Oncolytics Biotech Inc. (ONCY)

[onco_investor]

Dr.Patrick Lee Dr.Shashi Gujar Reovirus and Immunology

http://www.dmrf.ca/en/home/mollyappeal/aboutus/facesofmolly/dalresearchers/cancerresearchers/drpatrickleeanddrshashigujar.aspx



Keeping cancer from coming back

Dr. Patrick Lee and Dr. Shashi Gujar

see reovirus as a powerful way to stop cancer recurrence

Dr. Patrick Lee, a virologist who is world famous for finding that viruses can infect and kill cancer cells without harming healthy cells, is taking this groundbreaking discovery to a new level with help from immunologist Dr. Shashi Gujar. These Dalhousie Medical School researchers are pursuing a strategy that could turn the common and harmless human reovirus into a potent means of preventing cancer from coming back after treatment.

"We've found from our studies that when you treat a cancer with reovirus, cancer is prevented from coming back," says Dr. Lee, noting that recurrence is one of cancer's most difficult to solve problems - especially since recurrent cancers tend to resist treatment.

This protective effect is due to a change in the body's immune response against cancer cells after they've been infected by reovirus. "After the initial wave of cancer-killing infection, we've found that the remaining cancer cells suddenly become visible to the immune system," explains Dr. Lee, a professor in the department of Pathology and Microbiology & Immunology. "Cancer cells are usually able to hide from the immune system, but the virus forces them to give up their shields so now the immune system can see and destroy them. As a result, no cancer cells remain to seed a future cancer of that type,"

Dr. Gujar's expertise in immunology is helping make reovirus treatment even more effective. "The problem with using a virus to treat cancer is that the immune system wil try to stop the virus before it has a chance to infect the cancer," says Dr.Gujar, a postdoctoral fellow in Dr. Lee's lab. "But we have isolated the particular immune cells that attack reovirus and programmed them to self-destruct as soon as they recognize the reovirus - so the reovirus can attack and kill cancer cells unhindered."

These researchers hope reovirus will become a standard treatment to use in conjunction with chemotherapy. Calgary-based Oncolytics Biotech is currently conducting phase three clinical trials on reovirus-chemotherapy combinations, so this treatment option may soon be available.


Additional Details - Thanks matdu

The first publication below details the finding in the article described by Drs. Lee and Gujar. The second publication (you can access the entire paper via the link) demonstrates interesting relationship between p53 and cancer cell susceptibility, also authored by the Lee's group.

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0054006

(1) Reovirus Virotherapy Overrides Tumor Antigen Presentation Evasion and Promotes Protective Antitumor Immunity
Shashi A. Gujar, Paola Marcato, Da Pan and Patrick W.K. Lee
+ Author Affiliations

Authors' Affiliation: Department of Pathology and Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
Corresponding Author:
Patrick W.K. Lee, Department of Pathology and Microbiology and Immunology, Dalhousie University, Room 7-P, Sir Charles Tupper Medical Building, 5850 College Street, Halifax, Nova Scotia, Canada B3H 1X5. Phone: [phone]; Fax: [phone]. E-mail: [e-mail]
Abstract

Tumor-associated immunosuppressive strategies, such as lack of tumor antigen recognition and failure of lymphocyte activation and homing, resist the development of tumor-specific immunity and hamper the immune response–mediated elimination of cancerous cells. In this report, we show that reovirus virotherapy overrides such a tumor immune evasion and establishes clinically meaningful antitumor immunity capable of protecting against subsequent tumor challenge. Reovirus-mediated destruction of tumor cells facilitates the recognition of tumor antigens by promoting the display of otherwise inaccessible tumor-specific immunogenic peptides on the surface of dendritic cells (DC). Furthermore, on exposure to reovirus, DCs produce IL-1á, IL-1â, IL-6, IL-12p40/70, IL-17, CD30L, eotaxin, GM-CSF, KC, MCP-1, MCP-5, M-CSF, MIG, MIP-1á, RANTES, TNF-á, VCAM-1, VSGF, CXCL-16, AXL, and MCP-2; undergo maturation; and migrate into the tumor microenvironment along with CD8 T cells. These reovirus-activated DCs also acquire the capacity to prime tumor antigen–specific transgenic T cells in vitro and intrinsic antitumor T-cell response in vivo. Further, reovirus virotherapy augments the efficacy of DC- or T cell–based anticancer immunotherapies and synergistically enhances the survival in tumor-bearing mice. Most importantly, antitumor cellular immune responses initiated during reovirus oncotherapy protect the host against subsequent tumor challenge in a reovirus-independent but antigen-dependent manner. These reovirus oncotherapy–initiated antitumor immune responses represent an anticancer therapeutic entity that can maintain a long-term cancer-free health even after discontinuation of therapy. Mol Cancer Ther; 9(11); 2924–33. ©2010 AACR.

(2) Activation of p53 by Chemotherapeutic Agents Enhances Reovirus Oncolysis

Da Pan, Paola Marcato, Dae-Gyun Ahn, Shashi Gujar, Lu-Zhe Pan, Maya Shmulevitz, Patrick W. K. Lee

Abstract

Mammalian reovirus is a benign virus that possesses the natural ability to preferentially infect and kill cancer cells (reovirus oncolysis). Reovirus exploits aberrant Ras signalling in many human cancers to promote its own replication and spread. In vitro and in vivo studies using reovirus either singly or in combination with anti-cancer drugs have shown very encouraging results. Presently, a number of reovirus combination therapies are undergoing clinical trials for a variety of cancers. Previously we showed that accumulation of the tumor suppressor protein p53 by Nutlin-3a (a specific p53 stabilizer) enhanced reovirus-induced apoptosis, and resulted in significantly higher levels of reovirus dissemination. In this study, we examined the role of p53 in combination therapies involving reovirus and chemotherapeutic drugs. We showed that sub-lethal concentrations of traditional chemotherapy drugs actinomycin D or etoposide, but not doxorubicin, enhanced reovirus-induced apoptosis in a p53-dependent manner. Furthermore, NF-êB activation and expression of p53-target genes (p21 and bax) were important for the p53-dependent enhancement of cell death. Our results show that p53 status affects the efficacy of combination therapy involving reovirus. Choosing the right combination partner for reovirus and a low dosage of the drug may help to both enhance reovirus-induced cancer elimination and reduce drug toxicity.