LIVE 1:30 – 4:30 8/29 BIOMARKERS AND IMPROVING VIRUS ACTIVITY @IMMUNO-ONCOLOGY SUMMIT – AUGUST 29-30, 2016 | Marriott Long Wharf Hotel – Boston, MA
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1:30 – 4:30 BIOMARKERS AND IMPROVING VIRUS ACTIVITY
1:25 Chairperson’s Remarks
David Kirn, M.D., CEO & Co-Founder, 4D Molecular Therapeutics & Adjunct Professor of Bioengineering, UC Berkeley
1:30 New Biomarkers that Predict Response to Oncolytic Virus Immunotherapy
Howard L. Kaufman, M.D., FACS, Associate Director, Clinical Sciences, Rutgers Cancer Institute of New Jersey; Professor and Chief, Division of Surgical Oncology, Rutgers Robert Wood Johnson Medical School
T-VEC is the first oncolytic virus approved for the treatment of melanoma, and will soon enter clinical trials for treatment of other cancers. Further studies using T-VEC in combination with T cell checkpoint inhibitors are underway and showing promising early results. The identification of predictive biomarkers of response would be helpful for improving patient selection and optimizing therapeutic outcomes. We have recently focused on HSV-1 entry receptors and oncogenic signaling pathways within cancer cells as potential biomarkers of T-VEC response.
- Why we wish to have biomarkers?
- identify patients
- efficacy
- cost/avoid over/under tretment
- molecular therapeutics understandin
- PD1 – expression is the ONLY biomarker we currently have for eligibility to participate
- Biomarker discovery – Biopsy or blood, many indicators to measure
Biological challenges: Tumor and lesion heterogeneity
- detection frequency for DNA vs. protein serum vs imaging modality
- prior treatment
- Circadian rhythm
Technical/Logistical
OV Immunotherapy
- Tumor cell intrisic factors
- Host Factore
- Immune Ssytem factors
Tumor cell intrisic factors
- Viral cell surface – viral infection
- signalling receptors – Nectin1, Nectin2 molecules
- HVEM
- NCB160
mRNA expression of HSV-1 receptors on NCI 60 cell line panel
Oncogenic pathways – apoptosis of cell — abberation of this process prevent apoptosis and
- Treatment with T-VEC – response to BRAF and NRAS
- MEK inhibition sentisizes mealnoma cell line to lysis by T-VEC
- mutation status,
- Oncolytic viruses trigger immunity through release of PAMPs
- Patients with low serum HMGB1
- Balancing the inflamed tumor microenvironment
- Expression of PD-L1 and IDO associated with CD8+ T cell infiltrate, Fox
- ICOS plus plus T cells after T-VEC CD4+
- Immune model: B16 Nectin-1 on one side
- in 4 days Post Injection and viral infection –>> Increase in microphage – CD8+
- Anti HSv – glycoprotein B lead to anti Herpes: Left vs right Flank
- HSV-1 antigens – recognized by Human CD4+
- PD-L1 Expression in Melanoma – PFS
- NIVO _IPI, FoxP3, CD163, DAPI, PD-L1, CD 3, CD8
- LA-07 CALM Study: Best % of Change in tumor size T1 and 8 days later T8
- Interferon – NanoString analysis: Immune
- Mutation Load andneoantigen
- Mutation Burden correlates with PF
- Avelumab antiPD-L1
- MCPyV and PPD-L1 therapy: MCpyV positive va negative MCC: at the extremes of mutational frequency
Conclusions
- predictive biomarkers
- Intrinsic tumor cell factors
Viralytics
Questions:
- Intra Tumor injection – pushback by MDs – Yes, virus need be in different room than chemotherapy
2:00 Therapeutic Viral Vector Evolution: A Robust Platform for the Discovery of Optimized Vectors – Lessons in 20 yers
David Kirn, M.D., CEO & Co-Founder, 4D Molecular Therapeutics; Adjunct Professor, Bioengineering, University of California, Berkeley
Therapeutic virus vectors hold great promise for cancer gene and immunotherapy. However, novel vectors with improved efficacy are needed. Therapeutic Vector Evolution is a discovery platform from which optimized and proprietary viral vectors can be identified with beneficial characteristics of interest.
- Translational
- Design of 2nd generation VT
- Adenovirus 2/5 deletion mutant Onxy-015 (d/1520) – cancer targeting selelctivity: p53 inactivation in cancer cells
- 1996-2001: ONXY 015 experience in humans
- first engineered OV in human: Intratumoral, Peritumor, Intraperiteneal, Intra-atrial, IV
- Well tolerated acure, flu- like symptoms
- Tumor specific replication of ONXY-015 in head & neck complete response vd peripheral escape and viral clearance
- Tumor response limited IT only
- No systemic anti-tumor efficacy
- no IV delivery
- No anti-tumor immune response demonstrated
- Resistance
- OV can sensitize tumors for chemotherapy
- Hepatic artery
- Pharma executives: nich unless given IV – in 2016 the position changed
- VACCINIA Biology: The virus pharmacophore Library
- Vaccinia Vs other visuses:
- JX-594 (Pexa-Vec): Novel 3-pronged MOA
- Studies:
- Neutrophil induction correlates with GM-CSF in serum
- Tumor liver injected – complete response
- Systemic efficacy: carcinoma in the abdomen
- Lytic effect: Vaccinia, other virus
- Resist disease control: Randomized Phase 2A HCC trial design: High vs Low dose: Baseline Wek8 month 21
- Uninjected week8 week 14 chronic inflammation
- JX-594 (Pexa-Vec) experience in Humans (2007-2014): IV infusion vs IT injection
Biology mover to Vaccine – induce local injection in Gene Therapy with applications to CANCER
- Therapeutic Vector Evolution DIscovery Platform: Overcoming hurdles 1st generation
4D Molecular Therapeutics:
Partnerships:
- Roche on Retina – opthalmology
- Pfizer – Cardiovascualr and
- Therapeutic Vector Evolution Discovery Platform
- D. Schaffer – Developed at UC, Berkeley – 4DMT Vector Discovery Programs:
- Human Organotypic Lung POC for Vector Evolution” 4DMT variant transduction superior to 1st gen AAV
- Untransduceed CF vs transduced two dominant motifs – hepatocytes
- Summary
- predictive biomarkers
- overcome ECM
- overcome antiviral immunity’pharmaceutical partnerships
- Optimize ICI combination
- more tumors injected prior to activation of immune system better results
2:30 Enhancing Oncolytic Virus Activity by Engineering of Artificial MicroRNAs
John Bell, Ph.D., Senior Scientist, Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Professor, Departments of Medicine and Biochemistry, Microbiology & Immunology, University of Ottawa We have devised a novel strategy to enhance the ability of oncolytic viruses to infect malignant cells by expressing artificial microRNAs (amiRNAs) from the oncolytic virus genome. We have screened a variety of amiRNAs and identified a number that enhance virus replication within tumour but not normal cells. The characterization of these miRNAs and their targets will be discussed.
- Immune adjuvant Gene therapy
- Iv/IT agents
- Virus
- OV – are exquisitely specific: Cancer cells – behavior
- multiple pahtologically activated pathways mitigate cellular antiviral response
- Pikor, Bell, Diallo (2015) Trends in CANcer Vol 1 266-277
- WNT pathway
- MEK
- Vascular attack by Rhabdovirus and Vaccinia OV
- VEGF inhibits interferone production leading to OV replication and spread
- Tumor/wounded OV infected endothelium –
- OV: A sustemic therapy for Metastatic Cancer
Tumor Specific Anti-VIral defects: – Patient/tumor Heterogeneity will impact Tx activity of OV
- Oncolysis
- antitumor Immune Activity
- Maraba virus: Oncolytic and vaccine candidate: Rhabdovirus Structure
- How to increase therapeutic potency?
- manipulate the infected Host cell with amiRNAs: Host determinants of Virus Repliccation
- Library screen on Pancreatic CancerP) of SV-LIB (16,000 unique clones) serial Passaging of viral go to deep sequencing = Large scale genome sreening to identity virus
- Enriched amiRNAs confer enhanced OV cytotoxicity
- ARID1A: member of SWI/SNF gene Family
- Helicase/ATpase – Synthetic Lethality – double mutant lethality
- GSK126: EZH2 inhibitor (an epiegnetic) HPAF II cells – virus– GSK126 — readout
- miRNA transfer via exosomes may mediate bystander effect
- OV Infection of Tumor cells Stimulates exosome secretion
- Is amiR6 present in exasomes shed by infected cells?
- miRNA transfer via exosomes
- Epstein-Barr virus-infected cells secrete exosomes that containn EBV-encoded miRNA (Pegtel et al, PNAS, 2010)
3:00 Refreshment Break
3:30 Immuno-Oncolytic Viruses as Cancer Therapies
Stephen Thorne, Ph.D., Professor and Scientific Advisor, Inventor, Western Oncolytics
Oncolytic viruses primarily act as immunotherapies, yet most vectors still rely on the virus’ inherent immune activation, often coupled to single cytokine transgene expression. However, for optimal activity they will need to overcome the tumor¹s immunosuppressive microenvironment, to raise anti-tumor CTL and allow repeated systemic delivery. Approaches to achieve all of these activities in a single vector are being developed.
- insitu vaccination
- capacity to modify immuno therapeutic activity
- Optimizing immune activation
- – Th1 vs Th2 response
- overcoming local immunosuppression wihtin the Tumor – get the OV overcome the immunosuppression
- Vaccinia infection of TLT2-/- mice resulted in reduced production of neutrlizing
- Re-direction TLP Activation – Toll-Like Receptor Signaling
- Deglycosylating viral practices reduced TLR2 activation
- Deglycosylating Vacinia – does os
- In vivo ablating TLR2 activation through Deglycosylation leads systemic delivery of the virus
- TRIF expression alters immune response and enhances therapeutic activity in vivo after single IV delivery of virus
- Deglycosylation evades anti-viral neutralizing antibody: Tumor Volume vs % neutralized
- Maximize immune activation, overcoming immunosupression
- MDSC – blocks the resistence – as tumor grows resistence increases – and cycolytic capabilities of the Viral therapy
- G-MDSC in tumor: % of cells vs PBS< anti-PGE2, celecoxib
- T-cell transfer
- Immune checkpoint blockade
- Optimized Imune activation
- Overcoming the localized immune suppression
- Over Effects, novel vector WO-12
4:00 Arming the Oncolytic Virus Enadenotucirev to Develop Tumor-Localized Combination Immunotherapeutics
Brian Champion, Ph.D., Senior Vice President, R&D, PsiOxus Therapeutics Ltd.
We have developed a systemically deliverable, oncolytic adenoviral platform for directing efficient and selective local production of a combination of biotherapeutic agents selectively within the tumor. This has the potential for enhanced efficacy while reducing side effects by limiting systemic exposure. Up to three separate biomolecules can be encoded in the same virus without affecting oncolytic properties of the virus.
- Endenotucirev (EnAd): Oncolytic, reduces tumor burden – Carcinoma Ovarian cancer
- “Armed” (ENAd): – Tumor-Specific Immuno
- Research Virus Platform: antibody production: Virus Replication
- Selectivity: Replication vs Anti-VEGF Ab vs Infectious Virus
- HT-29 vs Hepatocytes
- Human dendritic cells: 48h post co-culture with GFP-expressing (ENAd)
- Payload to the Virus: Stay on or in the infected cell,
- Next gen virus: TUmor cell activation signals: anti-tumor immune response by T-cells
- Cytokines: INFalpha,
- EnAd vs EnAd-CMV-EpBiTE
- 3 unique TRANSGENES can be secreted ot inseted into the plasma membrane
- NG-348 class immune-gene therapy
- CAR-T/TCR Immunotherapyactivation via antigen selection
- Activating ligand
- IFNgamma secretion
Summary
NG-348, lead candidate –> selective expression of ligands
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