Current standard-of-care immunotherapies target the interaction between tumor and T cells. However, frequently there are insufficient numbers of tumor-specific T cells present. Hence, these patients may benefit from adoptive cell transfer (ACT) with melanoma-specific T cells. The general conditioning and maintenance treatment for ACT consists of lymphodepleting chemotherapy with or without total body irradiation, and post-transfusion high-dose IL-2. In our hospital we replaced this rather toxic treatment scheme with low-dose interferon-alpha (IFNa).
Twenty-four patients with progressive metastatic melanoma received up to three infusions with ex vivo expanded tumor infiltrating lymphocytes (TIL) every three weeks, ranging between 1-10 x 108 T cells per infusion. One week before the first TIL infusion patients started with daily subcutaneous IFNa injections. These injections were continued for eleven weeks as a maintenance treatment. Total blood count was measured before the start of IFNa, and before each TIL infusion. Furthermore, serum and PBMC were collected at these time-points. Twelve weeks after the first TIL infusion the patients received a radiological response evaluation.
The combination of IFNa and ACT is safe and well tolerated. IFNa causes a mild lymphopenia, neutropenia and leukopenia. Both responders and non-responders show a decrease in these blood counts after one week of IFNa. Strikingly, persistence of leukopenia and in particular neutropenia predicts the response to TIL therapy. Furthermore, high leukocyte/lymphocyte and platelet/lymphocyte ratios are predictive biomarkers for response to treatment. Clinical benefit was seen in 7 out of 24 (29%) patients with stable disease for an average of 36 weeks. Although nineteen patients failed extensive pre-treatment with BRAF/MEK inhibitor and/or anti-PD1 and/or anti-CTLA4, five of them still displayed stabilization of disease (26.3%) after ACT.
The persistence of leukopenia induced by low-dose IFNa is a predictor of response to TIL therapy. Furthermore, this treatment combination is a viable option for heavily pre-treated metastatic melanoma patients.
Local Ethics Committee P04.085.
Medical Oncology, Leiden University Medical Center.
KWF (Dutch Cancer Society).
E.M.E. Verdegaal: In relation to research: Affiliations or financial involvement: ISA pharmaceuticals B.V., AIMM Therapeutics, PamGene. J.B.A.G. Haanen: Advisory boards, consultation and lectures: Pfizer, Bayer, MSD, BMS, Ipsen, Novartis, Roche/Genentech, Neon Therapeutics, Celsius Therapeutics, Gadeta BV, Immunocore. Grants to NKI: BMS, MSD, Novartis, Neon Therapeutics. E. Kapiteijn: Advisory boards: Roche, BMS, MSD, Novarits, Pierre-Fabre, Genzyme-Sanofi, Eisai, Servier, Sirtex, Delcath (for which LUMC received honoraria). Grant support to LUMC: Novartis, BMS. S.H. van der Burg: Advisory boards: ISA Pharmaceuticals B.V., PCI-Biotech, IO-Biotech; Corporate grant support: Innate Pharma, Kite Pharma EU B.V., AIMM Therapeutics; Service agreements: ISA Pharmaceuticals B.B., IO Biotech. All other authors have declared no conflicts of interest.