Adoptive T cell therapy as treatment for Epstein Barr Virus-associated malignancies : strategies to enhance potential and broaden application

Adoptive transfer of T-cells that are ex vivo selected for tumor-specificity is an attractive treatment strategy for cancer. Epstein Barr virus (EBV)-associated malignancies are ideal candidates to develop this type of immunotherapy as EBV-specific T-cells can readily be selected and expanded from peripheral blood of EBV-seropositive individuals. The first part of thesis describes a phase 1 clinical study which demonstrates the feasibility and safety of this approach in patients with advanced stage EBV-positive nasopharyngeal carcinoma. Unfortunately only a small number of cancers express viral antigens that are easily recognized by the immune system. Therefore a strategy is required to generate large numbers of T-cells specific for antigens that normally elicit no or only a weak immune response. In the second part of this thesis a method is described of engrafting T-cells with the required specificity using retroviral transfer of T-cell receptors (TCRs). The TCRs were further modified to incorporate costimulation signals (CD28, OX40) that are essential to initiate and sustain an effective anti-tumor response but are often lacking on the target tumor cells. Finally, an inducible safety switch was developed that allows for the ablation of the infused T-cells in vivo in case of toxicity, which will facilitate the implementation of these novel immunotherapy approaches in clinical studies.LEI Universiteit LeidenFellowship Leiden University Medical Centre, grants from the Ter Meulen Fund, Ank van Vlissingen Fund, The Dutch Cancer Society, NIH (PO1 CA94237), The Doris Duke Charitable Foundation and a fellowship from The Methodist Hospital.Immunobiologie van minor Histocompatibiliteits antigenen