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PDF file - 31K, Polyfunctional analysis of vaccine-induced T-cell cultures

PDF file - 64K, Analysis of chemokine receptor expression

PDF file - 90K

PDF file - 66K, Correlations between multiple immunological parameters and DFS

PDF file - 44K, Patient characteristics

PDF file - 54K, Flow diagram for phase II randomized trial of adjuvanted multipeptide vaccination

PDF file - 100K, Assessment of peptide-specific recognition by in vitro short-term peptide sensitization assay (IVS)

PDF file - 56K, Number of IFNγ-forming spots/2 � 105 CD8+ T cells in APL-vaccinated patients

Purpose: The progressive immune dysfunctions that occur in patients with advanced melanoma make them unlikely to efficiently respond to cancer vaccines. A multicenter randomized phase II trial was conducted to test whether immunization with modified HLA class I tumor peptides in the context of adjuvant therapy results in better immunologic responses and improved clinical outcomes in patients with early melanoma (stages IIB/C-III).Experimental Design: Forty-three patients were enrolled to undergo vaccination (n = 22) or observation (n = 21). The vaccine included four HLA-A*0201–restricted modified peptides (Melan-A/MART-1[27L], gp100[210M], NY-ESO-1[165V], and Survivin[97M]) emulsified in Montanide ISA51 and injected subcutaneously in combination with cyclophosphamide (300 mg/m2) and low-dose IL-2 (3 × 106 IU). The immune responses were monitored using ex vivo IFN-γ–ELISpot, HLA/multimer staining, and in vitro short-term peptide sensitization assays.Results: Vaccination induced a rapid and persistent increase in specific effector memory CD8+ T cells in 75% of the patients. However, this immunization was not associated with any significant increase in disease-free or overall survival as compared with the observation group. An extensive immunologic analysis revealed a significantly reduced cross-recognition of the corresponding native peptides and, most importantly, a limited ability to react to melanoma cells.Conclusions: Adjuvant setting is an appealing approach for testing cancer vaccines because specific CD8+ T cells can be efficiently induced in most vaccinated patients. However, the marginal antitumor activity of the T cells induced by modified peptides in this study largely accounts for the observed lack of benefit of vaccination. These findings suggest reconsidering this immunization strategy, particularly in early disease. Clin Cancer Res; 18(23); 6485–96. ©2012 AACR.

Background: Structuring cancer care into pathways can reduce variability in clinical practice and improve patient outcomes. International benchmarking can help centers with regard to development, implementation, and evaluation. A further step in the development of multidisciplinary care is to organize care in integrated practice units (IPUs), encompassing the whole pathway and relevant organizational aspects. However, research on this topic is limited. This article describes the development and results of a benchmark tool for cancer care pathways and explores IPU development in cancer centers. Methods: The benchmark tool was developed according to a 13-step benchmarking method and piloted in 7 European cancer centers. Centers provided data and site visits were performed to understand the context in which the cancer center operates and to clarify additional questions. Benchmark data were structured into pathway development and evaluation and assessed against key IPU features. Results: Benchmark results showed that most centers have formalized multidisciplinary pathways and that care teams differed in composition, and found almost 2-fold differences in mammography use efficiency. Suggestions for improvement included positioning pathways formally and structurally evaluating outcomes at a sufficiently high frequency. Based on the benchmark, 3 centers indicating that they had a breast cancer IPU were scored differently on implementation. Overall, we found that centers in Europe are in various stages of development of pathways and IPUs, ranging from an informal pathway structure to a full IPU-type of organization. Conclusions: A benchmark tool for care pathways was successfully developed and tested, and is available in an open format. Our tool allows for the assessment of pathway organization and can be used to assess the status of IPU development. Opportunities for improvement were identified regarding the organization of care pathways and the development toward IPUs. Three centers are in varying degrees of implementation and can be characterized as breast cancer IPUs. Organizing cancer care in an IPU could yield multiple performance improvements.

Purpose: The progressive immune dysfunctions that occur in patients with advanced melanoma make them unlikely to efficiently respond to cancer vaccines. A multicenter randomized phase II trial was conducted to test whether immunization with modified HLA class I tumor peptides in the context of adjuvant therapy results in better immunologic responses and improved clinical outcomes in patients with early melanoma (stages IIB/C-III). Experimental Design: Forty-three patients were enrolled to undergo vaccination (n = 22) or observation (n = 21). The vaccine included four HLA-A*0201–restricted modified peptides (Melan-A/MART-1[27L], gp100[210M], NY-ESO-1[165V], and Survivin[97M]) emulsified in Montanide ISA51 and injected subcutaneously in combination with cyclophosphamide (300 mg/m2) and low-dose IL-2 (3 × 106 IU). The immune responses were monitored using ex vivo IFN-γ–ELISpot, HLA/multimer staining, and in vitro short-term peptide sensitization assays. Results: Vaccination induced a rapid and persistent increase in specific effector memory CD8+ T cells in 75% of the patients. However, this immunization was not associated with any significant increase in disease-free or overall survival as compared with the observation group. An extensive immunologic analysis revealed a significantly reduced cross-recognition of the corresponding native peptides and, most importantly, a limited ability to react to melanoma cells. Conclusions: Adjuvant setting is an appealing approach for testing cancer vaccines because specific CD8+ T cells can be efficiently induced in most vaccinated patients. However, the marginal antitumor activity of the T cells induced by modified peptides in this study largely accounts for the observed lack of benefit of vaccination. These findings suggest reconsidering this immunization strategy, particularly in early disease. Clin Cancer Res; 18(23); 6485–96. ©2012 AACR.

The effect of local and systemic delivery of the angiostatin gene on human melanoma growth was studied in nude mice. Liposome-coated plasmids carrying the cDNA coding for murine and human angiostatin (CMVang and BSHang) were injected weekly, locally or systemically, in mice transplanted with melanoma cells. The treatment reduced melanoma growth by 50% to 90% compared to that occurring in control animals treated with liposome-coated plasmid carrying the lacZ gene or in untreated controls. The growth of both locally injected and controlateral uninjected tumors in mice bearing two melanoma grafts was significantly suppressed after intratumoral treatment. Tumor growth inhibition was also observed in mice treated by intraperitoneal delivery, suggesting that angiostatin gene therapy acts through a systemic effect. Both melanoma growth suppression and delay in the onset of tumor growth were observed in treated mice. PCR performed on tumors and normal tissues showed that the lipofected DNA was present in tissues from treated mice, and angiostatin expression was demonstrated by RT-PCR. Histopathological analysis of melanoma nodules revealed an increase in apoptotic cells and a reduction in vessel density in tumors from treated mice. Our results suggest that systemic, liposome-mediated administration of genes coding for antiangiogenic factors represents a promising strategy for melanoma treatment in humans.