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

Straathof, K.C.M. (2006)

Doctoral Thesis

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.

• Caspase 9
• Chimeric T-cell receptor
• Costimulation
• Cytotoxic T-cell
• Gene transfer
• Immunotherapy
• Nasopharyngeal carcinomaLatent membrane protein 2
• Retroviral transduction
• Suicide gene

• All authors: Straathof, K.C.M.
• Supervisor: Goulmy, E.A.J.M.; Egeler, R.M.
• Co-supervisor: Rooney, C.M.
• Qualification: Doctor (dr.)
• Awarding Institution: Department of Immunohematology and Paediatrics, Faculty of Medicine, Leiden University Medical Center (LUMC), Leiden University
• Date: 2006-09-28
• ISBN (print): 9090209476
• Court: LEI Universiteit Leiden
• Sponsorship: Fellowship 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.