thesis
Engineering of T cell receptor genes to advance T cell therapy: studies into TCR pairing, signaling and binding strength
- Publication date
- 2 October 2013
- Publisher
- 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.