Treatment of metastatic melanoma with autologous tumor infiltrating lymphocytes (TILs) is currently applied in several centers. Robust and remarkably consistent overall response rates, of around 50... Show moreTreatment of metastatic melanoma with autologous tumor infiltrating lymphocytes (TILs) is currently applied in several centers. Robust and remarkably consistent overall response rates, of around 50% of treated patients, have been observed across hospitals, including a substantial fraction of durable, complete responses. Purpose Execute a phase I/II feasibility study with TIL therapy in metastatic melanoma at the Netherlands Cancer Institute, with the goal to assess feasibility and potential value of a randomized phase III trial. Experimental Ten patients were treated with TIL therapy. Infusion products and peripheral blood samples were phenotypically characterized and neoantigen reactivity was assessed. Here, we present long-term clinical outcome and translational data on neoantigen reactivity of the T cell products. Results Five out of 10 patients, who were all anti-PD-1 naive at time of treatment, showed an objective clinical response, including two patients with a complete response that are both ongoing for more than 7 years. Immune monitoring demonstrated that neoantigen-specific T cells were detectable in TIL infusion products from three out of three patients analyzed. For six out of the nine neoantigen-specific T cell responses detected in these TIL products, T cell response magnitude increased significantly in the peripheral blood compartment after therapy, and neoantigen-specific T cells were detectable for up to 3 years after TIL infusion. Conclusion The clinical results from this study confirm the robustness of TIL therapy in metastatic melanoma and the potential role of neoantigen-specific T cell reactivity. In addition, the data from this study supported the rationale to initiate an ongoing multicenter phase III TIL trial. Show less
To increase cancer immunotherapy success, PD-1 blockade must be combined with rationally selected treatments. Here, we examined, in a poorly immunogenic mouse breast cancer model, the potential of... Show moreTo increase cancer immunotherapy success, PD-1 blockade must be combined with rationally selected treatments. Here, we examined, in a poorly immunogenic mouse breast cancer model, the potential of antibody-based immunomodulation and conventional anticancer treatments to collaborate with anti-PD-1 treatment. One requirement to improve anti-PD-1-mediated tumor control was to promote tumorspecific cytotoxic T-cell (CTL) priming, which was achieved by stimulating the CD137 costimulatory receptor. A second requirement was to overrule PD-1-unrelated mechanisms of CTL suppression in the tumor microenvironment (TME). This was achieved by radiotherapy and cisplatin treatment. In the context of CD137/PD-1-targeting immunotherapy, radiotherapy allowed for tumor elimination by altering the TME, rather than intrinsic CTL functionality. Combining this radioimmunotherapy regimen with low-dose cisplatin improved CTL-dependent regression of a contralateral tumor outside the radiation field. Thus, systemic tumor control may be achieved by combining immunotherapy protocols that promote T-cell priming with (chemo) radiation protocols that permit CTL activity in both the irradiated tumor and (occult) metastases. Show less
Verdegaal, E.M.E.; Miranda, N.F.C.C. de; Visser, M.; Harryvan, T.; Buuren, M.M. van; Andersen, R.S.; ... ; Burg, S.H. van der 2016
Cancer immunotherapy has shown clinical effectiveness over the recent years, especially in patients with a high mutational load in the tumor. Mutated epitopes, so called 'neo-antigens', are... Show moreCancer immunotherapy has shown clinical effectiveness over the recent years, especially in patients with a high mutational load in the tumor. Mutated epitopes, so called 'neo-antigens', are presented on the tumor and can be regarded as foreign by the immune system. In this thesis, the importance of neo-antigens in the anti-tumor response is explored. First, the characteristics of antigens that can be recognized on human tumors are described, with a specific focus on neo-antigens. Second, technologies are described to systematically analyze neo-antigen specific reactivity in patients with cancer. Third, I show that neo-antigen specific reactivity is a common phenomenon in the CD4 and CD8 T cell compartments of patients with melanoma. Finally, I discuss what the expected value of neo-antigens is in the context of personalized cancer-immunotherapy. Show less
