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L19TNFα + melphalan is a combination therapy composed of a targeted cytokine fusion protein and a chemotherapeutic agent. L19TNFα is a fusion protein combining the fully human L19 antibody fragment (which targets the extra domain-B (ED-B) of fibronectin in tumor vasculature) with tumor necrosis factor alpha (TNFα), a pro-inflammatory cytokine with potent antitumor effects. Melphalan is an alkylating chemotherapy agent that crosslinks DNA, leading to cytotoxicity in dividing cells. The L19TNFα component selectively delivers TNFα to tumor sites, increasing vascular permeability and immune cell infiltration, and synergistically enhances the antitumor activity of melphalan, particularly in isolated limb perfusion (ILP) settings for locally advanced sarcoma and melanoma. This combination leads to heightened tumor cell kill while minimizing systemic toxicity. Preclinical and clinical studies indicate that L19TNFα + melphalan induces robust immune responses (increase in CD4+ and CD8+ T cells, reduction of regulatory T cells, and long-lasting antitumor immunity) and improves response rates and limb salvage in patients with locally advanced, unresectable sarcomas and melanoma confined to the limbs[1][4][6].
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