Abstract Purpose: Chemotherapy can induce prolonged remissions in patients with stage IV cancer (AC), yet nearly the majority of them, will ultimately relapse. In vitro studies suggest that natural killer cells (NK) mediate lytic activity against cancer cell lines and that high expression of vascular endothelial growth factor (VEGF) promotes tumor progression through neoangiogenesis. We have shown that a combination of low-dose interleukin-2 (IL-2) and 13-cis retinoic acid (RA) increased NK cells and decreased VEGF, in patients with AC with a clinical benefit from chemotherapy (Clin Cancer Res 7: 1251, 2001). Therefore, IL-2 and RA may improve long-term disease-free survival (DFS) and overall survival (OS) when administered in a post-chemotherapy minimal residual disease setting. Primary endpoint of the study was to evaluate if IL-2 and RA increased NK cells and decreased VEGF of patients with AC that had a clinical benefit from chemotherapy. Secondary endpoint was the evaluation of DFS, OS and toxicity of this regimen in various tumor types. Patients and methods: 500 patients with a wide range of AC that had a clinical benefit from chemotherapy were treated with self-administered subcutaneous IL-2, 1.8 X 106 IU and oral RA, 0.5 mg/Kg for 5 days/week for 2 consecutive cycles of 3 weeks, with a 1-week rest, for 1 year. Therapy was continued, with intermittent schedules for five years or until progression. NK cells, serum VEGF, tumor response and toxicity were assessed every 4 months. Results: Median age was 61 years (range 21-80), all patients had a good performance status and there were 248 females. After a median follow-up of 60 months (range 24-180), 4400 courses of chemotherapy and 2634 courses of immunotherapy were administered. A statistically significant improvement of NK cells [from a mean of 309 ± 76/mm3 to a mean of 579 ± 74 (p<0.001)] and a decrease of VEGF [from a mean of 520 ± 75 pg/mm3 to a mean of 150 ± 12 pg/mm3, (p<0.001)], with respect to baseline, post-chemotherapy values, were observed. 15 years DFS and OS were 32.6 and 36.8, respectively. Even with all the limitations of different patient populations, a significant improvement, with respect to NCI SEER data (*), could be observed in the 5-year OS rate for the most common treated metastatic cancers: Breast cancer 42.7% vs. 23.3% *, lung cancer 26.4% vs. 3.6% *, colorectal cancer 43.6% vs. 11.7%*, renal cancer 23% vs. 11% *. No WHO grade 3 or 4 toxicity was observed, while grade 2 cutaneous toxicity and fever occurred in 20% and 13% of patients, respectively. Mild hypothyroidism and grade 2 triglyceride elevation was observed in 5% and 15% of patients, respectively. 1 patient had to stop treatment for grade 2 urticaria. Conclusions: These data show that the administration of IL-2/RA, determines, with a modest toxicity profile, a sustained improvement of NK cells, a decrease of VEGF, and unexpected 5-year survival rates. Phase III randomized studies have been started, in Europe, for several tumor types. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5366. doi:1538-7445.AM2012-5366