Pilot Study to Test the Feasibility of IV Injected Tc-99m-tilmanocept for Imaging of M2-like Tumour Associated Macrophages in Metastatic Melanoma

According to the Swiss Federal Statistical Office, cancer has been the leading cause of death in Switzerland for men aged between 45 and 84 and women aged between 25 and 84. Melanoma, represents the deadliest and most aggressive form of skin cancer. The incidence of melanoma is rising and in Switzerland it is the fourth most occurring malignancy. In the recent years many advances have been achieved in the treatment of disseminated disease, namely targeted and immunomodulatory treatments (checkpoint inhibitors), either as monotherapy or in combination. Immune checkpoint inhibitors, such as anti-PD-1 are standard of care for advanced melanoma.

However, despite all the success by checkpoint inhibitors, still many patients do not benefit from treatment. Therefore, several attempts have been made to investigate possible prediction of outcome to PD1/PD-L1 treatment. Scientific studies reported mutational load, neoantigens or PD1/PD-L1 expression and/or CD8 infiltrates in melanoma to be predictive for response. However, it has further been shown that also PD-L1 negative tumours respond to PD1/PD-L1 blockade. One possible explanation could be the heterogeneity of intra-tumoural PD-L1 expression or the heterogeneity among different tumour sites in melanoma patients. Overall, the PD-L1 expression is highly dependent on extrinsic factors, as for example hypoxia and therefore highly versatile at different sites and over time.

Another important mechanism of resistance lies in the tumour microenvironment, mainly in inhibitory immune cells of the host. Among others, such as regulatory t-cells (Tregs) or myeloid derived stem cells (MDSC), tumour associated macrophages (TAMs) seem of particular importance in the immune-modulation of the tumour microenvironment.

TAMs in the tumour microenvironment play an essential role in cancer progression. Particularly, the alternatively activated M2 polarized phenotype (M2-like) is confirmed as indicator of poor patients' outcome. During melanoma progression the anti-tumoural M1 polarized phenotype (M1-like) shifts towards the M2 phenotype, which can directly suppress immunity for example via production of cytokines as TGFb or IL-10, cooperating in the reduction of specific CD8 derived immune response. The evolution in understanding the macrophage compartment led therefore to the development of further treatment strategies as CSFR-1 directed antibodies, showing promising synergizing effects with PD-1 directed treatment and reversed resistance to checkpoint inhibitor treatment.

CD206, also termed as MRC1 (C-type mannose receptor 1), is an M2-like macrophage marker in both mouse and human. Its upregulation in macrophages renders them to produce IL-10 and TGFb, identifying this TAM population as anti-inflammatory subtype.