A bedside to bench study of anti-PD-1, anti-CD40, and anti-CSF1R indicates that more is not necessarily better.

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.

Pioglitazone and cardiovascular risk reduction: time for a second look?

Insulin resistance, a fundamental pathophysiological abnormality in patients with type 2 diabetes, is associated with increased cardiovascular (CV) disease risk. In diabetes management, the macrovascular impact of antihyperglycemic agents that do not improve insulin sensitivity has generally been disappointing. In contrast, glucose-lowering drugs that work as insulin sensitizing agents have been postulated to reduce CV complications. The data to support this hypothesis have, however, been inconsistent. The impact of thiazolidinediones on macrovascular events is of particular interest. In this review, we discuss the results of trials reporting CV outcomes in patients treated with thiazolidinediones. We focus on the findings of the recent Insulin Resistance Intervention after Stroke trial that demonstrated a beneficial effect of pioglitazone on CV outcomes in stroke patients with insulin resistance. We discuss the Insulin Resistance Intervention after Stroke results and its implications for clinical practice. We discuss the selective use of pioglitazone as secondary prevention to reduce CV risk in insulin resistant patients.