Author:
Baginska Joanna,Nau Allison,Gomez Diaz Ilana,Giobbie-Hurder Anita,Weirather Jason,Vergara Juliana,Abrecht Charlotte,Hallisey Margaret,Dennis Jenna,Severgnini Mariano,Huezo Julia,Marciello Isabella,Rahma Osama,Manos Michael,Brohl Andrew S.,Bedard Philippe L.,Renouf Daniel J.,Sharon Elad,Streicher Howard,Ott Patrick A.,Buchbinder Elizabeth I.,Hodi F. Stephen
Abstract
Abstract
Background
Vascular endothelial growth factor is associated with reduced immune response and impaired anti-tumor activity. Combining antiangiogenic agents with immune checkpoint inhibition can overcome this immune suppression and enhance treatment efficacy.
Methods
This study investigated the combination of ziv-aflibercept anti-angiogenic therapy with pembrolizumab in patients with advanced melanoma resistant to anti-PD-1 treatment. Baseline and on-treatment plasma and PBMC samples were analyzed by multiplex protein assay and mass cytometry, respectively.
Results
In this Phase 1B study (NCT02298959), ten patients with advanced PD-1-resistant melanoma were treated with a combination of ziv-aflibercept (at 2–4 mg/kg) plus pembrolizumab (at 2 mg/kg), administered intravenously every 2 weeks. Two patients (20%) achieved a partial response, and two patients (20%) experienced stable disease (SD) as the best response. The two responders had mucosal melanoma, while both patients with SD had ocular melanoma. The combination therapy demonstrated clinical activity and acceptable safety, despite the occurrence of adverse events. Changes in plasma analytes such as platelet-derived growth factor and PD-L1 were explored, indicating potential alterations in myeloid cell function. Higher levels of circulating CXCL10 in non-responding patients may reflect pro-tumor activity. Specific subsets of γδ T cells were associated with poor clinical outcomes, suggesting impaired γδ T-cell function in non-responding patients.
Conclusions
Although limited by sample size and follow-up, these findings highlight the potential of the combination of ziv-aflibercept antiangiogenic therapy with pembrolizumab in patients with advanced melanoma resistant to anti-PD-1 treatment and the need for further research to improve outcomes in anti-PD-1-resistant melanoma.
Trial registration number
NCT02298959.
Funder
National Cancer Institute
Merck, Sharpe, and Dohme
Sanofi
Publisher
Springer Science and Business Media LLC
Reference23 articles.
1. Mehnert JM, McCarthy MM, Jilaveanu L, Flaherty KT, Aziz S, Camp RL et al (2010) Quantitative expression of VEGF, VEGF-R1, VEGF-R2, and VEGF-R3 in melanoma tissue microarrays. Hum Pathol 41(3):375–384
2. Oyama T, Ran S, Ishida T, Nadaf S, Kerr L, Carbone DP et al (1998) Vascular endothelial growth factor affects dendritic cell maturation through the inhibition of nuclear factor-kappa B activation in hemopoietic progenitor cells. J Immunol 160(3):1224–1232
3. Voron T, Colussi O, Marcheteau E, Pernot S, Nizard M, Pointet AL et al (2015) VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J Exp Med 212(2):139–148
4. Wada J, Suzuki H, Fuchino R, Yamasaki A, Nagai S, Yanai K et al (2009) The contribution of vascular endothelial growth factor to the induction of regulatory T-cells in malignant effusions. Anticancer Res 29(3):881–888
5. Jianda Yuan JZ, Dong Z, Tandon S, Kuk D, Panageas KS, Wong P, Wu X, Naidoo J, Page DB, Wolchok JD, Stephen Hodi F (2014) Pretreatment serum VEGF is associated with clinical response and overall survival in advanced melanoma patients treated with ipilimumab
Cited by
2 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献