AUGUST 30 8:30 am TRANSLATIONAL AND CLINICAL UPDATES
http://www.immuno-oncologysummit.com/uploadedFiles/Immuno_Oncology_Summit/Agenda/16/2016-The-Immuno-Oncology-Summit-Brochure.pdf
Leaders in Pharmaceutical Business intelligence (LPBI) Group
covers in Real Time the IMMUNO-ONCOLOGY SUMMIT using Social Media
Aviva Lev-Ari, PhD, RN,
Founder, LPBI Group & Editor-in-Chief
Streaming LIVE @ Marriott Long Wharf Hotel in Boston
TUESDAY, AUGUST 30 8:00 am Morning Coffee
TRANSLATIONAL AND CLINICAL UPDATES
8:25 Chairperson’s Opening Remarks
Joe Conner, PhD, CSO, Virttu Biologics
8:30 Phase I of Intravenous Vcn-01 in Patients with Advanced Cancer: Update on Clinical & Biologic Data
Manel Cascallo, Ph.D., Co-Founder, President and CEO, VCN Biosciences
A first-in-human Phase I dose escalation study of intravenous administration of VCN-01 (an oncolytic adenovirus with RB tumour-targeting properties and expressing hyaluronidase) with or without gemcitabine and Abraxane is ongoing for patients with advanced solid tumours including pancreatic cancer. Dose dependent tolerability data and VCN-01 levels in different biological samples (including blood and tumour biopsies) are available.
- VCN-01 – Pancreatic Cancer (IV)
- VCN-01 – Pancreatic Cancer (IT)
- Retinoblastoma (leV) –
- ABD Technology 0 VCN-02
- Immunoshift Technology VCN-03
Pancreatic tumor Treatment: Abraxane/Gemcitabine – 1st line
IHQ alpha-adenovirus
Tumor matrix composition can pose limitations to intratumor adenovirus spreading
Genetically modified adinovirus – sensitivity of replication in tumor cells –>> biodistribution slectivity (tumor targeting) –. tumor potency (fdiffusion)
modification in the fiber RGDK of the virus
- Evidence of enhanced intratumoral spreading of oncolytic adenovirus after Hyal expression by adenovirus genome
- Evidence of Hyal activity at long time points after systemic administration of VCN-01
- Evidence of sensitization of chemotherapy (GE) after administration of VCN-01
- systemic administration in mice
- intratumoral administration in humster
Clinical Protocol – IV administration of VCN-01 — P-VCNA-001 ->> NCT02045602 – adenovirus in human
- Patients with advanced tumor – Pancreatic tumor Treatment: Abraxane/Gemcitabine – 1st line
- combination with standard
- Part 1:
- Part 2: recruiting ongoing
Toxicity Profile
- Level of virus in blood – VCN-01 low dose level by day 8 no level in blood
- increase of dose to 3,3E12 vp/patient – dose dependent – level in blood remains to day 28 then clearance
- Immune response analysis: NAb’s generation
- Level 1-1, 1-2, 1-3, 1-4
- Part 2: Pancreatic tumor Treatment: Abraxane/Gemcitabine – 1st line – 28 cycle: DAy 1 highest – tumor biopsy – PET imaging day 28 post administration – 50% (5/10) metastasis improvement — RECIST vs 1.1 – antitumor evaluation
- Level of Toxicity: febrile neutropenia when combine adenovirus with Abraxane/Gemcitabine = virus +drug ->> febrile neuropenia observed
- Part 2: Level in Blood Part 1 vs Part 2
- Active replication of virus in the body cause infectionSamples positive at both dose level, Positivity observed in pancreatic lesions primary and in liver mestastatis
Immuno Markers in intratumor Biopsies
- Pathways: PD-1/PDL1 AXIS Day 0 (+) vs CD8/T reg AXIS
- explanatory Endpoints evaluationvs. Day 28 (-) CD8+ in tumor core
Summary
- evidence of clinical activity has been obtained 3PR observed until now, 4/6 patients beyond stablished
- viral replication
- level of virus in blood not correlated with Positive effect on tumor core
9:00 Reolsyin: A Clinical Update of a Directed Cytotoxic Agent and Immune Modulator
Brad Thompson, Ph.D., CEO, Oncolytics Biotech – Publicaly traded
REOLYSIN was initially investigated for its potential as a selective cytotoxin. However, recent research shows that it also functions as an immune modulator. This dual mechanism of action for a single viral agent suggests that the potential of viral therapies may be broader than previously anticipated.
- proprietary isolate of wide-type REOVIRUS SEROTYPE 3 DEARING
- SAFETY PROFILE
- 1,100 PATIENTS TREATED +1,000IV
- NO MAXIMUM TOLERATED DOSE (MTD) REACHED
- FIVE STUDIES CONFIRMED AND RANDOMIZED
REOLYSIN TWO MOA as an Oncolytic Therapy
- REOLYSIN – DIRECTED CYTOTOXIN: RAS PATHWAY: BRAF, KRAS, NRAS, HRAS, EDFR, P53,
- REOLYSIN – IMMUNE THERAPY – brings Immune System to baseline
Free Survival and Overall Survival: Effect of Ras Pathway Activation and /or p53 mutations on Progression Time in Month — Progression free survival 15 month vs control 5 month
By gender: Colonal rectal, Chron more prevalent in Females
REOLYSIN as an Immune Therapy
- transcription
- translation
TWO MOA as an Immune Therapy
- Vaccine
- Check point inhibitor up-reregulation
Pre-Clinical Immune Model – Steele 1995
REO 013: CHanges in Blood CHemokines/Cytokines
- TRAIL
- INFeron
- activation of blood Immune Calls Post-REOLYSIN
- REOLYSIN Increases PDL-1 Expression
- Glioblastomas treated with REOLYSIN: productive reoviral infection showed increases PD-L1 expression
- Multiple Myeloma: PD-L1 – Checkpoint protein
Combination Therapy
- REOLYSIN with Carfilzomib in Multiple Myeloma
- Variable MARKERS: CD8, PD-L1, caspase-3, NK cells, CD68
- IDO-1, CTLA-4
- Intracraneal Murine Brain Cancer Model:
- % Survival: 50 days GM-CSF/REO, GM-CSF/REO, anti PD-1 +anti-CTLA4 – now in Pediatrics
- infiltration, proliferation, activates T-cell population
CANCER AND METASTESIS
- 1.2 DEATH OF LIVER METASTESIS
- REOLYSIN – ON LIVER METASTASIS = cross BBB, genetics: Ras Pathway defects
- REO 013: Liver metastasiss in REOLYSIN Monotherapy treated Pt
- RNA Transcription yes with REOLYSIN
- Post cycle 6 – vs. Post cycle 2 (radiation) vs. Pre-Treatment:
- Randomized Tumor-Specific Data: REOLYSIN/carboplatin/Paclitaxel/Combinations
- IND 210: Colon rectal : randomized Specific Data
- 51% increased reduction in median total liver tumor volume
- New colon rectal: Oncolytics: FOLFOX
Manufacturing – Commercial scale
Patent Portfolio: +400 patents issued Worldwide
Highlights
- REOLYSIN treated patients +1,100
- Does not work on Melanoma – it is IV and does not get to skin,
- REOLYSIN is effective for Pancreatic and Liver, colon rectal, head and neck
9:30 Retroviral Replicating Vectors for Cancer-Selective Immuno/Gene Therapy: Translational and Clinical Update
Noriyuki Kasahara, M.D., Ph.D., Professor, Departments of Cell Biology and Pathology, CoLeader, Viral Oncology Program, University of Miami
Pro-drug activator gene therapy with retroviral replicating vectors is tumor-selective, and can lead to development of anti-tumor immunity. Ascending dose Phase I trials by Tocagen Inc. in recurrent high-grade glioma demonstrated favorable safety and tolerability, intratumoral virus spread, radiographic responses, and survival surpassing historical benchmarks. Based on these results, a randomized controlled Phase II/III trial is now underway.
- Viruses as gene delivery vehicles:
- Adenovirus
- retrovirus – infect cancer cells and persists – unique RRV – Retroviral Replicating Vector – NOT lytic
- armed with 5-FC – CNS fungus infection – used for glioblastoma
- tumor produce his own drug after fungal infection
- RRV-CD reservoir +5FC – become part of the CNS – continue infected cycle multiple times
- RRV – mediated Prodrug Survival 300 days without
- Immune activation, virus not immunogenic, T-cells vs Tumor Burden T-cells and B- cells infiltration causing decrease in tumor burden
- MDSC vs CD4 helper cells vs CD8 cytotoxic cell
- Naive control vs Previosly cured at 30 days
- Anti tumor immunity – immunized T cells
- immunized unfractionated spleen cells
- RRV Administered — RRV spread through tumor
- High Grade Glioma (HGG) :
- Toca 511: RECURRENT gliomaindication Orphan Drug – gene present only in tumor sample
First in human injection of RRV Toca 511 in recurrent HGG
Favorable Safety Profile – for oncology drug
IV Study
Tocagen subject – Near complete response in Patients with Glioblastoma
Survival 70 weeks – Toca511: 13.6 month
- Higher dose cohort: 14.6 month
- 1st and 2nd Recurrence
49 Centers; 50% in US
Toca5: Ongoing Trial – 128 patients:
- GBM or AA with tumor <5cm and 1st and 2nd Recurrence
- No vector
- IV
- Surgery intracranial local administration
- dose ascalation on 303 patients
- alive after >1 year: Comparison
Efficacy in multiple Cancer types:
- Higher doses of RRV increased efficacy
- Systemic 5-FU – Toxicity
- Improve survival no trop in White blood cells
- Toca 6 Trial: University of Miami: New indication – IV studies
- Prodrug activator is the start killer gene added RRV MOA applied
10:00 Seprehvir, an Icp34.5 Deleted OHSV with Both Direct and Covert Modes of Action Joe Conner, Ph.D., CSO, Virttu Biologics
Seprehvir, an oncolytic HSV, is a complex biologic with multi-mechanistic modes of action. Lytic cytotoxicity, induction of Th1 cytokines/chemokine responses, recruitment of innate and adaptive immune cells and changes in the tumor microenvironment can enhance therapeutic efficacy in combination with other anti-cancer agents. How these modes of action intersect with PD-1 checkpoint inhibitors, CAR T cells and small molecule targeted therapies will be discussed. 10:30 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing
- Oncolutic immunotherapy induces anti-tumor immune response in patients
- Combination for apoptosis – direct lysis
- Seprehvir, an oncolytic HSV – Oncolytic Immune therapy
- Delivery Intratumoral – 83% systemic administration
- Mesothelioma (malignant Pleural (MPM)
- Seprehvir persistent in Pleural Fluid: HSV DNA, HMGB1, Cytokine signatures: Th1, Granzyme B, Immune Cells – three dose regime
- Isolate imune cells – Gene expression profiling of Immune cells recruited post Seprehvir: Binding density
- Seprehvir induces CD8+ Y cell infiltration and activity: CD3, CD8, FLT3 ligand – T-cell stimulatoe, NK cells, Fox3P,Granzyme B, Granulysin,
- Seprehvir induces: anti-tumor IgG immune response: Proteins associated: Ferritin, D52 like 1&3 and tumor antigens (Mage A8/9) – anti tumor response and anti viral response
- Noval IgG targets increases post Seprehvir
Combinations
- Seprehvir and PD-1: Increase CD4+ and CD8+
- CAR-T against GD2+ human Ewing Sarcome xenograft model – treated with PFU Seprehvir or PBS intratumorally on day 3,5,7
- Seprehvir combines synergistically with mTOR/VEGFR signaling axis, AKT, P13K, cMET/VEGFR
- Targeted therapies inhibit Seprehvir replication
- mTOR/TK inhibitors and Seprehvir – induces intrinsic apoptosis: Caspases
- Indication of synergies and apoptosis
- Maurine 3T6 cells export a death signal – infected with Seprehvir – causes cell death
- exported death signal MEK inhibitor and mTOR
- did not worked with MEK (GSK)
- Invitro in Cell lines: Seprehvir _ aurora Kinase A inhibitor Alisertib
- Combination Seprehvir with Alisertib in vitro
11:15 Virus Manufacturing Comes of Age: Turning Bugs into Features Anthony Davies, Ph.D., COO, 4D Molecular Therapeutics
Viruses destroy the host in which you’re trying to produce them and then must be separated from all components of those cells. Many solutions to these challenges have been invented since the earliest production of viral vaccines in primary cells obtained directly form animals. But few have proven amenable to cost-effective, compliant and scaleable operation.
- Glybera – AAV1 – Lipoprotein
- Imlygic – T-VEC atenuated HSV
- CMC = COGS (cost of Goods)
- PROVENCE
- Xtandi – Medivation bought by Pfizer
- Head room vs cost
- OV are diverse and have specific requirements
- Master Cell Banks & Master Virus Banks
Personalized Gene Therapy
- Centralized manufacturing – cold storage
- Distributed manufacturing – consistency across sites
Adenovirus
- non-enveloped icosahedral nucleocaspid
- affinity, anion
HSV
- enveloped icosahedral caspid
- 120-300nm
- 152 kb dsDNA
Measles Family Virus
- enveloped icosahedral nucleocaspid
4DMT Manufacturing Methodology – JMP Statistical Discovery Software
- Control chart
- long term continuous process improvement
- Technology Transfer
- Campaign monitoring
- Reference standard
- Precision makes Perfect
- qPCR titration of AAV viral genomes (Precision for one variant 33%, closely related 22%
4DMT Analytical Processes
Design of Experiment – Design Space – range of parameters
- JMP SW- Optimal design
- DOE SW
11:45 Manufacturing Large Enveloped Oncolytic Viruses for Human Clinical Trials
Mark J. Federspiel, Ph.D., Professor and Director, Viral Vector Production Laboratory, Mayo Clinic
The large-scale production and purification of larger enveloped oncolytic viruses are particularly challenging. We have developed enveloped virus GMP production processes using suspension cells in combination with gentle but effective purification using hollow fiber tangential flow filtration that result in greater than 99.5% removal of contaminants and greater than 100-fold increases in final infectious virus titers.
- Measles Viruses – a promising oncolytics – easy to sheer, toxic
- Local vs systemic (more) – concentration and titer different
- Reporter Gene: genomic contamination – Vaccine – neutralizer efficient release – Aseptic throughput
- – size 100-300 nM – envelop Virus
- MV – CEA – secreted from
- MV-NIS
- FDA Concerns:
- Genomic DNA contanimation
- risk vs benefit to patient
- Initial Large-Scale Production method for MV-NIS – Optimized – composition of product after purification – Purification Steps – for standard titer
- 3 micron initial filter bioprocess bags
- FLOW FILTRATION USING HOLLOW-FIBER CARTIDGES
- buffer control
- anti measle vaccine getting titer dose
- HeLA S3 – suspension – serum free – Aseptically Vialed Clinical Product
- Protein concentration
- DNA concentration – residual cellular DNA in MV-NIS Preps
- 10 to power of 10 and 10 to the power of 11 dose possible
- Residual cellular DNA in MV-NIS Preps
- None of HPV genomes are intact
- analysis of MV-NIS residual DNA by qPCR: HeLA S3 dilution vs MV-NIS dilution
- Tumorgenicity of large amount of noval agents – studies published of no risk of
WHY Patient 11.2 responded so well?
12:15 pm Close of Oncolytic Virus Immunotherapy
Like this:
Like Loading...
Read Full Post »
2012pharmaceutical
sjwilliamspa