A Randomized, Double Blind, Multicenter Phase 3 Trial of BMS-986489 (BMS-986012+Nivolumab Fixed Dose Combination) in Combination With Carboplatin Plus Etoposide vs Atezolizumab in Combination With Carboplatin Plus Etoposide as First-Line Therapy in Participants With Extensive-Stage Small Cell Lung Cancer (TIGOS).

The Purpose of the Study is to Compare the Efficacy and Safety of BMS-986489 (Anti-fucosyl-GM1+ Nivolumab Fixed Dose Combination) in Combination with Carboplatin plus Etoposide to that of Atezolizumab with Carboplatin plus Etoposide as First-Line Therapy in Participants with Extensive-Stage Small Cell Lung Cancer.

开始日期2025-01-21

申办/合作机构

Bristol Myers Squibb Co.

NCT04702880 / Active, not recruiting临床2期

A Randomized, Open-label Phase 2 Clinical Trial of BMS-986012 in Combination With Carboplatin, Etoposide, and Nivolumab as First-line Therapy in Extensive-stage Small Cell Lung Cancer

The purpose of this study is to demonstrate that treatment with BMS-986012 in combination with carboplatin, etoposide, and nivolumab will have acceptable safety and tolerability and will improve progression-free survival compared with carboplatin, etoposide, and nivolumab alone in newly diagnosed participants with extensive-stage small cell lung cancer (ES-SCLC).

开始日期2021-03-17

申办/合作机构

Bristol Myers Squibb Co.

JPRN-JapicCTI-163424 / Unknown status临床1期

A Phase 1 Study of the Safety and Tolerability of BMS-986012 in Subjects With Small Cell Lung Cancer

开始日期2017-01-01

申办/合作机构

Bristol-Myers Squibb KK

100 项与 Fuc-GM1 相关的临床结果

登录后查看更多信息

100 项与 Fuc-GM1 相关的转化医学

登录后查看更多信息

0 项与 Fuc-GM1 相关的专利（医药）

登录后查看更多信息

项与 Fuc-GM1 相关的文献（医药）

2024-03-05·Microbiology Spectrum

Campylobacter jejuni extracellular vesicles harboring cytolethal distending toxin bind host cell glycans and induce cell cycle arrest in host cells

Article

作者: Cramond, Angus ; Poly, Frederic ; Le, Lena Hoang My ; Elgamoudi, Bassam ; Ying, Le ; Korolik, Victoria ; Colon, Nina ; Ferrero, Richard L

ABSTRACT Cytolethal distending toxins (CDTs) are released by Gram-negative pathogens into the extracellular medium as free toxin or associated with extracellular vesicles (EVs), commonly known as outer membrane vesicles (OMVs). CDT production by the gastrointestinal pathogen Campylobacter jejuni has been implicated in colorectal tumorigenesis. Despite CDT being a major virulence factor for C. jejuni , little is known about the EV-associated form of this toxin. To address this point, C. jejuni mutants lacking each of the three CDT subunits (A, B, and C) were generated. C. jejuni cdtA, cdtB, and cdtC bacteria released EVs in similar numbers and sizes to wild-type bacteria, ranging from 5 to 530 nm (mean ± SEM = 118 ±6.9 nm). As the CdtAC subunits mediate toxin binding to host cells, we performed “surface shearing” experiments, in which EVs were treated with proteinase K and incubated with host cells. These experiments indicated that CDT subunits are internal to EVs and that surface proteins are probably not involved in EV-host cell interactions. Furthermore, glycan array studies demonstrated that EVs bind complex host cell glycans and share receptor binding specificities with C. jejuni bacteria for fucosyl GM1 ganglioside, P1 blood group antigen, sialyl, and sulfated Lewis x . Finally, we show that EVs from C. jejuni WT but not mutant bacteria induce cell cycle arrest in epithelial cells. In conclusion, we propose that EVs are an important mechanism for CDT release by C. jejuni and are likely to play a significant role in toxin delivery to host cells. IMPORTANCECampylobacter jejuni is the leading cause of foodborne gastroenteritis in humans worldwide and a significant cause of childhood mortality due to diarrheal disease in developing countries. A major factor by which C. jejuni causes disease is a toxin, called cytolethal distending toxin (CDT). The biology of this toxin, however, is poorly understood. In this study, we report that C. jejuni CDT is protected within membrane blebs, known as extracellular vesicles (EVs), released by the bacterium. We showed that proteins on the surfaces of EVs are not required for EV uptake by host cells. Furthermore, we identified several sugar receptors that may be required for EV binding to host cells. By studying the EV-associated form of C. jejuni CDT, we will gain a greater understanding of how C. jejuni intoxicates host cells and how EV-associated CDT may be used in various therapeutic applications, including as anti-tumor therapies.

2022-11-01·JTO Clinical and Research Reports

BMS-986012, an Anti–Fucosyl-GM1 Monoclonal Antibody as Monotherapy or in Combination With Nivolumab in Relapsed/Refractory SCLC: Results From a First-in-Human Phase 1/2 Study

Article

作者: Urbanska, Katarzyna ; Markman, Ben ; Tannenbaum-Dvir, Sarah ; Rudin, Charles M ; He, Chunsheng ; DiPiero, Andrew ; Basciano, Paul ; Andelkovic, Vladimir ; Clarke, Stephen ; Juergens, Rosalyn A ; van Herpen, Carla ; Lin, Hongxia ; Sanghavi, Kinjal ; Leighl, Natasha B ; Surmont, Veerle ; Kim, Dong-Wan ; Kollia, Georgia ; Liu, Yu ; Sibille, Anne ; Ready, Neal ; Sanatani, Michael ; Rivera, Mirelis Acosta ; Snow, Stephanie ; Chu, Quincy ; Lathers, Deanne

IntroductionFucosyl-GM1 is a monosialoganglioside with limited expression in healthy tissues and high expression on SCLC cells. BMS-986012 is a nonfucosylated, first-in-class, fully human immunoglobulin G1 monoclonal antibody that binds to fucosyl-GM1.MethodsCA001-030 is a phase 1/2, first-in-human study of BMS-986012 as monotherapy or in combination with nivolumab for adults with relapsed or refractory SCLC. Safety is the primary end point. Additional end points include objective response rate, duration of response, progression-free survival, pharmacokinetics, and overall survival.ResultsPatients (BMS-986012 monotherapy, n = 77; BMS-986012 + nivolumab, n = 29) were predominantly of male sex (58%), 63 years old (mean), current or past tobacco users (97%), and treated previously with first-line systemic therapy (99%). The most common treatment-related adverse event was pruritus (n = 95 [90%]). Grade 4 treatment-related adverse events were reported in 2% (n = 2) of patients. The objective response rate (95% confidence interval [CI]) was higher with BMS-986012 plus nivolumab (38% [20.7%-57.7%]) than with monotherapy (4% [0.8%-11.0%]). Median (95% CI) duration of response with BMS-986012 plus nivolumab was 26.4 (4.4-not reached) months. Progression-free survival (95% CI) at 24 weeks with monotherapy and BMS-986012 plus nivolumab was 12.2% (6.0%-20.7%) and 39.3% (21.7%-56.5%), respectively. The pharmacokinetics profile of monotherapy and BMS-986012 plus nivolumab suggested dose proportionality across the tested dose range. Median overall survival (95% CI) with monotherapy and BMS-986012 plus nivolumab was 5.4 (4.0-7.3) and 18.7 (8.2-37.3) months, respectively.ConclusionsBMS-986012 in combination with nivolumab represents a well-tolerated, potential new therapy for relapsed or refractory SCLC. BMS-986012 is currently being explored in combination with carboplatin, etoposide, and nivolumab as a first-line therapy in extensive-stage SCLC (NCT04702880).

2021-10-01·Clinical advances in hematology & oncology : H&O

Immunotherapy for small cell lung cancer: established applications and novel approaches.

Review

作者: Hann, Christine L ; Scott, Susan C

Small cell lung cancer (SCLC) is a devastating disease that has a case fatality rate of more than 90% despite best available treatments. As a result, patients with SCLC are in critical need of improved therapeutic approaches. Immunotherapies, in particular immune checkpoint inhibitors (ICIs), have transformed the treatment of many cancers and are of great interest in SCLC. In recent years, the addition of anti-programmed death ligand 1 (PD-L1) inhibitors to frontline platinum-based chemotherapy in extensive-stage SCLC has improved survival, and combination chemoimmunotherapy is now approved as the standard of care. ICIs are also under investigation in other settings, including as consolidation therapy in limited-stage SCLC following chemoradiation and in combination with chemoradiation. PD-L1 expression and tumor mutational burden are not reliably associated with ICI benefit in SCLC, and predictive biomarkers of ICI response in SCLC are actively sought. Novel immunotherapeutic approaches are under investigation in SCLC. Rational targets and combinations, which stem from investigations of SCLC biology and the immune tumor microenvironment, include combinations with inhibitors of TIGIT or LAG3; targeting alternative signaling pathways, such as DNA damage repair; and co-targeting SCLC-specific tumor antigens, such as fucosyl-GM1 and DLL3. This review summarizes approaches to immunotherapy in SCLC, including current evidence and approvals, as well as key questions and future directions.