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: 6.23). 12/2010; 19(3):620-6. DOI: 10.1038/mt.2010.272
Source: PubMed


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
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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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    • "Genetic engineering technologies that allow for the redirection of lymphocytes to recognize and target a variety of tumor antigens has created new possibilities for the utilization of immunotherapy to treat metastatic cancer. T cell receptor (TCR) genes that target specific tumor antigens have been inserted into peripheral blood lymphocytes (PBL) and, when transfused back into patients in conjunction with administration of high-dose interleukin-2 after non-myeloablative chemotherapy, have been shown to effect tumor regression in patients with melanoma and synovial cell sarcoma [2-5]. Chimeric antigen receptors (CARs) have also been investigated as an alternative way to redirect T cells to recognize and destroy tumor cells. "
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    ABSTRACT: Background The development of immunotherapy has led to significant progress in the treatment of metastatic cancer, including the development of genetic engineering technologies that redirect lymphocytes to recognize and target a wide variety of tumor antigens. Chimeric antigen receptors (CARs) are hybrid proteins combining antibody recognition domains linked to T cell signaling elements. Clinical trials of CAR-transduced peripheral blood lymphocytes (PBL) have induced remission of both solid organ and hematologic malignancies. Chondroitin sulfate proteoglycan 4 (CSPG4) is a promising target antigen that is overexpressed in multiple cancer histologies including melanoma, triple-negative breast cancer, glioblastoma, mesothelioma and sarcoma. Methods CSPG4 expression in cancer cell lines was assayed using flow cytometry (FACS) and reverse-transcription PCR (RT-PCR). Immunohistochemistry was utilized to assay resected melanomas and normal human tissues (n = 30) for CSPG4 expression and a reverse-phase protein array comprising 94 normal tissue samples was also interrogated for CSPG4 expression. CARs were successfully constructed from multiple murine antibodies (225.28S, TP41.2, 149.53) using second generation (CD28.CD3ζ) signaling domains. CAR sequences were cloned into a gamma-retroviral vector with subsequent successful production of retroviral supernatant and PBL transduction. CAR efficacy was assayed by cytokine release and cytolysis following coculture with target cell lines. Additionally, glioblastoma stem cells were generated from resected human tumors, and CSPG4 expression was determined by RT-PCR and FACS. Results Immunohistochemistry demonstrated prominent CSPG4 expression in melanoma tumors, but failed to demonstrate expression in any of the 30 normal human tissues studied. Two of 94 normal tissue protein lysates were positive by protein array. CAR constructs demonstrated cytokine secretion and cytolytic function after co-culture with tumor cell lines from multiple different histologies, including melanoma, breast cancer, mesothelioma, glioblastoma and osteosarcoma. Furthermore, we report for the first time that CSPG4 is expressed on glioblastoma cancer stem cells (GSC) and demonstrate that anti-CSPG4 CAR-transduced T cells recognize and kill these GSC. Conclusions The functionality of multiple different CARs, with the widespread expression of CSPG4 on multiple malignancies, suggests that CSPG4 may be an attractive candidate tumor antigen for CAR-based immunotherapies using appropriate technology to limit possible off-tumor toxicity.
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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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