Article
Genetic engineering of T cells for adoptive immunotherapy.
Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania, 421 Curie Blvd-556 BRB II/III, Philadelphia, PA, 19104, USA.
Immunologic Research (impact factor:
3.03).
11/2008;
42(1-3):166-81.
DOI:10.1007/s12026-008-8057-6
pp.166-81
Source: PubMed
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Article: Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer.
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ABSTRACT: Although tumor-infiltrating T cells have been documented in ovarian carcinoma, a clear association with clinical outcome has not been established. We performed immunohistochemical analysis of 186 frozen specimens from advanced-stage ovarian carcinomas to assess the distribution of tumor-infiltrating T cells and conducted outcome analyses. Molecular analyses were performed in some tumors by real-time polymerase chain reaction. CD3+ tumor-infiltrating T cells were detected within tumor-cell islets (intratumoral T cells) in 102 of the 186 tumors (54.8 percent); they were undetectable in 72 tumors (38.7 percent); the remaining 12 tumors (6.5 percent) could not be evaluated. There were significant differences in the distributions of progression-free survival and overall survival according to the presence or absence of intratumoral T cells (P<0.001 for both comparisons). The five-year overall survival rate was 38.0 percent among patients whose tumors contained T cells and 4.5 percent among patients whose tumors contained no T cells in islets. Significant differences in the distributions of progression-free survival and overall survival according to the presence or absence of intratumoral T cells (P<0.001 for both comparisons) were also seen among 74 patients with a complete clinical response after debulking and platinum-based chemotherapy: the five-year overall survival rate was 73.9 percent among patients whose tumors contained T cells and 11.9 percent among patients whose tumors contained no T cells in islets. The presence of intratumoral T cells independently correlated with delayed recurrence or delayed death in multivariate analysis and was associated with increased expression of interferon-gamma, interleukin-2, and lymphocyte-attracting chemokines within the tumor. The absence of intratumoral T cells was associated with increased levels of vascular endothelial growth factor. The presence of intratumoral T cells correlates with improved clinical outcome in advanced ovarian carcinoma.New England Journal of Medicine 01/2003; 348(3):203-13. · 53.30 Impact Factor -
Article: Mesothelin: a new target for immunotherapy.
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ABSTRACT: Mesothelin is a differentiation antigen present on normal mesothelial cells and overexpressed in several human tumors, including mesothelioma and ovarian and pancreatic adenocarcinoma. The mesothelin gene encodes a precursor protein that is processed to yield the 40-kDa protein, mesothelin, attached to the cell membrane by a glycosylphosphatidyl inositol linkage and a 31-kDa shed fragment named megakaryocyte-potentiating factor. The biological function of mesothelin is not known. Mesothelin is a promising candidate for tumor-specific therapy, given its limited expression in normal tissues and high expression in several cancers. SS1(dsFv)PE38 is a recombinant anti-mesothelin immunotoxin that is undergoing clinical evaluation in patients with mesothelin-expressing tumors. There is evidence that mesothelin is an immunogenic protein and could be exploited as a therapeutic cancer vaccine. A soluble mesothelin variant has been identified and could be a useful tumor marker for malignant mesotheliomas.Clinical Cancer Research 07/2004; 10(12 Pt 1):3937-42. · 7.74 Impact Factor -
Article: High-avidity CTL exploit two complementary mechanisms to provide better protection against viral infection than low-avidity CTL.
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ABSTRACT: Previously, we observed that high-avidity CTL are much more effective in vivo than low-avidity CTL in elimination of infected cells, but the mechanisms behind their superior activity remained unclear. In this study, we identify two complementary mechanisms: 1) high-avidity CTL lyse infected cells earlier in the course of a viral infection by recognizing lower Ag densities than those distinguished by low-avidity CTL and 2) they initiate lysis of target cells more rapidly at any given Ag density. Alternative mechanisms were excluded, including: 1) the possibility that low-avidity CTL might control virus given more time (virus levels remained as high at 6 days following transfer as at 3 days) and 2) that differences in efficacy might be correlated with homing ability. Furthermore, adoptive transfer of high- and low-avidity CTL into SCID mice demonstrated that transfer of a 10-fold greater amount of low-avidity CTL could only partially compensate for their decreased ability to eliminate infected cells. Thus, we conclude that high-avidity CTL exploit two complementary mechanisms that combine to prevent the spread of virus within the animal: earlier recognition of infected cells when little viral protein has been made and more rapid lysis of infected cells.The Journal of Immunology 03/2001; 166(3):1690-7. · 5.79 Impact Factor
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Keywords
abundant proliferative reserves
ex vivo expansion protocols
gene therapy strategy wherein
HIV-1 infection
infectious diseases
intact effector functions
large numbers
Modified cells
starting cell population
T cell adoptive immunotherapy
