Tenosynovial giant cell tumour (TGCT) of the soft tissue (also known as pigmented villonodular synovitis (PVS)) is a joint tumour which arises from the synovium, bursae, and tendon sheaths of usually young adults between 20-40 years old. The knee is the most frequent (66-80%) lesion site, followed by the hip, ankle, elbow and shoulder. TGCT is a rare disease, with a prevalence of 44.3 per 100,000 persons for L-TGCT and 11.5 for D-TGCT.
In TGCT, a limited number of cells with abnormal translocation of 1p11 and 2q37 chromosome sites are responsible for pathological CSF-1 over-expression. This drives a destructive proliferation of synovial mononuclear cells, mixed with multi-nucleated giant cells, foam cells, siderophages, and other inflammatory cells.
Lesions can be local or diffuse. The standard of care for local-TGCT is surgery, whereas diffuse-TGCT is more difficult to resect and has a high rate of recurrence of up to 50%. While TGCT is not in itself a life-threatening disease, it does result in important functional impairments, significant joint damage, and decline in quality of life, which carries a high healthcare demand and loss of work productivity. The key role of aberrant CSF-1 signalling in the evolution of d-TGCT makes this pathway an obvious target for systemic treatment of patients with unresectable or recurrent disease.
CSF-1 is a stimulatory ligand that differentiates monocytes and macrophages into tumour-associated macrophages (TAM). TAMs confer tumour resistance to therapy and induce immunosuppression. As a result, they are believed to promote tumour genesis, growth, and metastases. Emactuzumab is a recombinant humanised monoclonal IgG1 antibody directed against CSF-1 receptors, resulting in the depletion of TAMs. The change in the tumour microenvironment tips the balance in favour of the immune response, which effectively kills the target tumour (Exhibit 1).
Exhibit 1. Mechanism of action: Emactuzumab inhibits CSF-1 receptors on tumour-associated macrophages (TAMs), allowing immune cells to target the tumour effectively.