Vitiligo and melanoma-associated hypopigmentation (MAH): shared and discriminative features.

BACKGROUND: It is unclear if differences between melanoma-associated hypopigmentation (MAH) and classical vitiligo exist. PATIENTS AND METHODS: Hypopigmented areas and associated lesions (halo nevi, hypopigmented scars) in 15 melanoma patients and 31 patients with classical vitiligo were analyzed by digital photography. The activity of the respective lesions was assessed by the vitiligo disease activity (VIDA) score. Associated diseases were recorded by history and serological tests;genotyping of HLA class I antigens as well as histology/immunohistology were performed. RESULTS: MAH were diagnosed in 12 of 15 melanoma patients; mean onset was 4.8 years after the primary diagnosis of the melanoma. Three melanoma patients reported hypopigmentation more than 15 years before diagnosis of melanoma. In the history and family history of vitiligo patients, autoimmune diseases were much more frequent and haplotype HLA-A2 was twice as common compared to MAH patients. MAH lesions were most often distributed in a bilateral symmetrical pattern, corresponding to vitiligo. MAH was less progressive compared to classical vitiligo; however, it was more often associated with other acquired leukodermas. In both groups hypopigmentation spread centripetally to the trunk. Histological and immunohistological differences were not found. CONCLUSIONS: Whereas differences exist concerning associated autoimmune diseases, MAH and vitiligo shared many common clinical and histological features. Further studies are needed to assess the clinical relevance of vitiligo-like alterations in melanoma patients.

Complete remission of liver metastasis of pancreatic cancer under vaccination with a HLA-A2 restricted peptide derived from the universal tumor antigen survivin.

PURPOSE: As prognosis of advanced pancreatic cancer remains gloomy, novel therapeutic modalities have to be developed. Immunotherapy, which targets tumor-associated antigens of tumor cells or tumor stroma, is currently under investigation. As survivin is expressed by neoplastic and tumor endothelial cells, but rarely by normal cells, this antigen appears as an intriguing target molecule. METHODS: A 72-year old patient, suffering from pancreatic cancer refractory to gemcitabine therapy, received the survivin-based peptide vaccinations consisting of 100 mug of a modified HLA-A2 restricted survivin(96-104) epitope in Montanide(R). Each visit the patient was assessed for adverse events, quality of life and immunological response. Immuno-monitoring was performed by IFN-gamma-ELISPOT analysis of peripheral blood lymphocytes. Clinical outcome was evaluated by repetitive computed tomography. RESULTS: Under vaccination with survivin peptides the patient initially underwent partial remission of liver metastasis which proceeded after 6 months into a complete remission with a duration of 8 months. Immunological monitoring revealed strong vaccine-induced immune-reactivity against survivin. Unfortunately, after the patient was weaned from vaccination in state of no evidence of disease, he developed recurrent disease. CONCLUSION: T-cell responses against survivin-expressing cells of the tumor itself and tumor endothelium should impact tumor growth and metastasis. The presented patient with pancreatic cancer is the first example of a successful application of a survivin-based vaccination in the clinical setting. An ongoing phase I/II trial with HLA-A1, -A2 and -B35 restricted survivin peptides for patients with advanced cancer will provide further information towards this notion.

Lack of toxicity of therapy-induced T cell responses against the universal tumour antigen survivin.

Prognosis of disseminated melanoma remains gloomy as neither chemotherapeutic nor unspecific immune modulatory approaches were able to improve the overall survival of these patients. Hence, specific immunotherapy has received increasing attention. Disappointing clinical results, however, indicate that the choice of suitable antigens is of special importance. To this end, the inhibitor of apoptosis (IAP) protein survivin, which is over-expressed in several tumours but is largely undetectable in adult tissues, appears to be a promising target for vaccination purposes, since down-regulation or loss of expression is associated with impaired tumour progression. Consequently, five heavily pretreated stage IV melanoma patients were vaccinated with the HLA-A2 restricted survivin(96-104) epitope presented by autologous dendritic cells (DCs) in a compassionate use setting. Four of these patients mounted strong T cell responses to this epitope as measured by ELISPOT assay. Furthermore, in situ peptide/HLA-A2 multimer staining confirmed that these survivin reactive cells infiltrated both visceral and soft tissue metastases.

Aggregation of antigen-specific T cells at the inoculation site of mature dendritic cells.

Cellular immune responses are initiated by direct interaction of naive T cells with professional antigen-presenting cells, i.e., dendritic cells. In general, this interaction takes place in secondary lymphoid organs to which both naive T cells and mature dendritic cells preferentially home. This physiologic scenario differs substantially, however, from therapeutic dendritic-cell-based vaccinations used to treat human cancer. In fact, only a small fraction of intradermally injected dendritic cells migrate to the draining lymph node and the majority of cells remain at the site of inoculation. These sites are characterized by a distinct oligoclonal T cell infiltrate comprising both L-Selectin+/CD45RA+ and L-Selectin+/CD45RA- cells. Blood vessels expressing peripheral lymph node addressin represent possible entry channels for such naive and central memory T cells, the former probably attracted by dendritic cell-CK1 produced by the injected dendritic cells. In situ staining with multimeric peptide/major histocompatibility complex class I complexes revealed that infiltrating T cells specifically recognize peptide epitopes presented by the injected dendritic cells. Thus, the fraction of dendritic cells not migrating to secondary lymphatic tissue after therapeutic inoculation nevertheless seem to be involved in a specific immune modulation.