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Overwijk W.W., Theoret M.R., Finkelstein S.E., Surman D.R., de Jong L.A., Vyth-Dreese F.A., Dellemijn T.A., Antony P.A., Spiess P.J., Palmer D.C., et al. Tumor regression and autoimmunity after reversal of a functionally tolerant state of self-reactive CD8+ T cells. J Exp Med 198 (2003) 569-580. The first study in which TCR-transgenic T-cells targeting a natural tumor antigen were used for adoptive transfer experiments. All prior studies made use of TCR-transgenic T-cells targeting engineered auto-antigens, such as the OT-1/ovalbumin combination. The gp100-specific TCR was isolated from wild type, gp100-expressing mice. The poor binding of the murine gp100 epitope to MHC class I offers the most plausible explanation for escape of this high affinity TCR from thymic deletion, in spite of reported expression of gp100 by mTEC.
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This paper concludes a long stretch of papers suggesting that CEA-specific T-cell responses can be instrumental in selective eradication of CEA-overexpressing tumors in CEA-transgenic mice, and is the first one to acknowledge a role of T-cell responses against non-self-antigens. The authors propose that the CD8+ T-cell response against the retroviral antigen (the same as found described in Ref. [48]) is a result of antigen-spreading, due to killing of tumor cells by the CEA-specific response. More likely, the response against the retroviral antigen was primed as a result of tumor cell injection. Shortly after injection of transplantable tumor cells, many of these cells die. As such, they constitute a tumor cell vaccine that can result in, albeit inefficient, T-cell priming.
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Importantly, CEA-expression in the thymi of CEA-transgenic mice is mirrored by expression of this gene in human thymi, suggesting that the human CEA-specific T-cell repertoire is similarly blunted by central tolerance.
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This paper confirms that CEA is expressed in the human thymus. Furthermore, authors propose that, due to expression of highly glycosylated MUC1 in thymus, T-cell precursors recognizing hypoglycosylated peptides that may be presented by tumor cells (see also Ref. [50]) could escape thymic deletion.
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This paper shows that adoptive transfer of MUC1-specific T-cells does not result in toxicity. The quintessential experiment lacking from this paper is one that demonstrates tumor clearance by the adoptively transferred MUC1-specific T-cells.
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Turner M.S., Cohen P.A., and Finn O.J. Lack of effective MUC1 tumor antigen-specific immunity in MUC1-transgenic mice results from a Th/T regulatory cell imbalance that can be corrected by adoptive transfer of wild-type Th cells. J Immunol 178 (2007) 2787-2793. This paper shows that adoptive transfer of MUC1-specific T-cells does not result in toxicity. The quintessential experiment lacking from this paper is one that demonstrates tumor clearance by the adoptively transferred MUC1-specific T-cells.
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A pioneering study that, even though not perfect in design, demonstrated the feasibility of TCR gene therapy in human cancer patients. Two striking aspect of this study are the following. First, in vivo persistence of adoptively transferred T-cells appears much better if ex vivo expansion phase is kept as short as possible, in line with similar findings in mouse models. Secondly, the two patients showing objective regression were not reported to display any treatment-related signs of auto-immune skin depigmentation. This would be expected if infused T-cells were highly reactive against the MART-1 antigen. The lack of depigmentation is in line with the notion that the MART-1-specific TCR used was of limited affinity (see Ref. [84]).
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Morgan R.A., Dudley M.E., Wunderlich J.R., Hughes M.S., Yang J.C., Sherry R.M., Royal R.E., Topalian S.L., Kammula U.S., Restifo N.P., et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314 (2006) 126-129. A pioneering study that, even though not perfect in design, demonstrated the feasibility of TCR gene therapy in human cancer patients. Two striking aspect of this study are the following. First, in vivo persistence of adoptively transferred T-cells appears much better if ex vivo expansion phase is kept as short as possible, in line with similar findings in mouse models. Secondly, the two patients showing objective regression were not reported to display any treatment-related signs of auto-immune skin depigmentation. This would be expected if infused T-cells were highly reactive against the MART-1 antigen. The lack of depigmentation is in line with the notion that the MART-1-specific TCR used was of limited affinity (see Ref. [84]).
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Science
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Preclinical proof of concept study demonstrating the efficacy and safety of cancer targeting through an - albeit engineered - prostate-specific antigen.
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de Witte M.A., Bendle G.M., van den Boom M.D., Coccoris M., Schell T.D., Tevethia S.S., van Tinteren H., Mesman E.M., Song J.Y., and Schumacher T.N. TCR gene therapy of spontaneous prostate carcinoma requires in vivo T cell activation. J Immunol 181 (2008) 2563-2571. Preclinical proof of concept study demonstrating the efficacy and safety of cancer targeting through an - albeit engineered - prostate-specific antigen.
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