Immunotherapy of melanoma : toward clinical application

Abstract

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 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.