8033 Background: We previously defined the magnitude of the minimum statistically significant change in value for the MHC tetramer and ELISPOT assays (Comin-Anduix, Clin Cancer Res 2006). We used those reference change values (RCV) to determine if the administration of ticilimumab to patients with melanoma expands the circulating populations of tumor antigen-specific T cells. Methods: HLA-A2.1+ pts with sIIIc or IV melanoma and baseline circulating MART-1-specific T cells above the low limit of detection by tetramer assay (LLD, 0.03% of CD8+ T cells) received ticilimumab at 10 mg/kg monthly. Two 40 ml blood samples were collected at baseline, and one at 1 and 2 weeks after each dose for 4 cycles. Primary endpoint was immune response for MART-1 by tetramer assay, for which the RCV is 80% (expressed as percent change from baseline). Results: Of 15 pts (2 sIIIc, 5 sIVa, 2 sIVb, 6 sIVc), 1 was not treated and 2 received only 1 dose due to rapid progression. The 12 remaining pts received 2–11 doses. Clinical immunologic response to ticilimumab was evidenced by immune-related toxicity (G3 diarrhea in 2 pts, G2 hypophysitis in 1 pt, G3 hepatitis in 2 pts) and by anti-tumor activity: CR in 1 pt (15+ mo), PR in 2 pts (9+, 8 mo), and SD in 3 pts (11, 8+ and 4 mo); the rest had PD at 4 mo or less. A mean of 2 baseline and 7 follow up (range 5–9) time points were tested by tetramer and ELISPOT assays. 4 pts had an increase in MART-1-specific T cells beyond the RCV on 1 or more occasions, but no pt had a consistent pattern of change over time. Indeed, there was no consistent pattern of change in any pt in circulating T cells specific for MART-1, gp100, tyrosinase, EBV, or CMV by tetramer or by ELISPOT assay. One pt had accessible regressing lesions which on biopsy showed heavy infiltration by CD8+/Granzyme B+ CTL and a 10-fold enrichment of gp100-specific T cells compared to his peripheral blood. Conclusion: Ticilimumab administered monthly induces immune-related phenomena and tumor responses in patients with melanoma without a demonstrable expansion of circulating melanoma antigen-specific T cells. Evaluation of melanoma antigen-specific T cells within the tumor may be a better way to study the mechanism of antitumor activity of CTLA4 blocking mAb. [Table: see text]