Tuesday, August 20, 2013

Rhabdovirus-derived particles against leukemia

Greetings,

Fig 1: Oncolytic virus
     Cancer is one of the most scary term in the field of medicine. Considering the most happening in medical research, the most researched upon topic includes- Oncology, Stem cells, infectious diseases and vaccines. That is because Oncology is of great interest to pharma industries round the world as one of the most promising viable business. Wait a minute, Wasn't I supposed to post only about the stories pertaining with microbes? Well, Oncolotyic viruses as possible therapeutics has been fairly a new realm of molecular medicine.

Fig 2: Construction of the H101 oncolytic virus.
    An oncolytic virus is one that propagates selectively in tumor tissue and destroys it without causing excessive damage to normal (non-cancerous) tissues. From safety point of view, such viruses should be highly cancer specific, with minimal damage and destruction to normal tissues. A very large variety of Clinical trails are conducted based on variety of such oncolytic viruses. H101 type 5 Adenovirus (E1B-55KD, E3 gene Knockouts), known as Oncorine was approved for therapeutic purpose in 2005 in China for treating Head and neck cancers along with chemotherapy. The function of E1B 55K protein is to bind and inactivate p53 allowing viral replication. In the H101 adenovirus, deletion of the E1B 55K gene is responsible for replication only in tumor cells that have the inactivated p53. So cells that possess p53 will not support H101 viral replication. Graphical presentation shown below

Fig 3: Mechanism of H101 oncolytic action.
        Cancer immunity cycle (Review by Mellman etal; 2013) depicts the generation of immunity to cancer as a cyclic process that is self propagating. Activation of effector T cells by tumor cells lead to immune response and subsequent infiltration. The killing of cells leads to release of more tumor antigens and cycle continues. A resistance to this conferred by antigenic drifting of neoplastic cell via a process called as Immune- editing. With this idea it seems legitimate to ask, if a tumor cell can be lysed by using a oncolytic virus can it trigger the cancer immunity cycle? Think about it.

    2 Rhabdoviruses- Vesicular stomatitis virus (VSV) and Maraba, are explored and tested as potential anti-cancer materials. In its wild form these viruses may represent potential danger, and hence are genetically modified to attack only tumor cells. Moreover, they represent a weakened form of virus which cannot attack normal healthy host cells. In contrast cancerous cells have altered metabolism and impaired antiviral activity. Such specific viral materials can be derived by culturing in cancerous cell lines.

     The study by Batenchuk et al (Ottawa Hospital Research Institute), postulated that if you can create a non replicating viral particle with sufficient immunogenic and oncolytic activity the difficulty of dealing with safety can be overcome. For this study, Indiana Serotype of VSV (VSVI) and wild type Maraba virus was cultured in Vero cell medium. Using strong doses of UV light, biologically inert (in this case replication incompetence) viruses was harvested. Infectivity assays showed that it requires about 10 fold higher dose for the normal cells to be infected compared to cancerous cells.

Fig 3: NRRP induces cytolytic and immunogenic activity.
    These NRRPs (Non-replicating rhabdovirus-derived particles), were now able to selectively deplete leukemic cells of various types including the cells received from patients which were non responsive to standard drugs. The mouse model studies were encouraging with almost 80% efficacy, and 60 % of mice showing a complete cure. In contrast all of the untreated mice died of their leukemia within 20 days. The study is of great interest as it represents the first study using a biologically inert virus and not a actively replicating type which bypass the problem related to safety. The study also establishes that NRRPs provide both cytolytic and potent immunogenic properties in multiple acute leukemia models. I have illustrated the concept graphically based on my understanding form the paper in Fig 3. I have a question here. If the virus is non replicating, what is the driving factor to kill the cell? Authors have hinted that the viral particle's presence induces a phenomenon called as immunogenic apoptosis. It is a host defense mechanism essential for antiviral immunity which commits the cell to apoptosis. That again begets a question. Tumor cells are usually mutated for multiple apoptotic pathways and so how exactly this functions? In this case i don't have a proper explanation. Maybe I should get back to some reading.

    Dr. Conrad a hematologist involved with this study comments, "Our research indicated that a replicating virus might not be the safest or most effective approach for treating leukemia, so we decided to investigate whether we could make virus-derived particles that no longer replicate but still kill cancer. We were delighted to see that this novel therapy was very safe at high doses, and worked extremely well in our laboratory leukemia models. We hope to test this in patients in the near future." Source

     This is not the only example of Oncolytic therapy against Blood cancers. For example, Reolysin ®, proprietary variant of the Reovirus (Respiratory Enteric Orphan Virus, Serotype 3 Dearing) produced by Oncolytics Biotech. This is used in combination with chemotherapy for treating multiple myeloma.

ResearchBlogging.orgBatenchuk C, Le Boeuf F, Stubbert L, Falls T, Atkins HL, Bell JC, & Conrad DP (2013). Non-replicating rhabdovirus-derived particles (NRRPs) eradicate acute leukemia by direct cytolysis and induction of antitumor immunity. Blood cancer journal, 3 PMID: 23852158

Russell, Stephen J. (2007-07--1) Viruses as anticancer drugs. , 28(7), 326-333. DOI: 10.1016/j.tips.2007.05.005

Chen DS, & Mellman I (2013). Oncology meets immunology: the cancer-immunity cycle. Immunity, 39 (1), 1-10 PMID: 23890059

Vacchelli E, Eggermont A, Sautès-Fridman C, Galon J, Zitvogel L, Kroemer G, & Galluzzi L (2013). Trial watch: Oncolytic viruses for cancer therapy. Oncoimmunology, 2 (6) PMID: 23894720

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