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2052 CSF1R Inhibition Promotes Neuroinflammation and Behavioural Deficits during Graft-Versus-Host Disease in Mice

Program: Oral and Poster Abstracts
Session: 701. Experimental Transplantation: Basic and Translational: Poster I
Hematology Disease Topics & Pathways:
Research, Therapies, Adverse Events, Biological Processes
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Rachael C Adams1,2,3*, Dylan Carter-Cusack3*, Genesis T Llanes3*, Christopher R Hunter3*, Janaki Manoja Vinnakota, PhD2,4*, Marc Ruitenberg, PhD5*, Jana Vukovic, PhD5,6*, Patrick Bertolino, PhD7*, Kirat K. Chand, PhD8*, Julie A. Wixey, PhD8,9*, Samuel P Nayler, PhD3*, Geoffrey R Hill, MD10,11, Scott N Furlan, MD12*, Robert Zeiser, MD2,13,14 and Kelli PA MacDonald, PhD3*

1Faculty of Medicine, The University of Queensland, Brisbane, Australia
2Department of Medicine I, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany
3QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
4Albert-Ludwigs University, Faculty of Biology, Freiburg im Bresigau, Germany
5School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Australia
6Queensland Brain Institute, The University of Queensland, Brisbane, Australia
7Royal Prince Alfred Hospital, Centenary Institute and University of Sydney, AW Morrow Gastroenterology and Liver Centre, Newtown, Australia
8UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, Australia
9Perinatal Research Centre, Royal Brisbane and Women’s Hospital, The University of Queensland, Brisbane, Australia
10Division of Medical Oncology, Department of Medicine, University of Washington, Seattle, WA
11Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA
12Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, WA
13University of Freiburg, CIBSS – Centre for Integrative Biological Signalling Studies, Freiburg im Bresigau, Germany
14German Cancer Consortium (DKTK), Partner site Freiburg; and German Cancer Research Center (DKFZ), Heidelberg, Germany

Chronic graft-versus-host disease (cGVHD) remains a significant complication of allogeneic hematopoietic stem cell transplantation. Central nervous system (CNS) involvement is becoming increasingly recognised, where brain-infiltrating donor MHC class II+ bone marrow-derived macrophages (BMDM) are implicated mediators of pathology. Colony-stimulating factor 1 receptor (CSF1R)-dependent BMDM are established mediators of cutaneous and pulmonary cGVHD, and clinical trials assessing the efficacy of CSF1R antibody blockade to deplete macrophages are promising. We hypothesized that CSF1R antibody blockade may also be a useful strategy to prevent/treat CNS cGVHD.

We leveraged studies in acute GVHD (aGVHD) to determine the feasibility of an antibody-based approach for depleting brain microglia and macrophages. Moreover, we queried whether CSF1R blockade may be a viable therapy for CNS aGVHD, which has been shown to be mediated by host microglia. Increased blood-brain barrier permeability during aGVHD facilitated CNS antibody access. However, CSF1R blockade early post-transplant induced region-specific microglia depletion and was associated with unexpected exacerbation of aGVHD neuroinflammation, including increased T cell and inflammatory monocyte infiltration, and whole brain cytokine levels. In established cGVHD, vascular changes and anti-CSF1R efficacy was more limited. Anti-CSF1R-treated mice retained donor BMDM, activated microglia, CD8+ and CD4+ T cells, and local cytokine expression in the brain. These findings were recapitulated in GVHD recipients where CSF1R was conditionally depleted in donor CX3CR1+ BMDM. Notably, inhibition of CSF1R signalling post-transplant failed to reverse either acute or chronic GVHD-induced behavioral changes. Taken together, these data suggest that ongoing clinical trials of CSF1R inhibition should assess neurological adverse events in patients.

In contrast to the lack of efficacy with CSF1R inhibition, transfer of Ifngr-/- grafts reduced MHC class II+ BMDM infiltration, resulting in improved behaviour. Furthermore, single nuclei RNA sequencing of brains from mice receiving wild-type or Ifngr-/- allografts revealed a disease-associated interferon-inducible mature oligodendrocyte population in the cGVHD brain. This was markedly reduced in recipients of Ifngr-/- grafts, indicating that targeting this axis can promote brain repair beyond the myeloid compartment during cGVHD. In summary, our findings reveal unexpected neurological immune toxicity during CSF1R blockade and highlight the IFNGR pathway as an alternative target for the treatment of cGVHD within the CNS.

Disclosures: Hill: Serplus Technology: Research Funding; Heat Biologics: Research Funding; Generon Corporation: Consultancy; NapaJen Pharma: Consultancy; Commonwealth Serum Laboratories: Consultancy; Genentech: Research Funding; iTeos Therapeutics: Consultancy; Cynata Therapeutics: Consultancy; Neoleukin Therapeutics: Consultancy; Syndax Pharmaceuticals: Research Funding; Compass Therapeutics: Research Funding; Applied Molecular Transport: Research Funding; Laevoroc Oncology: Research Funding; iTeos Therapeutics: Research Funding. Zeiser: novartis: Consultancy, Honoraria, Research Funding; MNK: Consultancy, Honoraria; incyte: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Medac: Honoraria; VectivBio: Consultancy.

*signifies non-member of ASH