New approaches for finding immune-related biomarkers in treatment of unresectable or metastatic melanoma
Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
Melanoma is the 6th most common cancer type in Sweden and the incidence is increasing. The prognosis for patients with unresectable or metastatic melanoma has been poor since there have been no effective therapies for these patients. In recent years, two new firts line treatments for unresectable or metastatic melanoma have emerged; Ipilimumab (Yervoy®) and Vemurafenib (Zelboraf®). Ipilimumab is a fully human antibody that blocks CTLA-4 and thereby augments T cell response. Around 10% of patiens respond to treatment and the most common side effects associated with Ipilimumab are immune-related adverse events. Vemurafenib is a small molecule drug that inhibits the MAPK pathway. Most patients respond well to treatment with Vemurafenib, and undergo a rapid tumor reduction. However, almost all patients develop a resistance to the drug within a few months of treatment.
There is a need for better understanding of the effects that these two drugs have on the immune response and to find immune-related biomarkers. In this study we focused on the possible effects of Ipilimumab on the induction and suppressive functions of MDSC-like cells educated in vitro by coculturing monocytes from healthy donors with early passage melanoma cells. For vemurafenib, we improved an assay for immune monitoring of blood samples from patients undergoing treatment and analyzed samples from five patients takenbefore start of treatment, after 8 weeks of treatment and again after 16-20 weeks of treatment.
the experiments with Ipilimumab and MDSCs did not give any conclusive answers to the effects that blocking of CTLA-4 may have on the induction or functions of these suppressive cells. However, knowledge regarding the coculture method has been gained and the firststeps towards further investigations have been taken. An assay for immune monitoring of patient samples was improved by fine tuning four panels and adding an extra panel. These panels will be used for future immune monitoring in ourresearch group. The immune monitoring of Vemurafenib patients yielded results in form of trends of higher activation of T cells and NK cells after 8 weeks of treatment. The increase in activation could still be seen in the samples taken 16-20 weeks into treatment. Also a trendof decrease in central memory CD4+ and CD8+ T cells was found. These results might in the future be taken into consideration to help in the understanding of the effects that Vemurafenib treatment has on the immune response in different disease stages.
Place, publisher, year, edition, pages
Nelanoma, Ipilimumab, T-cells, Immunotherapy, Vemurafenib
Engineering and Technology
IdentifiersURN: urn:nbn:se:kth:diva-163679OAI: oai:DiVA.org:kth-163679DiVA: diva2:801778
Pico de Coaña, YagoKiessling, Rolf