Abstract
BackgroundAdoptive cell therapy may be based on isolation of tumor-specific T cells, e.g. autologous tumor infiltrating lymphocytes (TIL), in vitro activation and expansion and the reinfusion of these cells into patients upon chemotherapy induced lymphodepletion. Together with high-dose interleukin (IL)-2 this treatment has been given to patients with advanced malignant melanoma and impressive response rates but also significant IL-2 associated toxicity have been observed. Here we present data from a feasibility study at a Danish Translational Research Center using TIL adoptive transfer in combination with low-dose subcutaneous IL-2 injections.MethodsThis is a pilot trial (ClinicalTrials.gov identifier: NCT00937625) including patients with metastatic melanoma, PS ≤1, age <70, measurable and progressive disease and no involvement of the central nervous system. Six patients were treated with lymphodepleting chemotherapy, TIL infusion, and 14 days of subcutaneous low-dose IL-2 injections, 2 MIU/day.ResultsLow-dose IL-2 considerably decreased the treatment related toxicity with no grade 3–4 IL-2 related adverse events. Objective clinical responses were seen in 2 of 6 treated patients with ongoing complete responses (30+ and 10+ months), 2 patients had stable disease (4 and 5 months) and 2 patients progressed shortly after treatment. Tumor-reactivity of the infused cells and peripheral lymphocytes before and after therapy were analyzed. Absolute number of tumor specific T cells in the infusion product tended to correlate with clinical response and also, an induction of peripheral tumor reactive T cells was observed for 1 patient in complete remission.ConclusionComplete and durable responses were induced after treatment with adoptive cell therapy in combination with low-dose IL-2 which significantly decreased toxicity of this therapy.
Highlights
Adoptive cell therapy may be based on isolation of tumor-specific T cells, e.g. autologous tumor infiltrating lymphocytes (TIL), in vitro activation and expansion and the reinfusion of these cells into patients upon chemotherapy induced lymphodepletion
All patients were previously treated with high-dose IL-2 according to an intravenous decrescendo regimen previously described by Keilholz et al [22]
We have recently shown that IFN-γ is able to increase the immunogenicity of melanoma cells thereby restoring the responsiveness in otherwise unresponsive T cells in clinical TIL products (Donia M et al accepted for publication, J Invest Dermatol, 2012) and IFN-α has in a previous study been shown to be able to induce clinical responses in combination with Adoptive cell therapy (ACT) [27]
Summary
Adoptive cell therapy may be based on isolation of tumor-specific T cells, e.g. autologous tumor infiltrating lymphocytes (TIL), in vitro activation and expansion and the reinfusion of these cells into patients upon chemotherapy induced lymphodepletion. Together with high-dose interleukin (IL)-2 this treatment has been given to patients with advanced malignant melanoma and impressive response rates and significant IL-2 associated toxicity have been observed. Chemotherapy and radiotherapy have limited efficacy, and treatments with curable potential have been restricted to Interleukin(IL)-2 and Interferon(IFN)-α which has high toxicity, and low response rates. Several new treatment modalities have been approved for the treatment of metastatic melanoma. This includes the anti-CTLA-4 antibody, Ipilimumab [2,3] and the B-RAF inhibitor, Vemurafenib [4], along with new drugs in the pipeline, e.g. PD-1 antibodies [5,6] and MEK-inhibitors [7].
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