Author:
Djureinovic Dijana,Weiss Sarah A.,Krykbaeva Irina,Qu Rihao,Vathiotis Ioannis,Moutafi Myrto,Zhang Lin,Perdigoto Ana L.,Wei Wei,Anderson Gail,Damsky William,Hurwitz Michael,Johnson Barbara,Schoenfeld David,Mahajan Amit,Hsu Frank,Miller-Jensen Kathryn,Kluger Yuval,Sznol Mario,Kaech Susan M.,Bosenberg Marcus,Jilaveanu Lucia B.,Kluger Harriet M.
Abstract
Abstract
Background
Stimulating inflammatory tumor associated macrophages can overcome resistance to PD-(L)1 blockade. We previously conducted a phase I trial of cabiralizumab (anti-CSF1R), sotigalimab (CD40-agonist) and nivolumab. Our current purpose was to study the activity and cellular effects of this three-drug regimen in anti-PD-1-resistant melanoma.
Methods
We employed a Simon’s two-stage design and analyzed circulating immune cells from patients treated with this regimen for treatment-related changes. We assessed various dose levels of anti-CSF1R in murine melanoma models and studied the cellular and molecular effects.
Results
Thirteen patients were enrolled in the first stage. We observed one (7.7%) confirmed and one (7.7%) unconfirmed partial response, 5 patients had stable disease (38.5%) and 6 disease progression (42.6%). We elected not to proceed to the second stage. CyTOF analysis revealed a reduction in non-classical monocytes. Patients with prolonged stable disease or partial response who remained on study for longer had increased markers of antigen presentation after treatment compared to patients whose disease progressed rapidly. In a murine model, higher anti-CSF1R doses resulted in increased tumor growth and worse survival. Using single-cell RNA-sequencing, we identified a suppressive monocyte/macrophage population in murine tumors exposed to higher doses.
Conclusions
Higher anti-CSF1R doses are inferior to lower doses in a preclinical model, inducing a suppressive macrophage population, and potentially explaining the disappointing results observed in patients. While it is impossible to directly infer human doses from murine studies, careful intra-species evaluation can provide important insight. Cabiralizumab dose optimization is necessary for this patient population with limited treatment options.
Trial registration
ClinicalTrials.gov Identifier: NCT03502330.
Funder
Wenner-Gren Stiftelserna
National Institutes of Health
Yale SPORE in Lung Cancer
Yale Calabresi Immuno-Oncology Training Program
Helleneic Society of Medical Oncologists
Yale SPORE in Skin Cancer, USA
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Oncology,Molecular Medicine
Cited by
1 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