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
This thesis describes different immunotherapeutic strategies that can be used for the treatment of cancer in general, and of melanoma in particular. Tumor-specific T cell responses can be induced... Show moreThis thesis describes different immunotherapeutic strategies that can be used for the treatment of cancer in general, and of melanoma in particular. Tumor-specific T cell responses can be induced via either active or passive immunization. Active immunization can be used to target tumors for which high affinity T cells are present within the endogenous repertoire. This thesis describes a vaccination method where a tattoo device is used to deliver a DNA vaccine into the skin. The vaccine-induced anti-tumor effect can be further enhanced by combining vaccination with host conditioning and adoptive transfer. Passive immunization via TCR gene transfer is the preferred strategy when targeting tumor self antigens, because this can circumvent limitations of the endogenous T cell repertoire and does not require extensive in vitro culture. This thesis describes several factors that can improve the anti-tumor ac tivity of TCR modified cells. In addition, we describe a procedure for the selection of a human TCR that is well expressed and highly affine, and that is therefore likely to enable more efficient targeting of human melanoma. Implementation of these factors in the design of clinical trials is likely to positively affect the clinical efficacy of TCR gene therapy. Show less
