Udo Hofmann

Phase 2 trial of vaccination with tyrosinase peptides and granulocyte-macrophage colony-stimulating factor in patients with metastatic melanoma.

This phase II study was performed to determine the induction of a specific T-cell response, the clinical response rate, and toxicity of vaccination with different HLA class I–binding peptide epitopes derived from the melanocyte differentiation antigen tyrosinase in patients with stage IV melanoma. The study population consisted of 16 patients with metastatic disease and two patients who were macroscopically free of disease at study entry after resection of recurrent skin lesions. Patients received intradermal injections of 200 mg peptide corresponding to their HLA type on day 3, and 75 or 150 &mgr;g granulocyte-macrophage colony-stimulating factor on days 1 to 4. Vaccinations were repeated at weeks 2, 4, 6, 10, and 14. Monitoring of peptide-specific T-cell frequencies in the peripheral blood was performed using an interferon&ggr; ELISPOT assay. Eleven of the 16 patients with metastatic disease went off the protocol within the first 10 weeks because of tumor progression. Of the five patients with metastatic disease who received all six vaccinations, one patient showed a mixed response with regression of some lung metastases; two patients with progressive disease before vaccination had stable disease for 6 and 18+ months; and two patients had progression of their disease. The two patients who had all their metastases resected before vaccination did not have relapses for 6 and 12+ months after vaccination. Induction of tyrosinase-reactive T cells was found in these two patients and in two others with metastatic disease, including the one who achieved a mixed response and one with stable disease. This study shows limited clinical and immunologic activity of HLA class 1-peptide vaccination in combination with granulocyte-macrophage colony-stimulating factor in stage IV melanoma patients.

Clusters of Perifollicular Macrophages in Normal Murine Skin: Physiological Degeneration of Selected Hair Follicles by Programmed Organ Deletion

In back skin sections from adolescent C57BL/6 mice, regularly distributed, perifollicular inflammatory cell clusters (PICC) were found located around the distal noncycling portion of about 2% of all hair follicles examined. The PICC and the affected hair follicles were characterized during spontaneously developed or induced hair cycle stages, using antibodies against MHC Class II,F4/80, ER-MP23, NLDC 145, CD4, CD8, γδTCR, IL-1 receptor, and ICAM-1. PICC consisted predominantly of macrophages (MAC), accompanied by a few CD4+ cells, whereas γδTCR+ and CD8+ cells were absent. During anagen and catagen, some of the PICC+ hair follicles showed variable degenerative phenomena reminiscent of scarring alopecia: thickened basement membrane, ectopic MHC II expression, MAC infiltration into the follicle epithelium, and signs of keratinocyte apoptosis. Loss of distal outer root sheath keratinocytes was detected in 10% of PICC+ hair follicles (0.2% of all hair follicles). Because PICC were located in the vicinity of the bulge region, MAC-dependent damage to follicle stem cells might eventually lead to follicle degeneration. These perifollicular MAC clusters around selected hair follicles may indicate the existence of a physiological program of MAC-dependent controlled follicle degeneration by which damaged or malfunctioning follicles are removed by programmed organ deletion (POD).

Effects of granulocyte-macrophage colony-stimulating factor and foreign helper protein as immunologic adjuvants on the T-cell response to vaccination with tyrosinase peptides

Immunologic adjuvants are used to augment the immunogenicity of MHC class I–restricted peptide vaccines, but this effect has rarely been systematically evaluated in a clinical trial. We have investigated, in a phase I study, whether addition of the 2 adjuvants GM‐CSF and KLH can enhance the T‐cell response to MHC class I peptide vaccines. Forty‐three high‐risk melanoma patients who were clinically free of disease received 6 vaccinations with MHC class I–restricted tyrosinase peptides alone, with either GM‐CSF or KLH or with a combination of both adjuvants. The primary end point was induction of tyrosinase‐specific T cells, and serial T‐cell monitoring was performed in unstimulated peripheral blood samples before and after the second, fourth and sixth vaccinations by ELISPOT assay. Tyrosinase‐specific IFN‐γ‐producing T cells were detected as early as 2 weeks after the second vaccination in 5 of 9 patients vaccinated with tyrosinase peptides in combination with GM‐CSF and KLH but not in any patient vaccinated with tyrosinase peptides without adjuvants or in combination with either adjuvant alone. After 6 vaccinations, tyrosinase‐specific T cells were found in patients immunized with peptides either without adjuvants (3 of 9 patients) or in combination with the single adjuvant GM‐CSF (4 of 9 patients) but not with KLH (0 of 10 patients). Our results suggest that addition of either GM‐CSF or KLH as a single adjuvant has little impact on the immunogenicity of tyrosinase peptides. The combined application of GM‐CSF and KLH was associated with early induction of T‐cell responses.

Linac-based radiosurgery of cerebral melanoma metastases. Analysis of 122 metastases treated in 64 patients.

Purpose: Stereotactic radiosurgery is an alternative option to neurosurgical excision in the management of patients with brain metastases. We retrospectively analyzed patients with brain metastases of malignant melanoma who were treated at our institution for outcome and prognostic factors. Patients and Methods: 64 patients with 122 cerebral metastases were treated with stereotactic radiosurgery between 1986 and 2000. Twelve patients (19%) showed neurologic symptoms at the time of treatment, and 46 patients (72%) had extracerebral tumor manifestation at that time. The median dose to the 80% isodose line, prescribed to encompass the tumor margin, was 20 Gy (range, 15–22 Gy). Results: Neurologic symptoms improved in five of twelve symptomatic patients. 41 patients remained asymptomatic or unchanged in their neurologic symptoms. Only five patients (8%) temporarily worsened neurologically after therapy despite no signs of tumor progression. With a mean follow-up time of 9.4 months, actuarial local control was 81% after 1 year. There was a statistically significant dose and size dependency of local tumor control. Median actuarial survival after treatment was 10.6 months. Patients without extracerebral tumor manifestation showed a superior survival (p = 0.04). Conclusions: Despite high local tumor control rates, the prognosis of patients with cerebral metastases of malignant melanoma remains poor. Stereotactic radiosurgery has the potential of stabilizing or improving neurologic symptoms in these patients in a palliative setting.Ziel: Die stereotaktische Radiochirurgie hat sich als Alternative zur neurochirurgischen Exzision bei der Behandlung zerebraler Metastasen erwiesen. Wir analysierten retrospektiv den Verlauf und prognostische Faktoren bei Patienten, die wegen Hirnmetastasen bei malignem Melanom in Heidelberg stereotaktisch behandelt wurden. Patienten und Methodik: Zwischen 1986 und 2000 wurden insgesamt 122 Hirnmetastasen bei 64 Patienten mit metastasiertem malignem Melanom mit einer stereotaktischen Einzeitbestrahlung behandelt. Zwölf Patienten (19%) zeigten zum Zeitpunkt der Therapie neurologische Symptome. 46 Patienten hatten zum Therapiezeitpunkt extrazerebrale Tumormanifestationen. Die mediane Dosis, die auf die tumorumschließende 80%-Isodose appliziert wurde, betrug 20 Gy (Spannweite 15–22 Gy). Ergebnisse: Die neurologischen Symptome besserten sich bei fünf der zwölf symptomatischen Patienten. 41 Patienten blieben während der weiteren Nachbeobachtung neurologisch asymptomatisch oder stabil. Eine vorübergehende neurologische Symptomverschlechterung ohne Tumorprogression zeigte sich bei fünf Patienten (8%). Die aktuarische lokale Tumorkontrolle lag, mit einer mittleren Nachbeobachtungszeit von 9,4 Monaten, nach 1 Jahr bei 81%. Die lokale Tumorkontrolle zeigte sich statistisch signifikant abhängig von der Höhe der applizierten Dosis und der Größe der Metastasen. Das mediane Überleben nach Therapie lag bei 10,6 Monaten. Das Fehlen einer extrazerebralen Tumormanifestation war mit einem verlängerten Überleben assoziiert (p = 0,04). Schlussfolgerungen: Patienten mit zerebral metastasiertem malignem Melanom haben trotz hoher zerebraler lokaler Tumorkontrollwahrscheinlichkeit eine schlechte Prognose, insbesondere bei zusätzlicher extrazerebraler Tumorlast. In palliativer Zielsetzung bietet die stereotaktische Einzeitbestrahlung die Möglichkeit, neurologische Symptome positiv zu beeinflussen.

Seltene Tumoren des Integuments

An der Haut manifestieren sich die häufigsten Malignome des Menschen, die epidermalen Plattenepithel- und Basalzellkarzinome, sowie auch maligne Melanome mit steigender Inzidenz. Darüber hinausgehend sind eine beträchtliche Zahl weiterer, verschiedenartigster, jedoch vergleichsweise seltener Tumore am Integument zu beobachten. Das vor allem histologisch bunte Bild resultiert aus Gewebsanteilen meso- und ektodermalen Ursprungs, welche in ausgesprochener Differenzierungsvielfalt die Haut und Unterhaut konstituieren. Bedenkt man beispielsweise, daß sich allein die Haar-Talgdrüsen-Einheit, eines der prominentesten Adnexorgane der Haut, aus mehr als 20 verschiedenen Zellpopulationen mit teilweise pluripotenten Differenzierungseigenschaften zusammensetzt, wird die histogenetische Potenz des Integuments zu einer extrem facettenreichen Tumorausprägung verständlich. In diesem Artikel sollen die häufigsten dieser seltenen malignen Hauttumoren systematisch nach ihren Ursprungsgeweben dargestellt werden, dabei übergehend von den Neubildungen epithelialen zu denen mesenchymalen Ursprungs und abschließend mit den erst sekundär in der Haut enstehenden Malignomen.