LIVE – 8/28 – CHI’s 5th Immune Oncology Summit – Oncolytic Virus Immunotherapy, August 28-29, 2017 Sheraton Boston Hotel | Boston, MA
Reporter: Aviva Lev-Ari, PhD, RN
ANNOUNCEMENT
Leaders in Pharmaceutical Business Intelligence (LPBI) Group will cover the event in
REAL TIME
Aviva Lev-Ari, PhD, RN will be streaming live from the floor of the Sheraton Hotel in Boston on August 28 and August 29, 2017
#IOSummit
http://www.immuno-oncologysummit.com/Oncolytic-Virus-Immunotherapy/
MONDAY, AUGUST 28
7:30 am Registration & Morning Coffee
LATEST UPDATES AND FUTURE DIRECTIONS IN ONCOLYTIC VIRUS IMMUNOTHERAPY
8:25 Chairperson’s Opening Remarks
Brian R. Champion, Ph.D., CSO, Psioxus Therapeutics Ltd.
- Virus: Design, Selection, Pre-Clinical Testing
8:30 KEYNOTE PRESENTATION: Engineering and Bio-Selection to Optimize an Oncolytic Virus Platform
John Bell, Ph.D., Senior Scientist, Center for Innovative Cancer Research, Ottawa Hospital Research Institute
Oncolytic viruses are therapeutics that are designed or selected to specifically infect and destroy cancer cells. There are multiple strategies that can be employed to create viruses that replicate in and kill tumors; however, one common feature of malignant cells is that they lack a potent anti-viral response. I will discuss the molecular basis for these defects, how best to exploit them to create tumor killing therapeutics and strategies to improve manufacturing output of oncolytic viruses from manufacturing cell lines based upon these principles.
Oncolytic Viruses (OV)
- Anti Vascular, Selective Oncolytic Replicating Cancer Gene Therapy Immune Adjuvant
- OV selective to Tumor cells – selectivity of OV – Cellular Anti-Viral Responses and Malignant Evolution-Incompatibilite?
- p53, Ras, Rb, Wnt, PTEN, VPV, E6/E7, VEGF, FGF2
- OV Therapy – exploits Cancer biology – Cellular Antiviral Responses – multiple pathologically activated Pathways
- Bio-Selection of Optimal Oncolytic Virus Strains
- Maraba Oncolytic Virus Platform – Rhabdovirus Structure, Life cycle, Key Features: no genotoxicity. Systemic Theraphy for Metastatic Cancer: Lang Tumours, Targeted Infection, Tumour Clearance
- Viccinia Virus as systemic Therapeutics – PexaVec (Sillajen, Transgene)
- How do SYStemically delivered Oncolytic Viruses ENTER tumours? – selective infection of tumor vascular EndothelialCells – response to cell proliferation
- In ovarian cancer
- Localized infection affects microenvironment – cytokines – nano string analysis 2 days post IV Infection — increase in PD-1 expression
- personalized InSitu Vaccine
- Oncolytic Herpes Virus expressing activation of T-Cells
- Effects are Stochastic and unpredictable
- OV — T-Cell Vaccine: COmbine principles of Vaccinology and OVTherapy
- adivo virus + Maraba-Tumour Ag–>> ptoduced TCell Responses: Prime Immune analysis –>> Boost immune analysis: %IFNgCD8+ T Cells – Days Post engraftment
- Patient Heterogeniety: Immunr stimulating Activity Gene thHerapy
IMPROVING THE TARGETING AND EFFICACY OF ONCOLYTIC VIRUSES
9:00 Tumor Selective HSV-Based Oncolytic Vectors for Treatment of GBM
Paola Grandi, Ph.D., Senior Research Director, Immunology/Virology, Oncorus, Inc.
Oncorus oHSV is controlled by certain microRNAs (miRNAs) that are present in healthy cells, but absent in cancer cells. Typically, miRNAs regulate the ability of classical messenger RNA (mRNAs) to be translated into protein or promote the degradation of mRNAs. By engineering miRNA binding sites into essential viral genes, oHSV replication and cellular destruction is prevented in healthy cells. Since cancer cells lack these specific miRNAs, Oncorus oHSV is free to replicate in and destroy them.
- Harnessing the body’s power to fight tumors – Developing Best-in-class Next-Gen oHSV Vectors to trigger Immune response
- Infection of Tumor cells >> Oncolysis –>>
- Glioblastoma Multiforme: Lead Candidate -ONCR-001 – when armed with immune modulatoring payloads, shows more promising results: Vehicle: Oncorus Unarmed oHSV (matrix modification); Armed oHSV (matrix modification +xx)
- Insertion of miR-Target Cassettes Controls Expression of Essential Viral Genes and Payloads
- Proof of Concept: no neurotoxicity of miR controlled virus after intracrenial injection, WT HSV-1 fatal
- Multiple-miR Attenuation nenables pursuit of Cancer beyond Brain (Liver)
- Robust Neurovirulence Factor: Attenuates neurotoxicity; Inhibits autophagy by binding to Beclin-1; Inhibit IDO: indirect regulation – IDO expands, recruits and activates MDSCs, converts trytophan to kynurenine production stimulated by IFNgamma
- Targeted Viral Entry for replication – remove portion of native gD gene and insert EDFR binding domain
- Receptor Engineering: WIld type, gD
- EGFR retargeted vector: Tumor Volume vS Days after virus injection – Intracranial HSV injection in normal and in GBM mice
- Enhanced Viral Spreading: Control vs EGFR-retargeted vs Matrix Modified Payload + EGFR-retargeted (Immune Modulatory) – TUMOUR VOLUME reduced the most for MatrixModified Payload + EGFR-retargeted
- T-cells, NK cells,
- ONCR-001 IND in GBM anticipated H2 2018
10:00 WO-12, a Multi-Mechanistic Immuno-Oncolytic Therapy
Steve H. Thorne, CSO, Western Oncolytics Ltd.
The next generation of oncolytic viruses will likely combine multiple genetic modifications (transgenes and viral genetic alteration) that act to synergistically target tumors through multiple mechanisms. In particular, approaches that (i) enhance systemic delivery and viral spread within and between tumors, (ii) activate a potent anti-tumor T-cell response, and (iii) modify the tumor microenvironment to enhance the activity of both the viral therapy and other therapies would produce additional benefits. The Western Oncolytics platform and its lead product WO-12 aim to achieve these goals. WO-12 has demonstrated enhanced activity in preclinical models and will soon enter clinical testing.
- 2015 IMLYGIC becomes first approved OV in US [1904 – Rabies Virus Vaccination, live non-attenuated virus Egypt 101 Virus, Cancer 1952]
- Viral replication inhibited – Normal cell SPARED
- Tumor Lysis – Virus spread – Vaccinia
- Next Generation Vectors modify tumor microenvironmentaddition of transgenes can enahnce activity
- Expression of combinations of multiple Tx transgenes and viral modifications
- WO-12 Design – Vaccinia Virus
- surface deglycosylation – does not effect infectivity and reduces TLR2 ligand activation
- HPGD Insertion – # of anti-viral CTL after vaccination of naive BALB/c mice with different vectors: Increase in WR.TK-TRIF
- TRIF Insertion
- TK & C12L Deletions
- Optimizing immune activation – increase systemic anti tumor CTL response while reducing anti-viral: Reduced anti-viral: Tumor Volume/days after virus
- Re-directing TLP Activation to enhance cell mediated immune responses
- Immunogenic cell death and IFN response leading to a primarily
- Overcoming immunosuppression – Resistance to oncolytic virus correlates with higher @ of myeloid derived suppressor cells (MDSC) in tumor
- Expression of murine HPGD decreases MDSC and T-regs in the Tumor
- Targeting of PGE2
- % Survival vs Day after Treatment and Tumor Volume vs Day of Treatment
- Pre-clinical Efficacy – nWO-12 – Avoid antiviral Immunity and immune suppression
- IV (intra-venous) Delivery vs IT (intra-tumor) Delivery
10:30 Pepticrad, a Novel Oncolytic Virus-Based Therapeutic Cancer Vaccine
Sari Pesonen, Vice President, Clinical Development, Valo Therapeutics, Finland
PeptiCRAd (Peptide-coated Conditionally Replicating Adenovirus) is an innovative and unique way of combining two clinically proven cancer immunotherapy approaches: an oncolytic adenovirus and a cancer-specific peptide vaccine, to take advantage of the best features of both technologies. The idea is straightforward: to use immunogenic virus as active carrier of tumor-specific peptides to direct the immune system to specifically target and kill cancer cells.
- PeptiCARd
- Oncolytic Adenovirus (negative charge)
- Tumor-specific Peptides (positive charge)
- Patient-specific Treatment – OV highly immunogenic –>>> Peptide Vaccine ANti-tumor immunity is high and anti-virus immunity is low
- OV are potential Cancer Vaccine/Immunotherapy candidates
- Genetic engineering for increased tumor specificity
- hig immunogenicity may help breaking cancer-driven immune tolerance
- limitation of OV is that they trigger a strong anti-virus immunity and only weak anti-tumor immune response in Cancer patients
- Per-existing immunity to OV potentiates its Therapeutic efficacy
- Virus replication
- 3 of T-regs in tumor
- #of T-cell in Tumor
- # CD4, CD8
- PeptiCRAd eradicates melanoma tumors
- PeptiCRAd was the most effective in controlling tumorgrowth >> induced high # of tumor peptide – presenting mature dendritic cells
- induced systemic tumor-specific CD8+
- targeting two antigens provides better anti-tumor efficacy
- Tumor Volume/days after treatment: PeptiCARd (TRP-2 – best efficacy
- Phase I Clinical Trial with PeptiCRAd – selected indications and checkpoint inhibitor (CPI) combination
- Triple negative BR CA
- Malignant Melanoma
- NSCLC
- CPI show clinical activity in PT with ongoing anti-tumor immune response
- local treatment with OV attracts T-cells — Intra-Tumor (IT) OV delivery is superior to systemic route (IV/IA (intra-arterial))
11:00 Synthetic Virology: Modular Assembly of Designer Viruses for Cancer Therapy
Clodagh O’Shea, Ph.D., Howard Hughes Medical Institute Faculty Scholar; Associate Professor, William Scandling Developmental Chair, Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies
Design is the ultimate test of understanding. For oncolytic therapies to achieve their potential, we need a deep mechanistic understanding of virus and tumor biology together with the ability to confer new properties. To achieve this, we have developed combinatorial modular genome assembly (ADsembly) platforms, orthogonal capsid functionalization technologies (RapAd) and replication assays that have enabled the rational design, directed evolution, systematic assembly and screening of powerful new vectors and oncolytic viruses.
- Future Cancer therapies to be sophisticated as Cancer is
- Targer suppresor pathways (Rb/p53)
- OV are safe their efficacy ishas been limited
- MOA: Specify Oncolytic Viral Replication in Tumor cells Attenuate – lack of potency
- SOLUTIONS: Assembly: Assmble personalized V Tx fro libraries of functional parts
- Adenovirus – natural & clinical advantages
- Strategy: Technology for Assmbling Novel Adenovirus Genomes using Modular Genomic Parts
- E1 module: Inactives Rb & p53
- core module:
- E3 Module Immune Evasion Tissue targeting
- E4 Module Activates E2F (transcription factor TDP1/2), PI3K
- Adenovirus promoters for Cellular viral replication __ Tumor Selective Replication: Novel Viruses Selective Replicate in RB/p16
- Engineering Viruses to overcome tumor heterogeneity
- Target multiple & Specific Tumor Cel Receptors – RapAd Technology allows Re-targeting anti Rapamycin – induced targeting of adenovirus
- Virus Genome: FKBP-fusion FRB-Fiber
- Engineer Adenovirus Caspids that prevent Liver uptake and Sequestration – Natural Ad5 Therapies
- Solution: AdSyn335 Lead candidat AdSyn335 Viruses targeting multiple cells
- Engineering Mutations that enhanced potency
- Novel Vector: Homes and targets
- Genetically engineered PDX1 – for Pancreatic Cancer Stroma: Early and Late Stage
11:30 Adenovirus-based virotherapy for disseminated disease
David T. Curiel, MD, PhD., Distinguished Professor of Radiation Oncology, D=rector, Biologic Therapeutics Center, Washington University
Effective virotherapy for disseminated neoplastic disease required precise =umor targeting. The unique molecular plasticity of adenovirus offers the p=tential to achieve the tumor selectivity required for virotherapy for meta=tatic disease.
- OV for DIsseminated Neoplastic DIsease
- Vector Targetinc:
- Restrict gene expression
- mitigate liver sequestration
- Transduction Targeting – integrin binding ligand capsid protein hexon HVR7 Chimerism basis of vector PLUS Transcriptional Targeting works synergistic – modification of Adenovirus Fiber Protein
- Replacement of Adenovirus Fiber with T4 Fibritin – Caspid dysthesis AdB2 cmvLuc
- Camelid sdAb Retargeting of Adenovirus – A robust technology CRAd-Based Tumor Selectivity
- Targeting Tumor cutotoxicity
12:00 pm Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own
12:30 Session Break
ONCOLYTICS IN DEVELOPMENT: UPDATE ON MAJOR CLINICAL AND PRECLINICAL THERAPIES
1:25 Chairperson’s Remarks
Fares Nigim, M.D., Massachusetts General Hospital and Harvard Medical School
1:30 Stroma Targeting Strategies for Oncolytic Virotherapy
Daniel Katzman, PhD., CEO, Unleash Immuno Oncolytics
- Clinical Trials: OV in Clinical Development – 35 Trials Meyer Oncology 2017
- Malignant Cells + Tumor Associated Stromal Cells
- normal stroma are different thn Tumor activated stromaLateralization
- SPARC is overexpressed in malignant and tumor associated stromal cells
- SPARC is a key regulator of proliferation
- number Cell type E4 copies ng DNA ratio/Hours after viral infection or /Days post injection
2:00 Development of OV Immunotherapy Using a Novel Preclinical GBM Model
Hiroshi Nakashima, Ph.D., Instructor, Neuroscience, Brigham and Women’s Hospital
Mechanism of action of the Oncolytic virus includes direct tumor killing and vaccine adjuvant. Since OV immunotherapy is emerge to apply in incurable glioblastoma multiforme (GBM) for the durable therapeutic effects, our new glioma mouse model will provide new opportunity to evaluate the combined OV therapies that work under the patient-mimicked immunological condition.
- Immunotherapy for TX of GBMs: Controlled Neurovirulence, defective to generate DNA resource
- Next generation of oHSV: Efficacy and Safety – GADD34 enhances expression
- Combination CheckPoint – PD-1 Aband OV: Tumor progression with T-Cell exhaustion Pro-tumor immunity- specific to tumor-antigen can mimic disease condition in GBM Patients
- and the timing of Immunotherapy in GBM models
- Antigen exposure & Tumor Growth: Acute infection, Naive, Chronic infection
- Antigen persistence, temporal Antigen exposure, no antigen experience
- PD-1 expression is high in brain-infiltrating GP33+ CTLs
- Blocking PD-1 rescued mice with exhausted T-cells from GBM
- Development of PD-1 blockade armed oHSV.
- Cross-talk between brain-infiltrating anti- and pro-tumor immune cells
- GP33 vs CD44
- Limitation of PD-1 Blockade to Cure- suggesting other pre-tumor immunity contributes to suppress anti-tumor immunity
2:30 Pexa-Vec: A Multi-Mechanistic Immunotherapeutic Modulator of the Tumor Microenvironment
Naomi De Silva, Associate Director, Preclinical Science, Sillajen Biotherapeutics, Inc.
Pexa-Vec (pexastimogene devacirepvec, JX-594) is an oncolytic and immunotherapeutic vaccinia virus, engineered to preferentially infect tumor cells, disrupt vasculature, and stimulate anti-tumor immune responses. A Phase III trial evaluating Pexa-Vec in the treatment of advanced primary liver cancer is underway.
- Broad Tropism – Infection and uptake to multiple receptor targets
- Vaccinia CD31 and CD8 and Granzyme B Positive in Metastatic Pancreatic Cancer – Oncolytic vaccinia targets tumor endothelial vasculature
- Anti-tumor responses important for eradication of malignancies
- Pexa-Vec increases T cells infiltration into tumors
- Oncolytic Vaccinia increases PD-L1 expression
- Combination of Oncolytic Vaccinia anf anti-PD-1 antibody decreases tumor growth
- Pexa-Vec’s ability to induce anti-tumor immune response
- Future study: Pexa-Vec in combination with checkpoint inhibitor CRC
3:30 Designing Clinical Trials to Elucidate Oncolytic Virus Mechanisms-of-Action
Caroline Breitbach, Ph.D., Vice President, Translational Development, Turnstone Biologics
Oncolytic viruses have been shown to target tumors by multiple complementary mechanisms-of-action, including direct oncolysis, tumor vascular targeting and induction of anti-tumor immunity. Phase I/II clinical trials can be designed to validate these mechanisms. Development experience of an oncolytic vaccinia virus and a novel rhabdovirus oncolytic vaccine will be summarized.
- Local effect: Cell Lysis
- Systemic: Immune response
- Turning Maraba (MG1) into T Cell Immunotherapy – ability to engage memory T cells to generate durable secondary immune response
- MG1 Mechanism of DIrect T Cell Induction
- Biology of T cell boosting:
- Virus infects follicualr B Cells
- Bcells provide virus to dendritic cells to present antigen
- DCT Prime – 9 days interval: Prime immune analysis
- DAy 14 boost induction
- Immune Boost in Tumor Greater in Improved Survival
- % survival vs days post treatment
- PK and viremia: Day 1,5,9,14, 11 days after dose #2
- Immunogenic Markers: Chemokines, Cytokines, Markers of Attack
- Evidence for Robust IMMUNE RESPONSE: HIGHEST RESPONDERS for self antigen
- Pembrolizumab Trial Design:Positive MAGE-A3 expressing tumors
- MG1 OV: systemic delivery and targeted metastatic tumor site
CMC, SCALE-UP AND COMMERCIAL MANUFACTURING
4:00 Development of an Attenuated Oncolytic Influenza a Virus Expressing Mycobacterial ESAT-6 Protein
Michael Bergmann, M.D., Ph.D., CMO, Vacthera
We have expressed ESAT-6 in a partial NS1-deletion influenza virus. ESAT-6 expressing viruses were associated with lower levels of NF-kB activating as compared to empty viral vectors. ESAT-6 expressing viruses led to higher titers in eggs up to 1010 TCID50. ESAT-6 expressing deletion viruses were still attenuated when applied to the upper respiratory tract of mice. Intra-tumoral application of virus into B16 melanoma significantly delayed tumor growth.
- Influenza A Virus (ESAT6 expressing partial NS1 deletion virus) – Lytic, Small RNA, Stable – live virus vaccine – infection affects Trypsin cleavage site, Elastase cleavage site
- Conditionally replicating – tumor ablation in PKR of INF-Defective Tumors
- Cytokine stimulation: CD14+ CD56+ CD19+
- Cytokine – IL15 – increased Intra tumor T-Cells and NK cells
- Virus titers are lost during purification
- AIM: Effective virus optimized for growth, genetic stability
- H1N1
- TLR2 inhibits TLR signaling in pmacrophageg
- Viral Input in ptoduction makes Oncolytics effect depend on amount of virus
- TB Vaccine TB/FLU-04 BCG-vaccinated healthy adults – Nasal Cytokine prduction
- Growth optimized viruses can be generated and appear to be safe – Onlcolytic influenza
4:30 Testing and Characterization of Oncolytic Viruses
Jerrod Denham, Ph.D., Principal & Senior Consultant, Dark Horse Consulting
Testing and characterization of oncolytic viruses typically follow the current principles for the majority of gene therapy product critical quality attributes. There are specific challenges with respect to adventitious agent safety testing and viral clearance studies. This presentation will walk through examples of how these challenges were resolved.
- Vaccinia, HSV-1, Adeno
- Cell QA: Cell counts, viability, identity. purity, potency,safety, stability
- Cell Production Process (CPP): Cells, virus, Plasmids, materials, equipment,settings test methods
- Experimental design for space cintrol
- Cell bank vs
- cGMP: Virus Bank – Master Virus Bank,Working Virus Bank
- Process Characterization: Mycoplasma & Endotoxin, sterility, pH, Metabolic Analysis, Viability, Vell Counts, visual inspection
- Unit Operation: Steile filter, concentrate, polish, purify
- Phase III: Drug substance: Formulate, bulk drug – fill & finish–>>> drug product
- Validation of Pre-Phase 3 manufacturing
- Clinical Lot: at least one batch: Bulk cell harvest, Final Drug Product
- Safety testing: Bovine, Porcine virus
- Adventitious Virus Testing: In Vitro Assay vs In Vivo Assay
- Neutralization: Agent for Neutralization – what if it does not work? Mock product
5:00 End of Day
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