Proposal Description:

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One of the biggest hurdles in effectively treating cancers is the tumor heterogeneity, which leads to treatment failure and allows some of the drug-sensitive cancer cells to eventually acquire resistance to treatment. Thus, despite progress in surgery, chemotherapy, radiation therapy, and development of tumor-specific monoclonal antibodies, advanced or metastatic cancers remains difficult to treat. Such development of resistance to classical chemo- and radio-therapies underscores the need for development of novel non-palliative therapeutic strategies.

These challenges have led to the re-emergence of oncolytic viro-therapy (OVT), a strategy using either naturally occurring or genetically modified viruses to selectively target and lyse tumor cells or kill them by apoptosis while leaving surrounding nonmalignant cells unharmed. Although the mechanisms of action of OVTs are still not fully understood, major advances have been made in our understanding of how OVTs function and interact with the host immune system, resulting in the recent Food and Drug Administration (FDA) approval of the first OVT for cancer therapy in the U.S. Given the adverse effects of chemotherapies and radiotherapies, today, OVTs represent an emerging class of cancer therapeutics, poised at the junction of biologic therapy and immunotherapy with highly significant impact for treatment of cancers in the future.

 Although clinicians noted the antitumor effect of naturally occurring viral infections in cancer patients more than 100 years ago, only recent advances in our knowledge of OVT led to the herpes simplex virus 1 (HSV-1) expressing granulocyte-macrophage colony-stimulating factor (GM-CSF) named T-VEC as the first OVT approved by FDA for the treatment of advanced melanoma in 2015, and a few others are in clinical trials. Despite these clinical trials with a few viruses that showed promise in terms of safety and tolerability, there remain formidable challenges, including:
1) the vulnerability of viruses to host an immune system, including complements, neutralizing Abs, and macrophages, which rapidly clears the virus from circulation;
2) nonspecific uptake by other tissues, e.g., by spleen and liver, and suboptimal viral escape from the vascular compartment decreases the virus reaching the tumor target; and
3) targeting the virus specifically to tumor, not healthy tissue.

Also, targeting oncolytic viruses to tumors and tumor cells in the lung remains a major unmet need. This short course will provide a comprehensive overview of the basic biology supporting oncolytic viruses as cancer therapeutic agents, describe oncolytic viruses in advanced clinical trials, and discuss the unique challenges in the development of oncolytic viruses as a new class of drugs for the treatment of cancer.

Learning Objectives:
•Review of the 'State-of-the-Art' of the oncolytic virotherapy
•Successes, failures and current challenges of the oncolytic virotherapy
•Targeted oncolytic virotherapy and various means of achieving targeting
•Oncolytic virotherapy, clinical trials and experimental approaches
•Future potential and path to precision cancer medicine