Inhibition of the function of CTLA-4, a molecule expressed on activated T cells which down-regulates T cell activity, has resulted in augmented immune reactivity, anti-tumor activity and autoimmunity in animal models. In patients with melanoma, results from early trials suggest that MDX-010, an antibody that inhibits CTLA-4, jhas clinical anti-tumor activity that correlates with the onset of autoimmune symptoms. A recently completed phase I trial of MDX-010 with a multi-peptide vaccine in patients with resected melanoma at our institution suggested that reversible autoimmunity correlated with prolonged time to relapse and survival and was dose related. In a small phase II trial of MDX-010 with a vaccine in stage IV metatstatic melanoma, three responses were observed in 14 heavily pre-treated patients, all of whom developed autoimmunity. In both trials, autoimmune toxicity was dose limiting. In order to establish whether there is a relationship between tolerable levels of autoimmunity and clinical benefit in melanoma, and to understand the mechanisms of autoimmunity in patients receiving MDX-010, we propose to conduct a phase II study of MDX-010 with a multi-peptide vaccine in patients with resected high-risk melanoma. The trial will be performed in a two-part Simon design but with the achievement of tolerable autoimmune toxicity in at least 50% of patients and the occurrence of no more than 20% dose limiting autoimmune or other toxicity as the desired endpoints. We will address the hypothesis that achieving an acceptable level of autoimmunity that is not dose limiting in a significant proportion of patients with high-risk resected melanoma treated with MDX-010 and a melanoma peptide vaccine will be associated with prolonged time to relapse and overall survival. A translational hypothesis to be tested is whether predicted physiologic effects of the CTLA-4 inhibiting antibody on T cells such as up-regulation of trafficking molecules, skewing of the repertoire against bacterial antigens found in the GI tract, altering of tryptophan metabolism or the presence of genotypic polymorphisms for CTLA-4 can be shown to correlate with the development of autoimmunity and show promise as surrogate markers for Jclinical benefit. Another translational hypothesis to be evaluated is whether effector-memory T cells that are peptide-specific can be enriched and amplified by an intense regimen of vaccinations over one year followed by booster vaccinations every six months for two years.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA109307-04
Application #
7256919
Study Section
Special Emphasis Panel (ZRG1-ONC-A (04))
Program Officer
Xie, Heng
Project Start
2004-09-01
Project End
2009-06-30
Budget Start
2007-09-18
Budget End
2008-06-30
Support Year
4
Fiscal Year
2007
Total Cost
$490,127
Indirect Cost
Name
H. Lee Moffitt Cancer Center & Research Institute
Department
Type
DUNS #
139301956
City
Tampa
State
FL
Country
United States
Zip Code
33612