International Symposium on Malignant Mesothelioma curemeso.org

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1 Measles virotherapy for malignant mesothelioma Manish R. Patel, D.O. Assistant Professor of Medicine University of Minnesota June 25, 2011

2 Medical Treatment of Mesothelioma Majority of patients are not eligible for curative surgery Only one standard chemotherapy regimen with proven survival benefit Cisplatin/Alimta Second line chemotherapy has no proven benefit Gemcitabine Taxanes Targeted therapy EGFR inhibitors have been disappointing (Tarceva Tarceva) Angiogenesis inhibitors (Bevacizumab and Sorafenib) do not appear to have a great benefit

3 Experimental Strategies Targets of interest AKT/mTOR inhibition Insulin like like Growth factor pathway Combination targeted therapy Immunotherapy has some promise Monoclonal antibody against mesothelin WT 1 peptide vaccine Adenovirus expressing Interferon β Oncolytic viruses

4 What is an Oncolytic Virus? Live replicating virus Onco = tumor Lysis = to destroy Able to infect tumor cells preferentially Through replication is able to kill the cancer cell Able to amplify itself and infect surrounding tumor cells

5 Why Virus Therapy? Observation of spontaneous tumor regression after infection Various defects in tumors promote viral infection Non pathogenic viruses retain antitumor activity

6 Rationale for virus as therapy Viruses are are able to infect cancer cells better than normal tissues Based on signaling events ents (Ras activity it for reovirus) Acidic tumor microenvironment ( VSV) Receptor overexpressed in cancers (CD46 for Measles virus, CAR for adenovirus) Other factors (loss of tumor suppressors, high rate of protein synthesis) Wong, HH, et al. Viruses 2010: 2(1):78 106

7 Clinical trials of virus therapy Virus Phase Disease Reovirus (Reolysin) III II I/II Head and neck cancer Non small cell lung cancer Numerous tumor types HSV (Oncovex GM CSF ) III Head and Neck cancer Melanoma Vaccinia (JX 594) II Hepatoma Colon cancer Measles I Ovarian Cancer Myeloma Gliomas Mesothelioma

8 Vaccine strain Measles Virus

9 Vaccine strains of MV Wild Type MV Vaccine strain SLAM CD46 Receptor Predominantly on B and T cells Overexpressed on tumors Immune effects Sequelae Profound Immunosupression Lymphopenia (B and T cells) Blocks type I IFN production Potentially lethal Latent infection can cause encephalitis Minimal Cannot inhibit IFN Used in humans for over 40 years Does not cause disease even in HIV+

10 Potential Limitations 98% of the population has been immunized against measles Rapid antibody responses may limit virus getting to the tumor and limit viral replication and spread Therefore, the clinical development has been limited mostly to tumors that are directly accessible

11 I ve heard this story before Measles virus cures cancer! But turns Manhattanites into cannabalistic i zombies Will Smith plays the scientist who is the lone survivor

12 Clinical trials with MV Phase I study of intraperitoneal MV CEA for ovarian cancer Intraperitoneal delivery to chemorefractory patients Dose escalation design (10 3 to 10 9 TCID 50 ) No grade ¾ toxicities Side effects: Low grade fever Skin rash Abdominal pain Galanis, et al, Cancer Res Feb 1;70(3):875 82

13 Results in Ovarian Cancer 14 of 21 patients had disease stabilization (longest for 8 months) Median survival 12 months vs expected survival of ~6 months 2 patients had decrease >30% decrease in CA 125 level Dose dependent increase in CEA detected in peritoneal fluid No significant change in Ab titers Galanis, et al, Cancer Res Feb 1;70(3):875 82

14 Other phase I studies Phase I study of IV administration for Multiple Myeloma (ongoing) Phase I study of intratumoral injection for gliomas (ongoing) Thus far, there has been no dose limiting toxicity with doses up to 10 9 TCID 50

15 MV for Mesothelioma The pleural space is * * * accessible Mesothelioma is tends to be a localized disease Overexpresses CD46 *P < 0.05 *

16 MV is Oncolytic for Mesothelioma MV infects Dose dependent cell mesothelioma cells in killing selectively for vitro mesothelioma cells

17 MV has efficacy in immunodeficient i mice Single intraperitoneal injection of MV 10 7 viral particles Conclusion: Measles has activity against experimental mesothelioma Sadiq, WCLC 2009

18 Measles virus for clinical Need to track the virus Virus engineered to express sodium iodide transporter (MV NIS) Allows infected cells to take up Radio Iodine I 123 allows for in vivo imaging g Future use of I 131 as a toxin to infected cells translation

19 Phase I study of Intrapleural injection of MV NIS for Mesothelioma Open at the University of Minnesota and the Mayo Clinic Dose escalation design (up to 3 x10 9 TCID 50 ) Key Eligibility criteria: Diagnosis i of Mesothelioma confined to single pleural l cavity Symptomatic pleural effusion No prior pleurodesis Able to undergo Pleurx catheter placement Immunized against Measles virus Not immunosuppressed

20 Phase I study of Intrapleural injection of MV NIS for Mesothelioma Up to 6 repeated treatments allowed Primary goal: Safety and feasibility of this approach No Zombies!! Secondary goals: Antitumor efficacy Evaluate the biological response to measles infection in the tumor and immune system

21 Correlative Science MV NIS for Mesothelioma What can we learn to refine the approach in future studies? Does the virus spread within the tumor? How long does it last? Which h patients t will benefit the most? How can we manipulate the virus or the immune system in favor of antitumor activity and/or safety?

22 Correlative Science MV NIS for Mesothelioma SPECT/CT scans Administer 123 Iodine to define time course of viral infection, dissemination, and elimination Also will assess virus dissemination into peripheral circulation and body fluids by standard virology assays Tissue will be assessed for: CD46 expression (Measles receptor) Markers that may predict for enhanced viral replication Activated protein translation Insulin like growth factor activation

23 Correlative Science MV NIS for Mesothelioma Immune system Effects of measles virus therapy on: Anti measles antibody levels Immune suppressor cells (Tregs or Myeloid suppressor cells) Anti tumor immune response (NK cell and T cell activation) Blood and pleural lfluid cytokines How to game the system in our favor? Combination therapy immune suppression or immune augmentation? Engineer the virus to express cytokines that might make it work better

24 Summary MV has clear oncolytic effects against mesothelioma Mesothelioma is an ideal tumor to target with oncolytic virus It is locally ll invasive i Widespread metastasis of mesothelioma is uncommon The pleural space is accessibly by pleural catheter Phase I study is about to begin Results will guide further clinical development for mesothelioma Provide rationale for making the next generation of measles oncolytic therapy

25 Acknowledgments UNIVERSITY OF MINNESOTA Investigators: Robert Kratzke, MD Principal Investigator Arkadiusz Dudek, MD, PhD Jonathon D Cunha, MD, PhD Priya Kumar, MD Clinical i l Trials Office Jill Aughey Gerri Anderson Hieu Ngo Funding Sources: Mesothelioma Applied Research Foundation Department of Defense MAYO CLINIC Investigators: Tobias Piekert, MD Principal Investigator Stephen Russell, MD, PhD Evanthia Galanis, MD Julian Molina, MD Mark Federspiel, PhD Molecular Virology Val Lowe, MD Biostatistics: U of M Bruce Lindgren Mayo Clinic Sumithra Mandrekar Minnesota Partnership for Biotechnology and Genomics Cooper Simmons Foundation

26 Thank You!