The benefits of combining an immunomodulator with a chemotherapy agent in chondrosarcoma : a proof of concept with mifamurtide

Tumor-associated macrophages (TAMs) play a critical role in the progression of various cancers, including chondrosarcoma, where they can constitute up to 50% of the tumor mass. In chondrosarcoma, TAMs are predominantly of the M2-like phenotype and are linked to more invasive and higher-grade disease. Despite the challenge of chondrosarcoma’s chemo- and radio-resistance due to its slow cell division and unique extracellular matrix, targeting TAMs has emerged as a promising strategy. Therapeutic approaches include inhibiting TAMs recruitment, reprogramming TAMs to a tumoricidal M1 phenotype, and depleting TAMs. Current clinical studies are exploring combinations of TAMs-targeting agents with chemotherapy in many cancers and some agent like mifamurtide, a TLR4 agonist, are already used with chemotherapy in cancer treatment, for pediatric non metastatic osteosarcoma. Recent preclinical studies have shown that targeting TAMs in chondrosarcoma can slow tumor growth but no preclinical data shown the relevance of immunomodulator and chemotherapy combination. Our research further evaluates the potential mifamurtide and chemotherapy combination using a 3D co-culture model and a murine xenograft model of chondrosarcoma. Our findings suggest that mifamurtide enhances the chemosensitivity of CH2879/THP-1 spheroids. In the CH2879 xenograft model, its combination with doxorubicin led to improved antitumoral efficacy and a decrease in intermediate-stage tumor-associated macrophages. These results highlight the importance of TAMs in modulating treatment response. This study provides a preclinical proof of concept for the efficacy of combining mifamurtide with doxorubicin in managing chondrosarcoma, highlighting the potential of immunomodulator and chemotherapy combinations in improving treatment outcomes.