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Olivera J. Finn

Bio: Olivera J. Finn is an academic researcher from University of Pittsburgh. The author has contributed to research in topics: Antigen & Cancer. The author has an hindex of 54, co-authored 197 publications receiving 11636 citations.


Papers
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Journal ArticleDOI
TL;DR: The findings reflect the current status of the cancer vaccine field, highlight the possibility that additional organized efforts and funding would accelerate the development of therapeutically effective cancer vaccines, and accentuate the need for prioritization.
Abstract: The purpose of the National Cancer Institute pilot project to prioritize cancer antigens was to develop a well-vetted, priority-ranked list of cancer vaccine target antigens based on predefined and preweighted objective criteria. An additional aim was for the National Cancer Institute to test a new approach for prioritizing translational research opportunities based on an analytic hierarchy process for dealing with complex decisions. Antigen prioritization involved developing a list of "ideal" cancer antigen criteria/characteristics, assigning relative weights to those criteria using pairwise comparisons, selecting 75 representative antigens for comparison and ranking, assembling information on the predefined criteria for the selected antigens, and ranking the antigens based on the predefined, preweighted criteria. Using the pairwise approach, the result of criteria weighting, in descending order, was as follows: (a) therapeutic function, (b) immunogenicity, (c) role of the antigen in oncogenicity, (d) specificity, (e) expression level and percent of antigen-positive cells, (f) stem cell expression, (g) number of patients with antigen-positive cancers, (h) number of antigenic epitopes, and (i) cellular location of antigen expression. None of the 75 antigens had all of the characteristics of the ideal cancer antigen. However, 46 were immunogenic in clinical trials and 20 of them had suggestive clinical efficacy in the "therapeutic function" category. These findings reflect the current status of the cancer vaccine field, highlight the possibility that additional organized efforts and funding would accelerate the development of therapeutically effective cancer vaccines, and accentuate the need for prioritization.

1,222 citations

Journal Article
TL;DR: It is shown that freshly obtained granulocytes from healthy donors, if activated, can also inhibit cytokine production by T cells, and that granulocyte-derived H( 2)O(2) is the major cause of severe systemic T-cell suppression.
Abstract: Impaired T-cell function in patients with advanced cancer has been a widely acknowledged finding, but mechanisms reported thus far are those primarily operating in the tumor microenvironment. Very few mechanisms have been put forth to explain several well-described defects in peripheral blood T cells, such as reduction in expression of signaling molecules, decreased production of cytokines, or increased apoptosis. We have closely examined the peripheral blood mononuclear cell (PBMC) samples derived from patients and healthy individuals, and we have observed an important difference that may underlie the majority of reported defects. We observed that in samples from patients only, an unusually large number of granulocytes copurify with low density PBMCs on a density gradient rather than sediment, as expected, to the bottom of the gradient. We also show that activating granulocytes from a healthy donor with N-formyl-L-methionyl-L-leucyl-L-phenylalanine could also cause them to sediment aberrantly and copurify with PBMCs, suggesting that density change is a marker of their activation. To confirm this, we looked for other evidence of in vivo granulocyte activation and found it in drastically elevated plasma levels of 8-isoprostane, a product of lipid peroxidation and a marker of oxidative stress. Reduced T-cell receptor zeta chain expression and decreased cytokine production by patients' T cells correlated with the presence of activated granulocytes in their PBMCs. We showed that freshly obtained granulocytes from healthy donors, if activated, can also inhibit cytokine production by T cells. This action is abrogated by the addition of the hydrogen peroxide (H(2)O(2)) scavenger, catalase, implicating H(2)O(2) as the effector molecule. Indeed, when added alone, H(2)O(2) could suppress cytokine production of normal T cells. These findings indicate that granulocytes are activated in advanced cancer patients and that granulocyte-derived H(2)O(2) is the major cause of severe systemic T-cell suppression.

851 citations

Journal ArticleDOI
TL;DR: The common and the unique challenges to cancer vaccines and the progress that has been made in meeting them are addressed.
Abstract: Whether vaccines are designed to prepare the immune system for the encounter with a pathogen or with cancer, certain common challenges need to be faced, such as what antigen and what adjuvant to use, what type of immune response to generate and how to make it long lasting. Cancer, additionally, presents several unique hurdles. Cancer vaccines must overcome immune suppression exerted by the tumour, by previous therapy or by the effects of advanced age of the patient. If used for cancer prevention, vaccines must elicit effective long-term memory without the potential of causing autoimmunity. This article addresses the common and the unique challenges to cancer vaccines and the progress that has been made in meeting them. Considering how refractory cancer has been to standard therapy, efforts to achieve immune control of this disease are well justified.

615 citations

Journal ArticleDOI
TL;DR: Detailed studies performed with one of the cytotoxic T-cell lines from pancreatic cancer patients show that it recognizes a specific antigen, a large and heavily glycosylated mucin molecule, expressed on pancreatic and breast tumors and tumor cell lines.
Abstract: We have previously reported the establishment of cytotoxic T-cell lines from pancreatic cancer patients, by continuously stimulating tumor-draining lymph node cells with allogeneic pancreatic tumor cell lines. After the preliminary characterization of their phenotype and tumor specificity, detailed studies performed with one of the cell lines, W.D., show that it recognizes a specific antigen, a large and heavily glycosylated mucin molecule, expressed on pancreatic and breast tumors and tumor cell lines. Although this recognition appears major histocompatibility complex (MHC)-unrestricted, the antigen receptor used by the cytotoxic T cell is the alpha/beta heterodimer, typically found on MHC-restricted T cells. The target antigen is atypical, however, in its ability to directly bind and activate the T cells in the absence of self MHC, presumably by abundant and regularly repeated antigenic epitopes. These findings are important because they demonstrate a specific T-cell response against a human tumor-associated antigen. In addition to pancreatic and breast tumors, various mucin molecules are known to be produced by other tumors of epithelial cell origin and could be expected to stimulate similar T-cell-mediated immune responses.

480 citations

Journal Article
TL;DR: The data suggest that the highly repetitive nature of the mucin allows cross-linking of the T-cell receptor on mucin-specific T-cells and therefore accounts for the lack of MHC restriction seen in the tumor-reactive CTLs of patients with breast adenocarcinoma.
Abstract: A population of tumor-reactive cytotoxic T-cells can be propagated from tumor-draining lymph nodes of patients with breast adenocarcinoma. These T-cells specifically recognize breast and pancreatic tumor cells in a major histocompatibility complex (MHC)-unrestricted fashion but not other tumors of epithelial origin or the natural killer target K562. The tumor-specific but MHC-unrestricted lytic activity of these cytotoxic T-lymphocytes (CTLs) is mediated through the alpha/beta T-cell receptor. The molecule recognized by these CTLs is ductal epithelial mucin produced by breast and pancreatic adenocarcinomas. The protein core of the mucin consists of multiple tandem repeats of a 20-amino acid sequence. Antibody SM3, directed against a determinant on the mucin protein core preferentially expressed on malignant cells is able to significantly inhibit lysis of tumor cells by the CTL, while other antibodies binding to different core epitopes are not. Normal breast epithelial lines, which also express mucin but not the SM3 epitope, are not lysed by these tumor-reactive CTLs or act as cold target inhibitors of lysis of tumor lines. The data suggest that the highly repetitive nature of the mucin allows cross-linking of the T-cell receptor on mucin-specific T-cells and therefore accounts for the lack of MHC restriction seen in this system. They further suggest that the mucin core epitope recognized on tumor cells is not expressed on normal epithelial cells in a manner that can be recognized by tumor-reactive CTLs. These findings support the role of mucins as important tumor-associated antigens mediating the cellular response to certain human cancers and suggest that epithelial mucin core sequences might form the basis for an effective vaccine to augment the antitumor immune response.

370 citations


Cited by
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Journal ArticleDOI
TL;DR: The origin, mechanisms of expansion and suppressive functions of MDSCs, as well as the potential to target these cells for therapeutic benefit are discussed.
Abstract: Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that expand during cancer, inflammation and infection, and that have a remarkable ability to suppress T-cell responses. These cells constitute a unique component of the immune system that regulates immune responses in healthy individuals and in the context of various diseases. In this Review, we discuss the origin, mechanisms of expansion and suppressive functions of MDSCs, as well as the potential to target these cells for therapeutic benefit.

5,811 citations

Journal ArticleDOI
25 Mar 2011-Science
TL;DR: A unifying conceptual framework called “cancer immunoediting,” which integrates the immune system’s dual host-protective and tumor-promoting roles is discussed.
Abstract: Understanding how the immune system affects cancer development and progression has been one of the most challenging questions in immunology. Research over the past two decades has helped explain why the answer to this question has evaded us for so long. We now appreciate that the immune system plays a dual role in cancer: It can not only suppress tumor growth by destroying cancer cells or inhibiting their outgrowth but also promote tumor progression either by selecting for tumor cells that are more fit to survive in an immunocompetent host or by establishing conditions within the tumor microenvironment that facilitate tumor outgrowth. Here, we discuss a unifying conceptual framework called "cancer immunoediting," which integrates the immune system's dual host-protective and tumor-promoting roles.

5,026 citations

Journal ArticleDOI
TL;DR: Known discrepancies in both innate and adaptive immunity are outlined, including balance of leukocyte subsets, defensins, Toll receptors, inducible NO synthase, the NK inhibitory receptor families Ly49 and KIR, FcR, Ig subsets andChemokine and chemokine receptor expression.
Abstract: Mice are the experimental tool of choice for the majority of immunologists and the study of their immune responses has yielded tremendous insight into the workings of the human immune system. However, as 65 million years of evolution might suggest, there are significant differences. Here we outline known discrepancies in both innate and adaptive immunity, including: balance of leukocyte subsets, defensins, Toll receptors, inducible NO synthase, the NK inhibitory receptor families Ly49 and KIR, FcR, Ig subsets, the B cell (BLNK, Btk, and lambda5) and T cell (ZAP70 and common gamma-chain) signaling pathway components, Thy-1, gammadelta T cells, cytokines and cytokine receptors, Th1/Th2 differentiation, costimulatory molecule expression and function, Ag-presenting function of endothelial cells, and chemokine and chemokine receptor expression. We also provide examples, such as multiple sclerosis and delayed-type hypersensitivity, where complex multicomponent processes differ. Such differences should be taken into account when using mice as preclinical models of human disease.

3,098 citations

Journal ArticleDOI
TL;DR: This work considers myeloid cells as an intricately connected, complex, single system and focuses on how tumours manipulate the myeloids system to evade the host immune response.
Abstract: Here, the authors discuss how the immune activities of myeloid cells, such as macrophages and dendritic cells, are affected by the immunosuppressive tumour environment. They propose that tumours can evade the immune system by promoting aberrant differentiation and function of the entire myeloid system.

2,966 citations

Journal ArticleDOI
Carl Nathan1
TL;DR: Neutrophils inform and shape immune responses, contribute to the repair of tissue as well as its breakdown, use killing mechanisms that enrich the concepts of specificity, and offer exciting opportunities for the treatment of neoplastic, autoinflammatory and autoimmune disorders.
Abstract: Scientists who study neutrophils often have backgrounds in cell biology, biochemistry, haematology, rheumatology or infectious disease. Paradoxically, immunologists seem to have a harder time incorporating these host-defence cells into the framework of their discipline. The recent literature discussed here indicates that it is appropriate for immunologists to take as much interest in neutrophils as in their lymphohaematopoietic cousins with smooth nuclei. Neutrophils inform and shape immune responses, contribute to the repair of tissue as well as its breakdown, use killing mechanisms that enrich our concepts of specificity, and offer exciting opportunities for the treatment of neoplastic, autoinflammatory and autoimmune disorders.

2,620 citations