Reovirus clearance of ras-mediated neoplastic cells from mixed cellular compositions

Patent Number: 7,431,932

Activation of innate immune responses is associated in some situations with anti-tumor effects.  It is known that viruses activate various cells of the innate immune system such as interferon producing plasmacytoid dendritic cells and natural killer cells.  In tumor immunology, it would be ideal if endogenous tumor cells died in the context of innate immune system activatory molecules.  In this manner, the antigens released from the tumor would be in proximity of an immune stimulatory environment, and therefore the possibility of inducing tumor-specific immunity would be higher.  This would alleviate the need to identify peptides that are specific to each tumor, and perhaps patient specific in many situations.

The current patent provides an easy and theoretically safe way to do this.  The owners of the patent, the company Oncolytics, has developed and clinically implimented the use of a virus, called reovirus, that selectively kills cancer cells but not non-malignant cells.

The patent here covers the use of reovirus to "purge" bone marrow cells of contaminating cancer cells.  This is important for two reasons.  Firstly, the dose-limiting side effect of chemotherapy is bone marrow toxicity, thus one approach that has previously been used is to mobilize the bone marrow of the cancer patient using compounds such as G-CSF, or more recently, parathyroid hormone, treat the cancer patient with high dose chemotherapy, and then subsequently re-introduce the mobilized hematopoietic stem cells.  The problem with this, as you may imagine, is that there may be contaminating tumor cells in the autologous graft.  The second reason why purging of cancer cells out of bone marrow is important, is for situations like hematological diseases, in which the malignant cells are actually part of the hematopoietic stem cell compartment.  Similar purging protocols have previously been developed in which there is a selective reduction in cancer cells.  For example, Dr. Eaves back in 1987 published that in long term bone marrow cultures, the leukemic cells actually die out faster than healthy bone marrow cells (Eaves et al. Clinical significance of long-term cultures of myeloid blood cells. Crit Rev Oncol Hematol. 1987;7(2):125-38).  Another interesting purging technology was developed by Dr. Catherine Verfaillie in which her group reported that depletion of a bone marrow graft of HLA DR positive cells was associated with reduction in leukemic cells (Verfaillie et al. Selection of benign primitive hematopoietic progenitors in chronic myelogenous leukemia on the basis of HLA-DR antigen expression. Blood. 1992 Feb 15;79(4):1003-10).  Unfortunately these approaches for one reason or another have not become implimented on a widespread basis.

The patent's only independent claim is "A method of reducing a risk of recurrence of tumor due to transplantation of autologous hematopoietic stem cell suspected of containing ras-mediated neoplastic cells, comprising harvesting from a subject to receive the transplant a cellular composition which comprises hematopoietic stem cells, contacting the cellular composition with a reovirus under conditions which result in oncolysis of ras-mediated neoplastic cells, and introducing the reovirus-treated composition back into the subject."

Dependent claims include various types of reovirus such as "mammalian reovirus, avian reovirus, human reovirus, serotype 3 virus, and the Dearing strain reovirus".

Given that Oncolytics has already demonstrated proof of principle that this reovirus approach is useful in treatment of clinical tumors, including glioma, it will be interesting to follow this company, which in our opinion has a very strong chance of developing a whole new field of cancer therapeutics.

Question: since the basis for the cancer selective killing of the reovirus is ras activation, will it kill tumor stem cells?

View this patent on the USPTO website.