Cancer cells often escape the attack of immune cells because they originate from self-tissue. Through T cell receptor gene transfer it is possible to equip peripheral T cells with a desired... Show moreCancer cells often escape the attack of immune cells because they originate from self-tissue. Through T cell receptor gene transfer it is possible to equip peripheral T cells with a desired specificity, and this strategy may be useful to generate tumor-specific T cells for the treatment of cancer in humans. This thesis describes several aspects in the functionality, safety and longevity of T cells modified by T cell receptor gene transfer in animal models. Show less
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... Show moreAdoptive 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. Show less
