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Cancer immunotherapy: moving beyond current vaccines 总被引:31,自引:0,他引:31
Great progress has been made in the field of tumor immunology in the past decade, but optimism about the clinical application of currently available cancer vaccine approaches is based more on surrogate endpoints than on clinical tumor regression. In our cancer vaccine trials of 440 patients, the objective response rate was low (2.6%), and comparable to the results obtained by others. We consider here results in cancer vaccine trials and highlight alternate strategies that mediate cancer regression in preclinical and clinical models. 相似文献
5.
Borbulevych OY Insaidoo FK Baxter TK Powell DJ Johnson LA Restifo NP Baker BM 《Journal of molecular biology》2007,372(5):1123-1136
Small structural changes in peptides presented by major histocompatibility complex (MHC) molecules often result in large changes in immunogenicity, supporting the notion that T cell receptors are exquisitely sensitive to antigen structure. Yet there are striking examples of TCR recognition of structurally dissimilar ligands. The resulting unpredictability of how T cells will respond to different or modified antigens impacts both our understanding of the physical bases for TCR specificity as well as efforts to engineer peptides for immunomodulation. In cancer immunotherapy, epitopes and variants derived from the MART-1/Melan-A protein are widely used as clinical vaccines. Two overlapping epitopes spanning amino acid residues 26 through 35 are of particular interest: numerous clinical studies have been performed using variants of the MART-1 26-35 decamer, although only the 27-35 nonamer has been found on the surface of targeted melanoma cells. Here, we show that the 26-35 and 27-35 peptides adopt strikingly different conformations when bound to HLA-A2. Nevertheless, clonally distinct MART-1(26/27-35)-reactive T cells show broad cross-reactivity towards these ligands. Simultaneously, however, many of the cross-reactive T cells remain unable to recognize anchor-modified variants with very subtle structural differences. These dichotomous observations challenge our thinking about how structural information on unligated peptide/MHC complexes should be best used when addressing questions of TCR specificity. Our findings also indicate that caution is warranted in the design of immunotherapeutics based on the MART-1 26/27-35 epitopes, as neither cross-reactivity nor selectivity is predictable based on the analysis of the structures alone. 相似文献
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Broad Complex (BRC) is an essential ecdysone-pathway gene required for entry into and progression through metamorphosis in Drosophila melanogaster. Mutations of three BRC complementation groups cause numerous phenotypes, including a common suite of morphogenesis defects involving central nervous
system (CNS), adult salivary glands (aSG), and male genitalia. These defects are phenocopied by the juvenile hormone mimic
methoprene. Four BRC isoforms are produced by alternative splicing of a protein-binding BTB/POZ-encoding exon (BTB
BRC
) to one of four tandemly duplicated, DNA-binding zinc-finger-encoding exons (Z1
BRC
, Z2
BRC
, Z3
BRC
, Z4
BRC
). Highly conserved orthologs of BTB
BRC
and all four Z
BRC
were found among published cDNA sequences or genome databases from Diptera, Lepidoptera, Hymenoptera, and Coleoptera, indicating
that BRC arose and underwent internal exon duplication before the split of holometabolous orders. Tramtrack subfamily members, abrupt, tramtrack, fruitless, longitudinals lacking (lola), and CG31666 were characterized throughout Holometabola and used to root phylogenetic analyses of Z
BRC
exons, which revealed that the Z
BRC
clade includes Z
abrupt
. All four Z
BRC
domains, including Z4
BRC
, which has no known essential function, are evolving in a manner consistent with selective constraint. We used transgenic
rescue to explore how different BRC isoforms contribute to shared tissue-morphogenesis functions. As predicted from earlier
studies, the common CNS and aSG phenotypes were rescued by BRC-Z1 in rbp mutants, BRC-Z2 in br mutants, and BRC-Z3 in 2Bc mutants. However, the isoforms are required at two different developmental stages, with BRC-Z2 and -Z3 required earlier than
BRC-Z1. The sequential action of BRC isoforms indicates subfunctionalization of duplicated Z
BRC
exons even when they contribute to common developmental processes.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
8.
Soon-Il Kim Je-Won Jung Young-Joon Ahn Linda L. Restifo Hyung-Wook Kwon 《Journal of Asia》2011,14(4):509-517
The fruit fly, Drosophila melanogaster, has been intensively used as a genetic model system for basic and applied research on human neurological diseases because of advantages over mammalian model systems such as ease of laboratory maintenance and genetic manipulations. Disease-associated gene mutations, whether endogenous or transgenically-inserted, often cause phenotypes in vivo that are similar to the clinical features of the human disorder. The Drosophila genome is simpler than that of mammals, in terms of gene and chromosome number, but nonetheless demonstrates extraordinary phylogenetic conservation of gene structure and function, especially notable among the genes whose mutations cause neurodevelopmental, neuropsychiatric, or neurodegenerative disorders. In addition, its well-established neuroanatomical, developmental, and molecular genetic research techniques allow many laboratories worldwide to study complex biological and genetic processes. Based on these merits of the Drosophila model system, it has been used for screening lifespan expansion and neuroprotective activities of plant extracts or their secondary metabolites to counteract pathological events such as mitochondrial damage by oxidative stress, which may cause sporadic neurodegenerative diseases. In this review, we have summarized that the fruit fly can be used for early-stage drug discovery and development to identify novel plant-derived compounds to protect against neurodegeneration in Alzheimer's disease and Parkinson's disease, and other neurological disorders caused by oxidative stress. Thus, the Drosophila system can directly or indirectly contribute to translational research for new therapeutic strategies to prevent or ameliorate neurodegenerative diseases. 相似文献
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Background
Distance-based methods are popular for reconstructing evolutionary trees thanks to their speed and generality. A number of methods exist for estimating distances from sequence alignments, which often involves some sort of correction for multiple substitutions. The problem is to accurately estimate the number of true substitutions given an observed alignment. So far, the most accurate protein distance estimators have looked for the optimal matrix in a series of transition probability matrices, e.g. the Dayhoff series. The evolutionary distance between two aligned sequences is here estimated as the evolutionary distance of the optimal matrix. The optimal matrix can be found either by an iterative search for the Maximum Likelihood matrix, or by integration to find the Expected Distance. As a consequence, these methods are more complex to implement and computationally heavier than correction-based methods. Another problem is that the result may vary substantially depending on the evolutionary model used for the matrices. An ideal distance estimator should produce consistent and accurate distances independent of the evolutionary model used. 相似文献10.