Background: TIL therapy has been used extensively in metastatic melanoma patients for many years, now with ongoing efforts to commercialize treatment. The efficacy of TIL outside of melanoma is largely unknown thus we designed and implemented a trial using TIL manufactured at a single academic center for treatment refractory metastatic colorectal (CRC), pancreas (PDAC) and ovarian (OVA) cancers. Methods: Patients with CRC, PDAC and OVA refractory to standard therapies with ECOG PS 0-1 and normal organ function were eligible for TIL harvest. Ex vivo TIL expansion and manufacturing was conducted at the MD Anderson TIL lab under conditions that included IL2 and 41BB stimulation (using urelumab). All patients received a lymphodepletion regimen consisting of cyclophosphamide 60mg/kg days -7 and -6 and fludarabine 25mg/m2 days -5 through day -1, followed by infusion of pooled ex-vivo expanded TIL. Patients received up to 6 doses of high dose IL-2 (600,000 IU/kg) after TIL infusion. The primary endpoint was evaluation of the objective response rate (ORR) using RECIST 1.1 criteria with secondary endpoints including disease control rate, duration of response, PFS, OS and safety. Results: A total of 17 patients underwent TIL harvest and 16 were treated on protocol; including 8 CRC, 5 PDAC and 3 OVA. Median age was 57.5 (range 33-70) and 50% were females. Median number of lines of prior therapy was 2 (range 1-8). Median number of TIL infused was 76 X 10⁹ (range 20.3 x 10⁹-150 x 10⁹). Median doses of cyclophosphamide and fludarabine administered were 2 (range, 2-2) and 3 (range, 1-5), respectively. Median doses of IL-2 administered was 6 (range, 1-6). There were no responders. Best response included prolonged SD in a patient with PDAC lasting until 18 months. Grade 3 or higher toxicities attributable to therapy was seen in 14 subjects (87.5%; 95% CI: 61.7 – 98.4) with the majority of toxicities representing expected pancytopenia from lymphodepletion. Infusion product analysis showed the presence of effector memory cells with high expression of CD39 irrespective of tumor type. Early on-treatment biopsy of PDAC patient with prolonged SD showed presence of proliferating (KI67+) CD4+ and CD8+ TIL. Conclusions: Generation of TIL at a single academic center for CRC, PDAC and OVA is feasible and treatment is associated with no new safety signals. For these tumor types, further research is required to identify host factors associated with resistance to TIL therapy and optimize manufacturing processes to create more effective TIL cell therapy. Clinical trial information: NCT03610490.