In both preclinical and clinical research studies, CSF1R-dependent macrophages accumulate in the fibrotic lesions found in patients with chronic graft-versus-host disease (cGVHD). Macrophage depletion using a monoclonal antibody directed at the CSF1R is a promising novel treatment approach and has markedly reduced cutaneous, pulmonary, and hepatic manifestations of cGVHD in phase 1 and 2 studies.

The ability to target the CSF1R signaling pathway in macrophages is a wonderful example of going from bench to bedside, using our understanding of cGVHD pathophysiology to devise therapeutics for patients with chronic and advanced sclerodermic or fibrotic manifestations. cGVHD biology is complex, since both alloreactive T-cell and B-cell axes are involved. These immune cells mediate the end tissue injury and fibrosis in multiple organ systems, which are a clinical hallmark of the disease.

T-helper 17 cells and self-reactive B cells trigger an exaggerated response in some macrophages. When these macrophages arrive at the site of tissue injury, they may stimulate tissue-resident macrophages and fibroblasts, leading to the production of matrix materials such as collagen. The fibroblasts deposit the scar issue that is common in advanced skin, lung, and liver cGVHD. Bruce R. Blazar, MD, and others have shown in preclinical models that CSF1 signaling through the CSF1R on macrophages results in these downstream effects. Therefore, targeting CSF1R has been a major focus, and this recently led to the development of the CSF1R-blocking monoclonal antibody axatilimab.

A phase 1/2 trial was recently published evaluating axatilimab in patients 6 years of age and older who had cGVHD that was refractory to at least 2 lines of systemic treatment. The phase 1 portion defined the optimal biologic dose as 3 mg/kg every 4 weeks, which is very convenient. After 6 cycles of treatment in the phase 2 portion, objective response rates were extremely high at 82%, and responses were seen in all affected organs. A reduction in skin macrophages expressing CSF1R was also reported. Promisingly, the number of patients with severe infections or other adverse events was low, and a high proportion of patients reported improvements in their quality of life. Since cGVHD is a chronic condition, you do not want to make patients sicker with treatment than they would be without treatment. A medication that helps treat the disease but makes patients feel miserable is a tougher “pill to swallow” than one that helps with both.

Based on these results, I think that axatilimab is quite promising, in terms of its preclinical aspects and its potential to reverse established advanced fibrosis. Turning back the tide is harder than stopping the initiation of the process. So, the fact that we now have this agent in clinical development is exciting, and we are eager for further clinical development and deployment.