Leaders in Pharmaceutical Business Intelligence (LPBI) Group

LIVE 9:55 – 12:00 8/29 UNDERSTANDING MECHANISMS OF ACTION @IMMUNO-ONCOLOGY SUMMIT – AUGUST 29-30, 2016 | Marriott Long Wharf Hotel – Boston, MA

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

http://pharmaceuticalintelligence.com

Streaming LIVE @ Marriott Long Wharf Hotel in Boston

Curation of Scientific Content @Leaders in Pharmaceutical Business Intelligence (LPBI) Group, Boston

 

9:55 – 12:00 UNDERSTANDING MECHANISMS OF ACTION

9:55 Chairperson’s Remarks

Fares Nigim, M.D., Massachusetts General Hospital and Harvard Medical School

First phase:

• OV infection/replication

Second phase

• Immune response

Clinical considerations: viral delivery, Patient’s selection, Biomarkers, combination with Immunomodulators

 

10:00 Designing Clinical Trials to Elucidate Oncolytic Virus Mechanisms-of-Action

Caroline Breitbach, Ph.D., Vice President, Translational Development, TurnstoneBiologics

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.

• Mechanism of Action:
• Clinical trial design and choosing population
• Pex-Vec: Oncolytic Vaccinia – Infection and SPread within tumors follwoing IV AdministrationCCRC vd Ovarian cancer
• dose threshold for IV delivery Defined
• Tumor-specific Trnsgene
• dose-dependent induction of antibodies to beta-galactosidase
• Delayed Virema and evidence of GM-CSF Expression – day 4 nad Day 6
• Oncolytic Viral Immunotherapy: Oncolytic Virus and T-cell Vaccine
• Maraba MG1 Oncolytic Virus – Rhabdovirus Structure – from insects not a human pathogen.
• MG1 boosts immunity- engage memory T cells,
• Unique Biology of T Cell Boosting:

1. virus infects follicular B cells: Lung metastesis DCT Prima, DCT Boost
2. COmparison MG1 to other Vaccine Platforms
3. Immunecheck Inhibitors – combined to augment Immune activity in preclinical models
4. T- cells recruited to tumors post Ad-GM!
5. MAGE-A3: in Human in CLinical studies – fresh peripheral blood underwent in vitro stimulation with MAGE-A3 peptide pools for 6 hours follwoed by staining and flow
6. First Human CLinical Trial – Status: Enrolling – 70 patients

• Arm A, B, C and Pahse II: Prescreen MA3, Screening CT/biopsy ADvirus Biopsy CT
• MOA – Amplification in tumor
• transgene expresion systemic delivery induction of anti-viral antibodies/immunity
• Efficacy ENdpoints:
• Radiographic endpoints
• Cancers with tumor markers
• must ensure suggogate endpoints are approvable
• Acute reduction of Perfusion after Pexa-Vec Treatment
• unmasking of existing lesions
• response in non-injected tumors: baseline, week 8,20
• Lymphocytic inflitrate
• Selection of Patient Population: Injectable Unresectable Stage IIIB -IV

Liver Cancer: HCC – First-lineLow and High dose

Phase 2b – Second-line: Single agent NOT approriate for advanced disease

Pharmacokinetics – unique Replication-dependent PK

• GM-CSF – cytokine autoimmunity

10:30 T- Stealth Technology Mitigates ANtagonism between Oncolytic Viruses and the Immune System through Viral Evasion of ANti-Viral T-Cells

Matthew Mulvey, PhD, CEO, BeneVir

Virus evading immune response – resist interferon

T-Vec vs T-Stealth = viral spread continues enhanced efficacy

T-Stealth – unique ability to evade clearance by T-cells in order to permit stimultaneous co-administration of OV and immune checkpoint inhibitors

• evades of T-cells
• induction and systemic anti tumor T-cells
• synergy with checkpoint
• Efficacy of repeat dose
• Inhibitor of innate immunity, T-cell
• Bladder cancer MBT-2 injection bi-lateral : T-Stealath + AntiPD1 + CTLA4
• improved T-Cell receptor diversity in untreated tumors suggestin that t-Stealth induces immune response system to target a wider range of tumor neo-antigens

DRUG PROFILE

1. Replicate,spread
2. mitigate antagonism with checkpoint inhibitorscan be armed with 3 additional transgenes to promote anti-tumor
3. One stop shopping
4. systemic OV dosing:
5. more efficacious because virus spreads

 

11:00 Improving Oncolysis and Therapy with Pharmacologic Modulation – Glioblastoma

Antonio Chiocca, Professor & Chairman, Department of Neurosurgery , Brigham & Women’s Hospital/ Harvard Medical School

Glioblastoma (GBM) – survival 15 month – heterogenous, target therapies – FAILED, subclones – mutation burden – OV – injection into tumor

• if inject into the Brain – bad effect – tolerated, efficacy NOT established
• Current therapies aimed at ICP6 – Herpes+ Nestin
• HSV strain attenuated ICP4 mutation
• UL39
• Mice models: Animal survival is 80% when OV is injected 7 days
• Animal survival is 50% when OV is injected 14 days after tumor implant
• GBM Clinical Trial
• VPA – Valporic Acid – FDA approved – antitumor efficacy of Herpes-based OV – Histone deacetylase
• HDAC6 – major deacetylase in cytoplasm – improves shuttling of post-entry oHSV into nuclei vs lysosomes
• 2015 – Histone deacetylase  6 Inhinbition enhances OV replication in glioma
• The nestin promoter in rQNestin34.5
• VPA demethylate oncolytic HSV promoter
• barriers to OV therapy and maneuvers to circovent
• Transcript profile analyses of Glioma
• NK cells are recruited to brain GBM following oncolytic HSV
• PD-L1 expression in Glioma Stem cells after oHSV
• immunocompetent mouse Glioma cells that replicate oHSV to high levels – testing
• Conclusions

 

 

11:30 Moving Toward MultiFunctionality in PoxvirusBased Oncolytic Virotherapy

Eric Quemeneur, Ph.D., Pharm.D., Executive VP and CSO, Transgene

Poxviruses are powerful immunotherapeutics and tumor-targeting platforms. We recently expanded Transgene’s portfolio of armed oncolytic Vaccinia Viruses (oVV) by engineering a vector that targets anti-PD1 IgG expression into the tumor. Local concentration of virus-encoded antibody was ~10-50 times higher than the reference mAb, leading to significant improvement of survival in a sarcoma preclinical model. Such results announce the next-generation OVs, combining immunogenic oncolysis with the capacity to deliver complex therapeutic modalities in the tumor micro-environment.

• The merit of poxyviruses for UV – envelop Virus – cytosol replocation
• suitable for molecular engineering: large genome
• Enzyme – Fcu1 VV(TK-RR-)-Fcu1
• FCU1 is a chimeric bifunctional enzyme
• Activity of TG6002 in human tumors: Growth control: SKOV (ovarian) and U87-MG (control) Ovarian
• TG6002 also active on Cancer stem cells, compatible with Chemotherapy: Human Pancreatic Cancer

Activity in immuno-competent models –

• TG6002 (WR) in mice synergy study and
• Lymphocyte infiltration into the tumor
• Complementarity with PD1 blocker
• induce abscopal response – effect on survival
• Combination OV/ICI in the clinic
• Genetic recombination of mAb expression cassettes

1. IgG
2. Fab
3. scFv

T cell depletion experiment – Anti- CD4 and CD8

Pre-Clinical results – in vivo expression and biodistribution of WR-mAb1

• Tumor growth inhibition & survival (MCA205 sarcoma model
• Overcoming the tumor access barrier
• cavitation-enhanced ultrasonic virus delivery

Summary

• Poxviruses – safe, potent and versatile
• IV route
• synergy with other immunotherapies
• platform is customizable