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Thymidylate synthase (TS) is a tumor-associated-enzyme crucial for DNA replication and inhibited by 5′-fluorouracil. TSPP is a previously characterized anticancer poly-epitope peptide vaccine to TS (Correale P, JNCI 2005 97:1437). TSPP/VAC-1 is a three-arm dose-finding Phase-Ib trial aimed to test in pretreated-advanced cancer patients, TSPP-vaccination alone (arm A), together with GM-CSF and low dose Aldesleukine (arm B), or together with chemo-immunotherapy according to the GOLFIG regimen (Correale P, JCO, 2005, 23:8950) (arm C). TSPP resulted safe, its MTD was not achieved, while its most-effective-biological-dose was 300µg. As the most promising antitumor effects of TSPP were observed in colo-rectal cancer (mCRC) patients (Cusi MG, CIIT, 2015, epub), we decided of carrying-out a new study to evaluate in this subset of patients, the potential ability of a predefined panel of markers to predict their antitumor response to TSPP. We thus evaluated41 mCRC patients, 20 males and 21 females, with a good performance status, enrolled between May 2011 and Jan 2013. Our parameters were correlated with progression free survival (PFS) and overall survival (OS) by performing a Kaplan Meier analysis. The baseline marker values were divided in two groups according to their median values, while the changes relative to baseline values (post-treatment values) were divided according to a fold ratio ≤ or >1. Patients' PFS and OS were 6.9 and 11.3 months, respectively; there were no significant differences in PFS and OS correlated with treatment arm (A vs. B vs. C), number and type of previous treatments, sex, age, TS expression, HLA2.1 haplotype or expression of peripheral CTLs, regulatory-T cells, central- and effector-memory-T cells. Patients bearing K-ras mutations, showed a trend to a shorter PFS (p:0.051) and no differences in OS (p=0.16). Patients' outcome was instead, inversely correlated with performance status (ECOG 0-1 vs. 2; PFS, p1, OS, p:0.039). These results suggest that inflammatory status and autoimmunity may affect TSPP antitumor activity in mCRC patients. These results deserve to be considered for the design of new studies.