*8.1. Gene Supplementation Therapies*

Wild type copies of each of the components of the antigen presentation pathway can in theory be encoded within oncolytic viruses and expressed locally within tumor cells to restore pathway function. Although this approach could be adopted for any pathway component, perhaps the most widely studied is β2M [74], where gene replacement with adenovirus has been shown to restore cell surface expression of classical class I HLA molecules, implying that β2M function has been restored [75]. Importantly, the restoration of β2M was also shown to lead to peptide-specific immune recognition by cognate antigenspecific T-cells [76].

Unfortunately, the therapeutic benefits of direct class I HLA gene replacement therapy will likely be very limited, because current understanding suggests that the expressed transgene product would be restricted only to cells that are actively infected with the oncolytic virus. This raises two immediate concerns—first, that functional antigen presentation would not be restored more broadly within the tumor, but only in cells that would be expected to be killed by direct oncolysis, and secondly that the restored HLA function in those infected cells might begin to present viral epitopes rather than TAAs, giving rise to an augmented antiviral T-cell response rather than stimulating an anticancer response. This might accelerate the immune-mediated clearance of the virus rather than empowering a cancer vaccination effect. Hence, the concept of replacing mutated components of the antigen presentation pathway appears flawed unless it can be somehow delivered more broadly within the tumor and not restricted just to virus-infected cells. One possible approach that might be worth exploring is the use of exosomes. Although still in its infancy, the potential for programming viruses to manipulate exosomes to distribute functional HLA molecules amongst cancer cells may be an effective way of restoring the presentation of TAAs to allow renewed immunosurveillance.
