Interleukin 2 (IL-2) is a promising immunotherapeutic agent for the treatment of metastatic
melanoma and
renal cell carcinoma. Systemic administration of high dose
IL-2 produces objective responses in up to 25% of
melanoma patients, and a low but significant proportion of these patients experience durable responses. Nevertheless, the cells and molecules responsible for induction of
tumor regression over the course of
IL-2 treatment remain unknown. New strategies in
tumor immunotherapy have evolved over the past decade as a consequence of significant progress in the field, in particular with respect to the characterization of
peptide epitopes derived from
tumor associated
antigens, and the role of antigen presenting cells in the initiation of cellular immune responses. Alongside with these factual as well as conceptual advances, new methods have been developed to monitor and characterize anti-
tumor T cell responses in
cancer patients. Application of these tools to dissect anti-
tumor responses has demonstrated that various immune therapeutic approaches can induce powerful systemic anti-
tumor cytotoxic T lymphocyte (CTL) responses. However, only limited efforts have been made to use present days tool to analyze anti-
tumor immune responses in patients treated with
IL-2 based
immunotherapy. We have examined CTL responses against known
tumor antigens in
melanoma patients over the course of
IL-2 based
immunotherapy (electrochemotherapy). Surprisingly, anti-
tumor CTL responses significantly declined upon initiation of
therapy, but reappeared when
IL-2 administration was paused. Molecular analyses of the clonotypic composition of responding T cells demonstrated that new clones emerged over the course of treatment, and that
tumor-specific T cells that had left the peripheral blood could subsequently be detected at the
tumor site. These data provide new insight into the
biological actions of
IL-2 and highlight the difficulties associated with the monitoring of anti-
tumor immune responses. This underlines the importance of frequent sampling of blood and
tumor biopsies to be analyzed with a combination of state of the art technologies in order to gain detailed information on the interactions between
cancer cells and cells of the immune system.