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T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis

Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Molecular Therapy (Impact Factor: 6.43). 12/2010; 19(3):620-6. DOI: 10.1038/mt.2010.272
Source: PubMed

ABSTRACT Autologous T lymphocytes genetically engineered to express a murine T cell receptor (TCR) against human carcinoembryonic antigen (CEA) were administered to three patients with metastatic colorectal cancer refractory to standard treatments. All patients experienced profound decreases in serum CEA levels (74-99%), and one patient had an objective regression of cancer metastatic to the lung and liver. However, a severe transient inflammatory colitis that represented a dose limiting toxicity was induced in all three patients. This report represents the first example of objective regression of metastatic colorectal cancer mediated by adoptive T cell transfer and illustrates the successful use of a TCR, raised in human leukocyte antigen (HLA) transgenic mice, against a human tumor associated antigen. It also emphasizes the destructive power of small numbers of highly avid T cells and the limitations of using CEA as a target for cancer immunotherapy.

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Available from: Nicholas P Restifo, Jul 27, 2015
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    • "It has been acting as mediator for cell adhesion on cancer cells (Hatakeyama et al., 2013). Parkhurst et al. (2011) reviewed the currently use of 31 active clinical drugs that target CEA, among 18 has target action and control the tumor development in colon cancer patients. But the other 11 drugs are in trails and have been found to less targeting CEA and lack of tumor response and related toxicities. "
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    • "Subsequent application of a higher affinity TCR against MART1 resulted in responses in 6/20 patients but anticipated 'on-target' anti-melanin complications in skin, eyes and hair were encountered (Johnson et al, 2009). Side effects were also reported following infusion of carcinoembryonic antigen-specific TCRs for colorectal carncinoma , where bowel inflammation developed after therapy (Parkhurst et al, 2011). Minor toxicity was reported in another study that targeted the cancer-testis antigen NY- ESO-1 with notable tumour regression in patients with melanoma and synovial cell carcinoma (Robbins et al, 2011). "
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    • "In one report, three patients with metastatic colorectal cancer were treated with T cells expressing TCRs specific for CEA, a protein that is overexpressed in these tumors but is also expressed in the normal epithelial cells of the gastrointestinal tract. Despite one patient achieving objective responses, all three patients developed severe inflammatory colitis and the study was closed [19]. Recently, two reports using TCR-modified T cells recognizing the MAGE-A3 antigen led to four deaths (2 in each study) owing to different mechanisms. "
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