Background: We previously confirmed the feasibility of adoptive cell therapy (ACT) with tumor infiltrating lymphocytes (TIL) for patients with advanced melanoma. Patients successfully treated had a 38% response rate, but patient attrition due to progression before ACT (21%) resulted in a response rate of only 26% based on intent to treat (IIT) analysis. We hypothesized that combination immunotherapy would decrease attrition due to progression. Here we present the final report of a pilot trial combining ipilimumab (IPI) and ACT. Methods: Thirteen patients with metastatic melanoma were accrued to an IRB-approved trial. All had >1 cm³ of soft tissue/nodal metastases amenable to resection leaving residual disease. Patients received 3 mg/kg of IPI two weeks prior to tumor resection for TIL generation. One week following resection, a second dose of IPI was administered. ACT included pre-conditioning chemotherapy and TIL infusion followed by IL-2. Two additional doses of IPI were given 2 and 5 weeks after ACT. Feasibility was a primary endpoint and considered achieved if ≥ 2 doses of IPI and TIL were infused to at least 60% of all patients. The clinical responses were assessed by RECIST 1.1 criteria at 12 weeks following TIL transfer. Results: All patients received at least 2 doses of IPI, and 12 of the 13 patients (92%) received TIL. One patient (7%) dropped out due to progression before TIL infusion. TIL were expanded from 47.2% of tumor fragments and 58.7% of these fragments generated TIL reactive to autologous tumor. Median number of infused TIL was 6.5e10 (2.29e10-1.04e11) and median 85% were CD8+ (27-99). At 12 weeks following infusion, of the 13 patients enrolled, there were 6 responders (46%). Median progression-free survival was 7.4 months (1.4-42.2). Grade ≥3 immune-related adverse events included colitis (1), uveitis (1), and hypothyroidism (1). Conclusions: IPI combined with ACT with TILs for patients with advanced melanoma is feasible with decreased attrition due to progression and is associated with promising clinical results based upon ITT analysis. This combination approach of TIL cell therapy and co-inhibitory blockade serves as a model for future efforts to improve the efficacy of immunotherapy for patients with cancer. Clinical trial information: NCT01701674