Circulation and homing of melanoma‐reactive T cells to both cutaneous and visceral metastases after vaccination with monocyte‐derived dendritic cells

Abstract

Anticancer immune therapies aim at the induction of tumor-specific T cells, which ultimately should kill tumor cells. The effector cells should, therefore, not only exert cytotoxic activity but also home to and infiltrate the tumor site. Hence, monitoring of immune modulating therapies should not be restricted to the circulating pool of peripheral blood mononuclear cells (PBMC) but also include tumor-infiltrating lymphocytes (TIL), as well as the correlation of these findings to the clinical course. We report here on the longitudinal immunologic workup of a melanoma patient who developed remarkably potent ex vivo detectable antimelanoma cytotoxic T-cell (CTL) responses after vaccinations with autologous peptide-pulsed dendritic cells. Such potent CTL responses to multiple tumor antigens have, to the best of our knowledge, not been described previously in melanoma patients, neither spontaneously nor after any therapy. This patient first experienced a transient response to therapy but finally succumbed to disease progression and died. Progression was associated with the decline of the numbers of tumor-reactive T cells in circulation and at skin metastases in addition to the loss of MHC class I antigens. The immunologic analysis revealed that fully functional tumor-specific T cells were present in the peripheral blood of this patient during the phase of a relatively stable disease, and in situ tetramer staining demonstrated that these cells were also accumulated at cutaneous and visceral tumor sites. Furthermore, comparative clonotype mapping of PBMC and TIL depicted an overlapping TCR repertoire usage among these 2 compartments. Since strong CTL responses as observed in this patient are the goal of cancer vaccination but are so far only rarely observed, the thorough analysis of patients exhibiting either exceptional clinical and/or immunologic responses appears critical to understanding how vaccine therapies work and can be further improved. © 2004 Wiley-Liss, Inc. Key words: dendritic cells; multimeric peptide/MHC-complex; T-cell receptor; cutaneous lymphocyte antigen; vaccinationImmune therapy for tumor patients aims at harnessing the immune system to fight cancer. Indeed, clinical trials have already shown that tumor-specific T cells can be induced even in advanced cancer patients. 1,2 The induction of tumor-specific T cells, however, is not necessarily associated with a clinical response. 3 A major obstacle in evaluating the success of a cell-based immunotherapy lies in the fact that systemic immune responses detected in the blood may not reflect the actual situation in the tumor. 4 Thus, we performed a thorough immunologic workup of a melanoma patient receiving DC vaccinations as well as other anticancer therapies such as isolated limb perfusion, surgery and chemotherapy. Initially, this patient experienced an objective clinical response followed by a phase of stability, which were associated with vigorous tumor-specific T-cell responses. However, despite an ongoing therapy, we observed the cessation of these...

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