A N Houghton

..The view of what the immune system can see is extending to mutations and parts of the genome that are normally invisible...

..Further studies of these selected novel STS antigens are warranted to identify and characterize potential antigen targets expressed by STS...

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..These are surprising observations, linking antibodies of the adaptive immune system to innate immune responses that drive epithelial carcinogenesis...

..Tumor endothelial marker 8 (TEM8) is expressed in the neovasculature of human tumors, and in the mouse melanoma B16, but its expression is limited in normal adult tissues. We describe a DNA vaccine combining xenogeneic tumor Ag and TEM8...

..These results show that immunity to TRP-2 following DNA immunization uses an IFN-gamma-dependent Th1 pathway, but immunity to gp75/TRP-1 is down-regulated by IFN-gamma...

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..1/2,000 in the second patient. These results demonstrate that modest expansion of peptide-specific CD8(+) T cells can be generated in vivo by immunization with peptide plus QS-21 in at least a subset of patients with melanoma...

..These studies demonstrate that ADAbp expression is lost with malignant transformation of melanocytes, presumably at an early stage in the transformation process...

..Tumor endothelial marker 8 (TEM8) is expressed in the neovasculature of human tumors, and in the mouse melanoma B16, but its expression is limited in normal adult tissues. We describe a DNA vaccine combining xenogeneic tumor Ag and TEM8...

..Insect cells expressing human HLA molecules provide a standard APC for monitoring CD8(+) T cell responses to tumor and viral peptides during immunotherapy...

..This HLA-matched APC line can be adapted to other HLA haplotypes, and has advantages for monitoring clinical trials of immunotherapy with limited availability of autologous APC and PBMC from patients...

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..Different glycan sites on the same tyrosinase family polypeptide can perform distinct functions, and conserved sites on tyrosinase family paralogues can perform different functions...

..e., antibody versus CD8(+) T cell. However, both pathways led to tumor immunity and identical phenotypic manifestations of autoimmunity...

..These findings show that ADAbp is a cell surface ectopeptidase that is tightly regulated during neoplastic transformation of melanocytes...

..These studies provided the impetus for development of a xenogeneic DNA vaccine program in CMM...

..Affinity column purification supported the specificity of IgM antibodies for globo H. On the basis of these data, globo H will constitute one component of a polyvalent vaccine for evaluation in high-risk breast cancer patients...

..Thus, by cytotoxicity assays, shared Ags were only recognized on melanoma cells but not on normal melanocytes. In summary, this analysis shows that melanoma cells share an Ag that is presented by HLA-DR15...

..The brown locus determines coat color in the mouse, suggesting that gp75 regulates or influences the type of melanin synthesized...

..The 9p region has been reported to be nonrandomly altered in human melanoma, suggesting a role for the region near the TYRP locus in melanocyte transformation...

..Most interestingly, the onset of antibody induction in these three dogs coincides with observed clinical responses and may suggest a means to account for their long-term tumor control and survival...

..LCs, transduced with a retroviral vector encoding full-length Ag, stimulate potent CTLs directed against multiple epitopes in a CD4(+) Th cell-dependent manner...

..Thus, presentation of a vast repertoire of antigen variants to the immune system can enhance the generation of adaptive immune responses to self...

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..The purpose of this study was to compare viral and plasmid DNA in combination vaccination strategies in the context of a tumor antigen...

..Later, in the battle of Marathon described by Herodotus, the Greeks learned the advantages of multipronged attacks, a strategy still used in modern warfare. Is the immune system similar in its approach to combatting pathogens or tumors?..

..Finally, this effect on vaccine-induced CD8(+) T-cell responses was partially independent of CD4(+) T cells (both helper and regulatory), consistent with a direct costimulatory effect on the effector CD8(+) cells themselves...

..Cloned cdr2-specific TCR genes provide a clinically relevant means for immunologic targeting of human gynecologic cancers...

..HER2/neu is frequently overexpressed in breast cancer. In a mouse model, vaccination with HER2/neu DNA elicits antibodies that confer partial protection against tumor challenge...

..Mouse and human TYR DNA vaccines were found safe and induced CD8(+) T-cell responses in 7 of 18 patients. T cells recognizing a native TYR peptide had a phenotype consistent with that of effector memory cells...

..We reviewed a contemporary, single-institution experience to evaluate the natural history of stage-IV melanoma metastatic to the lung and identify factors predictive of survival...

..These data demonstrate that this approach can serve as the basis of epitope-engineering against cancer and intracellular pathogens...

..To determine the clinical toxicities and antibody response against sTn and tumor cells expressing sTn following immunization of high-risk breast cancer patients with clustered sTn-KLH [sTn(c)-KLH] conjugate plus QS-21...

..Therefore, the efficacy and safety of temozolomide in combination with pegylated IFN-alpha-2b in patients with metastatic melanoma without brain metastases was investigated...

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..These observations provide little support for the use of this combination for melanoma brain metastases unless safe and effective methods to prevent thrombosis are developed...

..These results demonstrate that DNA immunization against tissue-restricted Ags after allogeneic T cell-depleted HSCT can induce potent antitumor effects without causing GVHD...

..Thus, we conclude that overall, GITR stimulation overcomes self-tolerance/ignorance and enhances T cell-mediated antitumor activity with minimal autoimmunity...

..Therefore large fusion vector panels such as those presented here can provide information to promote the successful advancement of gene-based vaccines...

..The current Phase II study examined the efficacy and safety of this combination in chemotherapy-naive patients with brain metastases...

..Vitiligo (autoimmune hypopigmentation) can be mediated by T cells, FcgammaR+macrophages and/or complement...

..This represents an example of intermolecular determinant recognition, but is not simply due to epitope spreading since antibodies against the antigen targeted by DNA vaccination are not typically detected...

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..CCS/MSP also has typical melanoma features, including immunoreactivity for S100 and HMB45, pigmentation, MITF-M expression, and a propensity for regional lymph node metastases...

..These studies provided the rationale for a trial of xenogeneic DNA vaccination in CMM using the human tyrosinase gene...

..CD8(+) T-cell responses were readily induced in TLR4-deficient mice immunized with DNA depleted of LPS. LPS in DNA vaccines is not required for CD8(+) T-cell responses...

..Autoimmunity uses similar mechanisms as tumor immunity, but tumor immunity and autoimmunity can uncouple. These studies open up strategies for active immunization against cancer...

..Thus, either complement or macrophages expressing activating Fc gamma R can independently and alternatively mediate disease in a model of autoimmune vitiligo...

..To establish a safe and tolerated regimen of an oral cytotoxic agent, temozolomide, and a cytostatic agent, thalidomide, in patients with unresectable stage III or IV malignant melanoma...

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..These results have implications for understanding early events in the immune response to DNA vaccines, and provide a basis for development of new approaches to cancer vaccines, including the use of cytokine genes as adjuvants...

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..These results establish the basis for clinical trials to test PSMA DNA vaccines in patients with solid tumors that either express PSMA directly or that depend on normal endothelial cells expressing PSMA for their continued growth...

..These results show that active immunization with xenogeneic DNA vaccines can induce CD8+ T cell-dependent immunity against CD20...

..These results show that regulatory T cells are the major regulators of concomitant tumor immunity against this weakly immunogenic tumor...

..Our findings indicate that GITR has opposite effects on the regulation of alloreactive CD4(+) and CD8(+) T cells...

..These results show that expression of FAP is a tumor suppressor that abrogates tumorigenicity through regulation of cell growth and survival...

..Based on these pre-clinical studies, we suggest that anti-CTLA-4 should be tested with xenogeneic DNA vaccines against cancer and that special attention should be given to sequence and schedule of administration...

..Thus, DPPIV functions as a tumor suppressor, and its downregulation may contribute to the loss of growth control in NSCLC cells...

..Studies examining the molecular basis for immunogenicity of conserved paralogues are facilitating the development of new strategies to rationally design vaccines that trigger adaptive immune responses to cancer...

..To further investigate the efficacy and safety of temozolomide plus thalidomide in patients with metastatic melanoma without brain metastases...

..In conclusion, we showed gene expression profiling to be useful in classification and diagnosis, providing insights into pathogenesis and pointing to potential new therapeutic targets of soft tissue sarcoma...

..Crucial to these approaches is the discovery and understanding of the molecular identity of antigens and the mechanisms involved in tumor immunity. In this review, strategies to overcome immune ignorance and tolerance are discussed...

..Our data show that BRAF mutation is common in melanoma metastases, regardless of their site, that mutations include both exons 11 and 15, and suggest that anti-RAS/RAF strategies may be effective in metastatic melanoma patients...

..The overall goal of this grant is to develop more effective strategies to use the immune system to recognize specific targets present on melanoma cells. ..

..In aim 4, we will continue to create more relevant mouse models of melanoma that develop endogenous invasive melanomas to study tumor immunity against differentiation and mutant antigens. ..

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..and 3) Develop mouse models that develop endogenous invasive melanomas and study immunity against differentiation antigens at different steps in tumor progression. ..

..These studies will give insights into immune recognition of differentiation and tumor-specific antigens expressed by cancer cells and provide strategies for construction of cancer vaccines...

..The overall goal of this grant is to develop more effective strategies to use the immune system to recognize specific targets present on melanoma cells. ..