Purpose: GOLFIG chemoimmunotherapy regimen proved to be a safe and very active chemoimmunotherapy regimen in advanced colon cancer patients. We have thus investigated the immunobiological feedback to the treatment and its possible correlation with the clinical outcome of these patients. Experimental Design:This clinical and immunologic study involved 46 patients, 27 males and 19 females, enrolled in the GOLFIG-1 phase II trial who received gemcitabine (1,000 mg/m 2 on days 1 and 15), oxaliplatin (85 mg/m 2 on days 2 and 16), levofolinic acid (100 mg/m 2 on days 1, 2, 15, and 16), and 5-fluorouracil (400 mg/m 2 as a bolus, and 800 mg/m 2 as a 24-hour infusion on days 1, 2, 15, and 16) followed by s.c. granulocyte macrophage colony-stimulating factor (100 Ag, on days 3-7) and interleukin 2 (0.5 Â 10 6 IU twice a day on days 8-14 and 17-29). Results: The regimen was confirmed to be safe and very active in pretreated patients with metastatic colorectal cancer. A subgroup analysis of these patients revealed a prolonged time to progression and survival in six patients who developed late signs of autoimmunity. A multivariate analysis validated the occurrence of autoimmunity signs as an independent predictor of favorable outcome. A parallel immunologic study detected in the peripheral blood mononuclear cells of these patients a progressive increase in lymphocyte and eosinophil counts, amplification in central memory, a marked depletion of immunosuppressive regulatory T cells, and activation of colon cancer^specific cytotoxicTcells. Conclusions: Our results suggest that immunity feedback to GOLFIG regimen and its antitumor activity are tightly correlated.Colorectal carcinoma is the second leading cause of cancerrelated deaths (1, 2). The best therapeutic option for the advanced disease is represented by polychemotherapy with fluorouracil (5-FU) +/-levofolinic acid together with irinotecan (FOLFIRI) or oxaliplatin (FOLFOX) given alone, or in combination with bevacizumab or cetuximab, two monoclonal antibodies, respectively, directed against the vascular-endothelial growth factor and the epidermal growth factor receptor (3, 6). These combinations induce high response rates (45-50%) and prolong the time to disease progression (TTP; 9-12 months) and overall survival (OS) of these patients; however, regardless of the type and sequence of administration, their average OS is still no more than 20 to 22 months (3 -6). In the attempt to improve these results, other therapeutic strategies are being investigated (5 -10). A newest polychemotherapy regimen combining gemcitabine with oxaliplatin, levofolinic acid, and
