A - Human Necessities – 61 – K
Patent
A - Human Necessities
61
K
A61K 48/00 (2006.01) A61K 39/00 (2006.01) A61K 39/12 (2006.01) A61K 39/235 (2006.01) A61K 39/39 (2006.01) A61P 35/00 (2006.01) A61P 35/04 (2006.01)
Patent
CA 2571348
Despite continued progress in understanding the pathophysiology of tumour progression and metastasis, curative therapeutic options are still missing for metastatic melanoma. Downregulation of MHC class I antigen expression is frequently associated with impaired transporter-associated-with-antigen- processing (TAP) expression in many tumours, including melanoma, making them invisible to effector cytotoxic T cells. One approach to making therapeutic vaccines is to use genetically engineered non-replicating viruses as vaccine vehicles to revive immunosurveillance mechanisms in order for tumours to be eradicated. A perceived problem with this approach is that the number of nonreplicating viruses used as vaccine inoculum does not remotely approximate the total number of cells in the body, nor even the number of tumour cells in the case of large tumour burden or metastasis, leaving some to argue that this is a poor method of anti-cancer vaccination. Here we addressed the hypothesis that a limited amount of inoculae (1 × 10 8) of recombinant non-replicating adenovirus encoding human TAP1(AdhTAP1) can induce protective immunity against (1.5 × 10 5) TAP-deficient, metastatic melanoma cells transplanted into a normal mouse (total of 1 × 10 11 body cells). We show that efficacious anti-tumour responses are indeed induced by injecting melanoma-bearing animals with small numbers of these recombinant viruses, resulting in increased animal survival and, importantly, in enhanced memory T cell subpopulations. These observations suggest that the inclusion of TAP in virus vaccines may promote and maintain long term anti-tumour responses even when the vector used to deliver TAP only infects a small fraction of the metastatic tumour cells. This novel approach uses a limited input inoculae relative to the tumour cell mass, and thus achieves an efficacious outcome that has so far eluded other vaccine, immunotherapeutic or gene therapeutic strategies where there is a requisite for the majority of tumour cells to be transduced for beneficial outcome to be achieved.
Chen Susan Shu-Ping
Jefferies Wilfred Arthur
Lou Yuanmei
Pearson Terry W.
Seipp Robyn P.
Smart & Biggar
Tapimmune Inc.
University Of British Columbia
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