December 10, 2010
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CD8+ Cytotoxic T-cells, Weapons of Selective Destruction
McMaster University ♦ Published in Molecular Therapy (npg), Nov. 30, 2010
Oncolytic viruses (OVs) are being investigated as a means to destroy tumour cells. They exert their cytotoxic effects either directly through infection, or indirectly, if they have been engineered to flag down cancer cells by delivering tumour-associated antigens for later destruction by cytotoxic T-cell lymphocytes. After an OV infects and bursts a cancer cell, a cascade of anti-tumour immune events is initiated. Antigens that are liberated by the destruction of cancer cells are internalized by a cell-type known as an antigen presenting cell (APC), broken down once inside, and then re-expressed on the surface of the APC. After migrating to the lymph nodes the APC ‘presents’ this protein signature to T-cells which deliver the final blow. Recognition of tumour antigens by T-cells drives the expansion of T-cell populations into cytotoxic T-lymphocytes (CTLs) and memory populations that seek out cancer cells. Upon finding cancer cells, CTLs latch on to their surface and release granules containing perforin and granzyme inducing cell breakdown. In recent work coming from the lab of Dr. Karen Mossman at McMaster University, researchers showed that a replication-defective Herpes Simplex Virus (HSV) possesses oncolytic properties in a breast cancer model. New work by this lab group stresses the importance of choosing appropriate in vitro models to study oncolytic viruses. Mossman found that the sensitivities of different cancer cell lines to in vitro oncolysis did not correlate well with in vivo oncolysis in more than one virus under study. These findings illustrate the importance of adaptive antiviral CD8+ cytotoxic T-cells in producing effective oncolytic viruses for virotherapy. Examples of such a therapies in late-stage clinical development include the OncoVEX technology being developed by BioVex for advanced melanoma and JX-594, an oncolytic virus being developed by Jennerex for the treatment of hepatocellular carcinoma.
Insulin Expression Driven by Synthetic Promoter
University of Calgary ♦ Published in Molecular Therapy (npg), Nov. 30, 2010
A step forward for gene therapy in the diabetes arena as researchers have engineered an adenovirus containing the insulin gene under the expression of a highly active and liver-specific promoter. Following IV delivery of the virus into a diabetic mouse model normal glycemia was maintained for greater than 30 days. Glucose tolerance tests also showed that diabetic mice were able to produce insulin and clear exogenous glucose from the bloodstream in a fashion similar to healthy mice. Scientists chose the liver as a target for gene therapy because hepatocytes are particularly sensitive to glucose. The strength of these preclinical findings is in part due to the promoter used to stimulate expression of the insulin DNA component. Dr. Hee-Sook Jun and his team generated a synthetic promoter library and scanned it for promoter components and arrangements that had the strongest transcriptional activity.