers were increased in the cerebrospinal fluid of patients that developed severe NT (Locke et al, ASH 2017). Therefore, we aimed to investigate the role of GM-CSF neutralization in preventing CRS and NT after CART cell therapy via monocyte control. First, we investigated the effect of GM-CSF blockade on CART cell effector functions. Here, we used the human GM-CSF neutralizing antibody (lenzilumab, Humanigen, Burlingame, California) that has been shown to be safe in phase II clinical trials. Lenzilumab (10 ug/kg) neutralizes GM-CSF when CART19 cells are stimulated with the CD19+ Luciferase+ acute lymphoblastic leukemia (ALL) cell line NALM6, but does not impair CART cell function in vitro. We have found that malignancy associated macrophages reduce CART proliferation. GM-CSF neutralization with lenzilumab results in enhanced CART cell antigen specific proliferation in the presence of monocytes. To confirm this in vivo, NOD-SCID-g-/- mice were engrafted with high disease burdens of NALM6 and treated with low doses of CART19 or control T cells (to induce tumor relapse), in combination with lenzilumab or isotype control antibody. The combination of CART19 and lenzilumab resulted in significant anti-tumor activity and overall survival benefit compared to control T cells (Fig 1A), similar to mice treated with CART19 combined with isotype control antibody, indicating that GM-CSF neutralization does not impair CART cell activity in vivo. This anti-tumor activity was validated in an ALL patient derived xenograft model. Next, we explored the impact of GM-CSF neutralization on CART cell related toxicities in a novel patient derived xenograft model. Here, NOD-SCID-g-/- mice were engrafted with leukemic blasts (1-3x106 cells) derived from patients with high risk ALL. Mice were then treated with high doses of CART19 cells (2-5x106 intravenously). Five days after CART19 treatment, mice began to develop progressive motor weakness, hunched bodies, and weight loss that correlated with massive elevation of circulating human cytokine levels. Magnetic Resonance Imaging (MRI) of the brain during this syndrome showed diffuse enhancement and edema, associated with central nervous system (CNS) infiltration of CART cells and murine activated myeloid cells. This is similar to what has been reported in CART19 clinical trials in patients with severe NT. The combination of CART19, lenzilumab (to neutralize human GM-CSF) and murine GM-CSF blocking antibody (to neutralize mouse GM-CSF) resulted in prevention of weight loss (Fig 1B), decrease in critical myeloid cytokines (Fig 1C-D), reduction of cerebral edema (Fig 1E), enhanced leukemic disease control in the brain (Fig 1F), and reduction in brain macrophages (Fig 1G). Finally, we hypothesized that disrupting GM-CSF through CRISPR/Cas9 gene editing during the process of CART cell manufacturing would result in functional CART cells with reduced secretion of GM-CSF. We designed guide RNA targeting exon 3 of the GM-CSF gene and generated GM-CSFk/o CART19 cells. Our preliminary data suggest that these CARTs produce significantly less GM-CSF upon activation but continue to exhibit similar production of other cytokines and exhibit normal effector functions in vitro (Fig 1H). Using the NALM6 high tumor burden relapse xenograft model as described above, GM-CSFk/o CART19 cells resulted in slightly enhanced disease control compared to CART19 cells (Fig 1I). Thus, modulating myeloid cell behavior through GM-CSF blockade can help control CART mediated toxicities and may reduce their immunosuppressive features to improve leukemic control. These studies illuminate a novel approach to abrogate NT and CRS through GM-CSF neutralization that also potentially enhances CART cell functions. Based on these results, we have designed a phase II clinical trial using lenzilumab as a modality to prevent CART related toxicities in patients with diffuse large B cell lymphoma. Disclosures Ahmed: Humanigen: Employment. Sahmoud:Humanigen: Employment. Durrant:Humanigen: Employment. Russell:Vyriad: Equity Ownership. Kay:Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Cytomx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Infinity Pharm: Membership on an entity's Board of Directors or advisory committees; Acerta: Research Funding. Kenderian:Novartis: Patents & Royalties; Tolero Pharmaceuticals: Research Funding; Humanigen: Research Funding.
- Published
- 2018
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.