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1.
J Immunother Cancer ; 12(8)2024 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-39142718

RESUMO

Engagement of programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) can interfere with the CD28 signaling requisite for T-cell activation. While immune checkpoint inhibitors (ICIs) can relieve this suppression, they are unable to drive CD28 costimulation that may mechanistically contribute to ICI resistance. Thus, CD28 costimulation in the context of checkpoint inhibition may activate immunosuppressed T-cells in the tumor microenvironment. Davoceticept (ALPN-202) is an Fc fusion of a CD80 variant immunoglobulin domain (vIgD) designed to mediate PD-L1-dependent CD28 costimulation while inhibiting the PD-L1 and CTLA-4 checkpoints. PD-L1-restriction of davoceticept's CD28 costimulatory activity may minimize systemic T-cell activation and avoid untoward systemic toxicities. At the same time, preclinical studies have suggested that treatment with davoceticept during PD-1 inhibition may enhance antitumor activity by upregulating PD-L1, potentially synergizing with davoceticept's PD-L1-dependent costimulatory mechanism. This report details two cases of fatal cardiac events following treatment with davoceticept in combination with pembrolizumab (anti-PD-1) in the phase 1 study, NEON-2. Both events occurred in females in their 60s; one with choroidal melanoma and prior immunotherapy, the other with ICI-naïve microsatellite stable colorectal cancer. The clinical courses were fulminant with symptom onset at 2 weeks, followed by rapid decline. Cardiac autopsy from one patient confirmed immune-related myocarditis, and immunosequencing revealed expansion of a single T-cell clone that was not present in the pretreatment tumor. These cases highlight the importance of understanding risk factors that may contribute to immune-related myocarditis and other severe immune-related adverse events when CD28 agonism is targeted in the context of checkpoint inhibition.NEON-2 (NCT04920383).


Assuntos
Anticorpos Monoclonais Humanizados , Inibidores de Checkpoint Imunológico , Miocardite , Feminino , Humanos , Pessoa de Meia-Idade , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Antígeno B7-H1/metabolismo , Antígeno B7-H1/antagonistas & inibidores , Antígenos CD28/metabolismo , Antígeno CTLA-4/antagonistas & inibidores , Evolução Fatal , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Miocardite/induzido quimicamente , Ensaios Clínicos Fase I como Assunto
2.
J Immunother Cancer ; 12(8)2024 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-39097413

RESUMO

BACKGROUND: Davoceticept (ALPN-202) is an Fc fusion of a CD80 variant immunoglobulin domain designed to mediate programmed death-ligand 1 (PD-L1)-dependent CD28 co-stimulation while inhibiting the PD-L1 and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) checkpoints. The safety and efficacy of davoceticept monotherapy and davoceticept and pembrolizumab combination therapy in adult patients with advanced solid tumors were explored in NEON-1 and NEON-2, respectively. METHODS: In NEON-1 (n=58), davoceticept 0.001-10 mg/kg was administered intravenous either once weekly (Q1W) or once every 3 weeks (Q3W). In NEON-2 (n=29), davoceticept was administered intravenously at 2 dose levels (0.1 or 0.3 mg/kg) Q1W or Q3W with pembrolizumab (400 mg once every 6 weeks). In both studies, primary endpoints included incidence of dose-limiting toxicities (DLT); type, incidence, and severity of adverse events (AEs) and laboratory abnormalities; and seriousness of AEs. Secondary endpoints included antitumor efficacy assessed using RECIST v1.1, pharmacokinetics, anti-drug antibodies, and pharmacodynamic biomarkers. RESULTS: The incidence of treatment-related AEs (TRAEs) and immune-related adverse events (irAEs) was 67% (39/58) and 36% (21/58) with davoceticept monotherapy, and 62% (18/29) and 31% (9/29) with davoceticept and pembrolizumab combination, respectively. The incidence of ≥grade (Gr)3 TRAEs and ≥Gr3 irAEs was 12% (7/58) and 5% (3/58) with davoceticept monotherapy, and 24% (7/29) and 10% (3/29) with davoceticept and pembrolizumab combination, respectively. One DLT of Gr3 immune-related gastritis occurred during davoceticept monotherapy 3 mg/kg Q3W. During davoceticept combination with pembrolizumab, two Gr5 cardiac DLTs occurred; one instance each of cardiogenic shock (0.3 mg/kg Q3W, choroidal melanoma metastatic to the liver) and immune-mediated myocarditis (0.1 mg/kg Q3W, microsatellite stable metastatic colorectal adenocarcinoma), prompting early termination of both studies. Across both studies, five patients with renal cell carcinoma (RCC) exhibited evidence of clinical benefit (two partial response, three stable disease). CONCLUSIONS: Davoceticept was generally well tolerated as monotherapy at intravenous doses up to 10 mg/kg. Evidence of clinical activity was observed with davoceticept monotherapy and davoceticept in combination with pembrolizumab, notably in RCC. However, two fatal cardiac events occurred with the combination of low-dose davoceticept and pembrolizumab. Future clinical investigation with davoceticept should not consider combination with programmed death-1-inhibitor anticancer mechanisms, until its safety profile is more fully elucidated. TRIAL REGISTRATION NUMBER: NEON-1 (NCT04186637) and NEON-2 (NCT04920383).


Assuntos
Anticorpos Monoclonais Humanizados , Antígeno CTLA-4 , Neoplasias , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Masculino , Feminino , Neoplasias/tratamento farmacológico , Pessoa de Meia-Idade , Idoso , Adulto , Antígeno CTLA-4/antagonistas & inibidores , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Idoso de 80 Anos ou mais , Antígenos CD28
3.
Health Promot Pract ; : 15248399231218938, 2023 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-38153140

RESUMO

PURPOSE: To examine differences in dietary, physical activity, and food selection behaviors of Utah SNAP-Ed participants who had varied breadth of engagement with various components of multilevel programming. METHOD: SNAP-Ed participants received a survey approximately 1 year after participating in nutrition classes. The survey measured diet, physical activity, and food selection behaviors and breadth of engagement with components of SNAP-Ed programming. Components of programming included nutrition education for adults and youth, nudge programs in food pantries and corner stores, farmers' market booths, social marketing campaign materials, and social media platforms. Kruskal-Wallis tests assessed differences in behaviors between varying breadths of program engagement. RESULTS: Among the 124 respondents, certain dietary behaviors improved with increased breadth of program engagement including intake of vegetables, low-fat dairy, and lean protein. Food selection behaviors including using MyPlate and preparing healthy foods on a budget, also improved with increased engagement. Physical activity was not impacted by additional breadth of exposure. CONCLUSIONS AND IMPLICATIONS: Findings suggest that multilevel comprehensive programming may enhance the impact of SNAP-Ed education for certain behaviors. Additional research is warranted on the impact of SNAP-Ed multilevel programming on targeted behaviors and health outcomes.

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