Adoptive Transfer of TILs Effective in Metastatic Uveal Melanoma

Preliminary results from an ongoing phase II trial indicate that adoptive transfer of autologous tumor-infiltrating lymphocytes (TILs) may stimulate tumor regression in patients with metastatic uveal melanoma, a rare disease with no established treatments. Immunotherapies used in other forms of melanoma, such as programmed death receptor 1 (PD-1) inhibitors, have limited efficacy in uveal melanoma.

The two-stage study examined responses to single infusion of autologous TILs and high-dose interleukin (IL)-2 (720 000 IU/kg every 8 hours) following treatment with a lymphodepleting conditioning chemotherapy regimen consisting of cyclophosphamide (60 mg/kg) for 2 days followed by fludarabine (25 mg/m2) for 5 days. Before treatment, all patients underwent metastasectomies to obtain tumor tissue for the purpose of generating autologous TILs for therapy. The median number of TILs given during therapy was 85 x 109 cells and number of given IL-2 doses varied based on clinical status (median 5). Objective tumor responses were seen in 7 of the 20 (35%) patients evaluable for response at data cut-off, fulfilling the primary endpoint, which included 6 partial responses and 1 complete response, and was still ongoing at 21 months post-therapy. Responses were also observed in 3 patients who were refractory to previous checkpoint inhibitors.

Adverse events (AEs) were primarily related to the lymphodepleting chemotherapy regimen. All patients experienced transient grade 3 or higher lymphopenia, neutropenia, and thrombocytopenia; grade ≥3 anemia, febrile neutropenia, and infection occurred in 67%, 29%, and 24% of patients, respectively. In general, infections were low grade, though one patient died due to sepsis-related complications. No acute toxicities occurred during the seven days associated with the TIL infusion, and IL-2-related AEs were mild and self-resolving. Autoimmune-related AEs were not seen after TILs, except in one patient who developed mild patchy vitiligo several months after treatment.

This study findings published in The Lancet Oncology represents the first report of successful use of TILs in patients with metastatic uveal melanoma, and challenges the belief that immunotherapy is ineffective in this malignancy. Following achievement of the primary endpoint, the study was expanded to a total of 33 patients. In an accompanying commentary in The Lancet Oncology, authors noted that while these data are preliminary and require confirmation in a larger trial, this study provides important evidence that immunotherapeutic approaches other than checkpoint blockade may be effective in uveal melanoma, providing a potential area for future investigation.

 Lancet Oncol. 2017 April 7. [Epub ahead of print].

 Lancet Oncol. 2017 April 7. (Comment) [Epub ahead of print].