Engineering of T cell receptor genes to advance T cell therapy: studies into TCR pairing, signaling and binding strength

The incidence of cutaneous melanoma has increased dramatically over the past 40 years. The yearly increase in incidence rates in the Netherlands is on average 4.1%. Although the 10-year survival rates improved over the last fifteen years, the yearly mortality rates are further increasing with 2.3%, mainly in elderly patients. In case cutaneous melanoma metastasizes, the 10-year survival rate drops dramatically to less than 10%. Table 1.1 lists the U.S. Food and Drug Administration (FDA)-approved treatments for melanoma. The current standard cares of treatment for melanoma are either administration of the alkylating agent Dacarbazine, which induces DNA damage, or administration of high-dose IL-2, which serves as a T cell growth factor. However, both treatments demonstrate fairly low response rates and significant adverse effects. More recent FDA-approved treatments for melanoma include: Ipilimumab, an antibody that blocks the T cell inhibitory molecule CTLA-4 to lower the threshold of T cell activation; Vemurafenib, a drug that inhibits the serine-threonine protein kinase B-RAF (BRAF), a kinase that is constitutively active in 36 to 54% of melanoma patients due to a V600E mutation; and pegylated interferon α2b, used as an adjuvant that demonstrates anti-proliferative effects on melanoma cells and modulates immune responses