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

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

  • Mol Cancer. 2023 Nov 14;22(1):182. doi: 10.1186/s12943-023-01884-x.
Dijana Djureinovic 1,  Sarah A Weiss 1,  Irina Krykbaeva 2,  Rihao Qu 2,  Ioannis Vathiotis 2,  Myrto Moutafi 2,  Lin Zhang 1,  Ana L Perdigoto 3,  Wei Wei 4,  Gail Anderson 1,  William Damsky 5,  Michael Hurwitz 1,  Barbara Johnson 1,  David Schoenfeld 1,  Amit Mahajan 6,  Frank Hsu 7,  Kathryn Miller-Jensen 8 9 10,  Yuval Kluger 2,  Mario Sznol 1,  Susan M Kaech 11,  Marcus Bosenberg 2 5 12,  Lucia B Jilaveanu 1,  Harriet M Kluger 13
Affiliations

Affiliations

  • 1 Department of Medicine (Medical Oncology), Yale University School of Medicine, 333 Cedar Street, WWW211B, New Haven, CT, 06520, USA.
  • 2 Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
  • 3 Department of Internal Medicine, Yale University, New Haven, CT, USA.
  • 4 Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA.
  • 5 Department of Dermatology, Yale University School of Medicine, New Haven, CT, USA.
  • 6 Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA.
  • 7 Apexigen, Inc., San Carlos, CA, USA.
  • 8 Department of Biomedical Engineering, Yale University, New Haven, CT, USA.
  • 9 Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT, USA.
  • 10 Systems Biology Institute, Yale University, New Haven, CT, USA.
  • 11 NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute, La Jolla, CA, USA.
  • 12 Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
  • 13 Department of Medicine (Medical Oncology), Yale University School of Medicine, 333 Cedar Street, WWW211B, New Haven, CT, 06520, USA. Harriet.Kluger@yale.edu.
PMID: 37964379 DOI: 10.1186/s12943-023-01884-x
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.

Keywords

CD40; CSF1R; Checkpoint inhibition resistance; Clinical trial; Melanoma; PD-1.

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