Intraperitoneal adoptive immunotherapy of ovarian carcinoma with tumor-infiltrating lymphocytes and low-dose recombinant interleukin-2: A pilot trial

Summary: A pilot study was conducted in patients who had advanced epithelial ovarian carcinoma, and who were refractory to platinum-based chemotherapy, to determine the feasibility and clinical effects of a schedule of intraperitoneal (IP) tumor-infiltrating lymphocytes (TIL) expanded in recombinant interleukin-2 (rIL-2), and low-dose rIL-2 IP. TIL were expanded from solid metastases or malignant effusions in serum-free AIM V medium supplemented with low concentrations (600 IU/ml) of rIL-2 using a four-step method of expansion that included a hollow fiber bioreactor (artificial capillary culture system). Patients received IP TIL suspended in dextrose 5% in sodium chloride 0.2% containing 0.1% human albumin and 6 × 10⁵IU rIL-2 on day 1, followed by 6 × 10⁵IU rIL-2/m²body surface area, administered daily by bolus IP injection, on days 2-4, 8-11, and 15-18. In the absence of disease progression, two additional 4-day cycles of IP rIL-2 were administered. Patients (n = 3) whose TIL failed to grow in vitro received IP IL-2 alone. Eight patients received rIL-2 expanded TIL (10¹⁰-10¹¹range) plus rIL-2 followed by several cycles of rIL-2 alone. One of these patients was treated twice with TIL plus rIL-2. Expanded TIL were primarily CD3⁺CD4⁺TCRαβ⁺(eight TIL-derived T-cell lines). One TIL-derived T-cell line was comprised mostly of CD3⁺CD8⁺TCRαβ⁺cells. Eleven patients (eight treated with TIL plus rIL-2 and three patients treated with rIL-2 alone) received a total of 38 cycles of rIL-2 without TIL. Grade 3 clinical toxicity (peritonitis) occurred in 1 of 9 cycles of TIL plus rIL-2 and 1 of 38 cycles of rIL-2 alone. Each cycle was 4 days long. Grade 3 anemia occurred in 1 of 9 TIL plus rIL-2 cycles and 3 of 38 cycles of rIL-2 alone. There were no measurable responses; however, four of eight patients treated with IP TIL plus rIL-2 had some indication of clinical activity: Ascites regression (two patients), tumor and CA-125 reduction (one patient), and surgically confirmed stable tumor and CA-125 values (one patient). The schedule of IP TIL plus low-dose rIL-2 shows manageable toxicity and is worthy of further evaluation in patients with epithelial ovarian cancer who have less tumor burden.