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Updated: Oct 10, 2026
Minimally Invasive Isolated Limb Perfusion (MI-ILP) for Locally Advanced Melanomas and Sarcomas of the Extremity
Published on: January 31, 2025
Synergistic antitumour effect of TNF-SAM2 with melphalan and doxorubicin in isolated limb perfusion in rats
J H de Wilt1, G Soma, T L ten Hagen
1Department of Surgical Oncology, University Hospital Rotterdam-Dr Daniel den Hoed Cancer Centre, Rotterdam, The Netherlands.
Abstract:
An isolated limb perfusion model (ILP) using soft tissue sarcoma bearing rats (BN175) was used to study antitumour activity of a tumour necrosis factor alpha mutant (TNF-SAM2) in combination with melphalan and doxorubicin. Progressive disease was demonstrated after ILP without agents (sham) or with 50 micrograms TNF-SAM2. ILP with 40 micrograms melphalan or 400 micrograms doxorubicin resulted in no change of tumour volume or progressive disease five days after perfusion. Partial and complete response rates were demonstrated in 76% of rats when the combination of TNF-SAM2 and melphalan was used. TNF-SAM2 in combination with doxorubicin was synergistic as well with a 70% response rate. Histopathologically these responses consisted of hemorrhagic necrosis of the coagulative type. 2 In conclusion, TNF-SAM2 has similar antitumour activity in combination with melphalan or doxorubicin as rHuTNF in sarcoma-bearing rats and is eligible to be tested in clinical ILP or organ perfusion settings because of its potential decreased toxicity.
Insights
Tumor necrosis factor alpha mutant (TNF-SAM2) combined with melphalan or doxorubicin showed significant anti-tumor activity in soft tissue sarcoma models. This combination therapy warrants further clinical investigation for potential reduced toxicity.
Area of Science:
- Oncology
- Pharmacology
- Biotechnology
Background:
- Soft tissue sarcomas are challenging to treat with conventional therapies.
- Isolated limb perfusion (ILP) offers a localized approach for limb tumors.
- Tumor necrosis factor alpha (TNF) has shown anti-tumor potential but with significant toxicity.
Purpose of the Study:
- To evaluate the anti-tumor efficacy of a novel TNF-alpha mutant (TNF-SAM2) in combination with melphalan or doxorubicin.
- To assess the safety and potential of TNF-SAM2 in ILP for sarcoma treatment.
- To compare the efficacy of TNF-SAM2 combinations with standard chemotherapies.
Main Methods:
- An isolated limb perfusion (ILP) model was established in rats bearing soft tissue sarcoma (BN175).
- Rats were treated with ILP using TNF-SAM2 alone, melphalan, doxorubicin, or combinations thereof.
- Tumor volume changes and histopathological responses were assessed post-perfusion.
Main Results:
- TNF-SAM2 alone or sham ILP resulted in progressive disease.
- Melphalan and doxorubicin monotherapies showed limited efficacy, with no change or progressive disease.
- Combination of TNF-SAM2 with melphalan achieved a 76% response rate (partial and complete).
- Combination of TNF-SAM2 with doxorubicin showed synergistic effects with a 70% response rate.
- Histopathology revealed hemorrhagic necrosis of the coagulative type in responding tumors.
Conclusions:
- TNF-SAM2 demonstrates significant anti-tumor activity when combined with melphalan or doxorubicin in a rat sarcoma model.
- The combination therapy showed comparable efficacy to recombinant human TNF (rHuTNF) but with potential for decreased toxicity.
- TNF-SAM2 is a promising candidate for clinical evaluation in ILP or organ perfusion settings for sarcoma treatment.
