ImmunoVEX ex vivo: A herpes simplex virus-based, dendritic cell-mediated anti-cancer vaccine platform

Abstract

Proc Amer Assoc Cancer Res, Volume 45, 2004 1248 Dendritic cell (DC)-based vaccines are promising for cancer treatment. However, there are significant problems of efficient antigen loading and practicality of current approaches. Herpes simplex virus (HSV), unlike most viruses, infects DC very efficiently suggesting its use for antigen delivery to DC. The large size of HSV allows delivery of multiple antigens (up to 30Kb), as may be beneficial for anti-cancer vaccination. However, DC infected with HSV loose the ability to become activated as is necessary for the induction of an effective immune response, probably to minimize immune responses to HSV. Thus, if the HSV- proteins which block DC activation were identified, and these removed from the virus, this might provide an ideal platform for antigen delivery to DC. We have iteratively tested an extensive range of HSV mutants with individual and combinations of genes deleted to identify the HSV DC blocking genes. This has allowed us to develop an optimal HSV backbone which activates DC similarly to LPS, rather than blocking activation as with wild type HSV. These viruses are deleted for the HSV virion host shutoff protein (vhs), which we found to be a key mediator of DC inactivation, ICP47, which blocks antigen presentation, UL43, deletion of which improves DC function, and ICP4, deletion of which blocks HSV replication. This virus significantly up-regulates levels of CD80, CD83, CD86 and MHC class I on infected cells, gives very high level transduction of DC at a low virus dose (MOI<1), and gives potent immune stimulation. These vectors therefore provide a platform for ex vivo transduction of DC for anti-cancer vaccination. Here automated magnetic bead technology is used for the preparation of human DC precursors from peripheral blood. Using DC prepared in this manner, which are transduced and frozen in aliquots for subsequent vaccination, a clinical trial is in preparation in melanoma where a vector has been constructed expressing the three full length melanoma-associated antigens MART-1, gp100 and tyrosinase. Pre-clinical data relating to this program will be presented. However, other vectors encoding other combinations of tumour antigens relevant to other tumour types are also at earlier stages of construction and development.