Är CTLA-4-inhibitorn ipilimumab bättre som monoterapi eller i kombination med andra läkemedel hos patienter med metastaserat malignt melanom?

Malignant melanoma is a growing problem with more and more people in Sweden and the world suffering from this cancer. Malignant melanoma is a disease that when discovered in time can be treated successfully with surgical methods, but the real challenge lies in treating the disease after its spread. Treatment in the past for advanced malignant melanoma has been unsuccessful with no positive effect on overall survival. However, in the last couple of years, new treatment has arrived with focus on priming the immune system to eradicate the tumors. One new drug is the CTLA-4 inhibitor ipilimumab that is given as intravenous infusion. CTLA-4 is a protein located on regulatory T-cells and that is upregulated on activated cytotoxic T-cells. This protein mediates an inhibitory signal that attenuates T-cell-activation. Treatment with the CTLA-4 inhibitor has been shown to increase overall survival. However, not much is known about how well ipilimumab synergizes with other drugs used for treatment of malignant melanoma. This is a literature study with the aim to evaluate if ipilimumab is used best as monotherapy or if it is of better use as part of a combination therapy. Search was made in PubMed with the key-words "Ipilimumab", "Ipilimumab treatment", CTLA-4 inhibitor" and "treatment malignant melanoma”. Six articles were chosen and each of these analyzed the effect of ipilimumab alone or combined with other agents against malignant melanoma. The combination of ipilimumab and the alkylating agent dacarbazine was shown to have a better impact on overall survival compared with monotherapy with dacarbazine, but this combination also showed an increase in serious adverse events. Ipilimumab also showed to work in synergy with both the PD-1-inhibitor nivolumab and the granulocyte macrophage colony-stimulating factor (GM-CSF) sargramostim. Combination with sargramostim was also shown to decrease the amount of serious adverse events. Combination with a gp100 peptide vaccine failed to show any positive effects on overall survival. Also prophylactic treatment with budesonide showed no further gain in overall survival. The effect of ipilimumab was found to have a dose-ranging effect, with higher dose treatment having a better effect but also with more serious adverse events. The results of this literature study showed that ipilimumab has a better effect with higher dose and that it can work in synergy with other agents such as nivolumab and sargramostim. Results also showed that occurring adverse effects during treatment with ipilimumab may be treated with systemic glucocorticoids that did not affect the tumor-killing ability of ipilimumab. These results should be evaluated in bigger studies and with longer follow up time