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4:30 8/29 PANEL DISCUSSION: ONCOLYTIC IMMUNOTHERAPY IN THE ERA OF CHECKPOINT BLOCKADE @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

 

4:30 8/29 PANEL DISCUSSION: ONCOLYTIC IMMUNOTHERAPY IN THE ERA OF CHECKPOINT BLOCKADE

Robert Coffin, Ph.D., CEO,

Replimmune Ltd Oncolytic immunotherapy treats cancer by virus-mediated tumor cell lysis and generation of a patient specific cancer vaccine, including to neo-antigens, in situ directly in the patient. Both are likely important for the clinical efficacy seen with single agent use, and also for the clinical synergy observed with immune checkpoint blockade. Background and data supporting single agent and combination use will be discussed, and future directions described.

  • synergistic with other therapies
  • 15 years of basic research now is available

David Kirn, MD, CEO, 4D Molecular Therapeutics

  • comnibation VT with IT
  • deliver into the tumor MDs are not agents og change, oral drug IV, IT injections intratumorally by Interventional Radiology is a fight worth fighting
  • Ovarian cancer – injection was a strugle
  • injection in to the eye is now the practice
  • IV
  • Angiogenic paradigm was throughn out
  • synergies with antivascular

Mattew Mulvey, PhD, CEO, BeneVir

  • consensus was IV ot iT
  • IT dosing targeting the tumor for IV dosing –  need ne IT in present time
  • Interested in the microboome, manipulate to achieve goals,
  • consolidation in the industry is unavaidable

John Bell, PhD, University of Ottawa

  • approval of single agent will change
  • viral particles to be used

Stephen Russell, MD, PhD, Mayo Clinic and VYRID

  • OV is the main event, other IT will be used in conjunction with OT which will LEAD the Therapy 
  • vascular enthotelium
  • cell therapyas carriers will act like vessels
  • Systemic delivery from AMGEN, Phase III is a proof
  • cycle of drug approval is 15 years, good is the enemy of Better, minor improvals are nmany

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

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

 

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?
  1. identify patients
  2. efficacy
  3. cost/avoid over/under tretment
  4. molecular therapeutics understandin
  5. PD1 – expression is the ONLY biomarker we currently have for eligibility to participate
  6. Biomarker discovery – Biopsy or blood, many indicators to measure

Biological challenges: Tumor and lesion heterogeneity

  1. detection frequency for DNA vs. protein serum vs imaging modality
  2. prior treatment
  3. Circadian rhythm

Technical/Logistical

OV Immunotherapy

  1. Tumor cell intrisic factors
  2. Host Factore
  3. 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
  1. 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

  1. predictive biomarkers
  2. 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:

  1. Roche on Retina – opthalmology
  2. Pfizer – Cardiovascualr and
  3. Therapeutic Vector Evolution Discovery Platform
  4. D. Schaffer – Developed at UC, Berkeley – 4DMT Vector Discovery Programs: 
  5. Human Organotypic Lung POC for Vector Evolution” 4DMT variant transduction superior to 1st gen AAV
  6. Untransduceed CF vs transduced two dominant motifs – hepatocytes
  7. Summary
  8. predictive biomarkers
  9. overcome ECM
  10. overcome antiviral immunity’pharmaceutical partnerships
  11. Optimize ICI combination
  12. 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
  1. WNT pathway
  2. MEK
  3. Vascular attack by Rhabdovirus and Vaccinia OV
  4. VEGF inhibits interferone production leading to OV replication and spread
  5. Tumor/wounded OV infected endothelium –
  6. 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
  1. Maraba virus: Oncolytic and vaccine candidate: Rhabdovirus Structure
  2. 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


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

 

 


LIVE 8:25 – 9:30 8/29 REALIZING THE POTENTIAL OF ONCOLYTIC VIRUS IMMUNOTHERAPY @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

 

8:25 – 9:30 REALIZING THE POTENTIAL OF ONCOLYTIC VIRUS IMMUNOTHERAPY

 

LIVE 8:25 Chairperson’s Opening Remarks

Brian Champion, Ph.D., Senior Vice President, R&D, PsiOxus Therapeutics Ltd

  • Different viruses
  • Engineering
  • Manufacturing: CMC
  • Systemic vs IT Delivery
  • Tumor Markers environment: Tumor cell lysis and immune response
  • Biomarkers Clinical Development
  • Role of Pre-clinical Models
  • regulatory affairs

8:30 T-Vec: From Market Approval to Future Plans

Jennifer Gansert, Ph.D., Executive Director, Global Development Lead, IMLYGIC, Amgen, Inc.

Talimogene laherparepvec (T-VEC) is a modified herpes simplex virus type -1 designed to selectively replicate in tumors and to promote an anti-tumor immune response. T-VEC is approved for metastatic melanoma based on a randomized phase III trial; T VEC significantly improved durable response rate vs GM-CSF. Data from the pivotal trial and combination studies with checkpoint inhibitors will be presented.

T-VEC – HSV-1

  • Viral Protein:
  1. ICP47 – Deleltion ,
  2. ICP34.5 – Deletion ,
  3. US11 – Temporal expression,
  4. GM-CSF – Insertion
  • Engineering Change:
  1. Injected Tumor
  2. Contralateral tumors
  • Dual MOA
  • Administration: Largest lesion first, 4 cycles of injections
  • OpTim – Phase III: N = 436 Stage III-IV Melanoma
  • T-VEC (N = 295)
  • GM-CSF (N=141)
  • Key ENTRY Criteria
  • END POINT: Primary and Secondary – Survival benefit
  • 2/3 – prior infection with HIV – melanoma not resectable with spread to lymph nodes
  • Response rate with T-VEC: 30% response 2/3 – control of the disease
  • Lesion-Level, Lesion-Type Response Analysis
  • Overal Survival:Over 20% reduction of burdon
  • Retrospective analysis: If not spread yet to lymph nodes: Best response to treatment
  • Early disease stage and early therapy are correlated
  • T-VEC double survival vs GM-CSF
  • Adverse effects: Cellulitis

Phase I

Phase II

Phase III

  • Regulatort Interactions for US BLA – Full approval in 10/2015
  • Rationale for Combination wiht CHeckPoint Inhibitors
  1. Immunologic response:
  2. Control
  3. OncoVEX mGM-CSF
  4. CTLA4
  5. Ipilimumab – 3
  6. Pembrolizumab -4
  7. Neoadjuvant – 2
  8. unserectable safety  – 1
  • Changes in Tumor Burden by DIsease CHange
  • Progression-Free Survival – 72%
  • Adverse events: as expected
  • Phase II design: Pembrolizumab 200mg
  • Monotherapy vs Combination
  • Address multiple Tumor type: Menaloma, RCC, mCRC, BrCA, Gastric, NSCLC, HCC
  • Other: Head & Neck (completed), Pacreatic (completed), Hepatic injection (ongoing), Pediatric study (planned)

9:00 Oncolytic Virotherapies as a Single Shot Cure?

Stephen J. Russell, M.D, Ph.D., Professor, Mayo Clinic

VYRIAD, CEO

Oncolytic virotherapy is increasingly used as a cancer immunotherapy. However, certain oncolytic viruses can also mediate wholesale tumor destruction independently of an antitumor immune response. This is the oncolytic paradigm, where a cytolytic virus with preferential tumor tropism spreads extensively at sites of tumor growth and directly kills the majority of the tumor cells in the body leaving only a few uninfected tumor cells to be controlled by the concomitant antitumor immune response.

  • Virus – does the heavy lifting – small virus inoculum, local spread, systemic virus spread – via blood stream -VIREMIA – killing of infected cells Immune response help Virus elimination
  • Engineer virus: Tropism, dose, route
  • Immune response: Killing Uninfected cells killing tumors cells
  • Second exposure – preformed antibodies: Viremia – neutrilized + Memory cytotoxic T-Cells CTL
  • Oncolytic ViroTherapyFirst dose more effecitve then subsequence
  • VSV- Vesiculat Stomatisis Virus: IFNbeta and NIS
  • SIngle dose: Intratumorally: complete regression – controlling tumor
  • Reaching mestastesis: IV delivery
  • After systemic delivery: Mode of Virus spread in Tumors: tumor distruction: density of tumors: Delivery and SPread
  • Second and subsequent – Ovarian Cancer: single dose vs six doses: no significant (three doses – NO additional therapeutic benefit
  • Pet-dog with lynphoma: Multi center – single shot
  • HUMAN: Clinical Trial in Mayo, Arizona, Redractory/Intolerant HCC: In Patient 12:necrosis of the tumors, markers: HCC – metastasis to ColonRectal Cancer – developed Day 13 Hepatorenal outcome – virus infected non-injected tumors
  • NGS – error rat 1 in 1000 of virus genome sequence – 164 mutations 103 coding and 61 are noncoding or silent mutations
  • What determined rapid virus spear in Patient12: 4 gees of thr 84 genes:
  1. antiviral state
  2. antiviral sensing and signaling
  3. IFN signaling
  4. Antigen processing and presenation

NOW Companion Diagnostics is been developed

CASE: Measles Seronegative: – Complete response to IV MV-NIS  – patient with melanoma

  • no systemic response – Oncolytic debulking and lasting immune control

Summary

  1. Single shot cure for cancer – and likely transform Cancer care
  2. Oncolytic and Immune two MOA – killing infected and uninfected tumor cells

Success: monitor viral spread

  1. exploit first dose
  2. develop tests to match with tumor
  3. combine with immuno modulatory drugs
  4. continue create better viruses

VYRIAD: Companion Diagnostic: Lung, Head & Neck, Bladder


What's The Big Data?

Google_YahooMany of the obituaries for Yahoo have contrasted its demise with the flourishing of Google, another Web pioneer. Why was Google’s attempt to “organize all the world’s information” vastly more successful than Yahoo’s? The short answer: Because Google did not organize the world’s information. Google got the true spirit of the Web, as it was invented by Tim Berners-Lee.

In his book Weaving the Web, Tim Berners-Lee writes:

I was excited about escaping from the straightjacket of hierarchical documentation systems…. By being able to reference everything with equal ease, the web could also represent associations between things that might seem unrelated but for some reason did actually share a relationship. This is something the brain can do easily, spontaneously. … The research community has used links between paper documents for ages: Tables of content, indexes, bibliographies and reference sections… On the Web… scientists could escape from the sequential organization of…

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Harvard Medical School researchers pinpoint enzyme that triggers cell demise in ALS – Blocking enzyme’s activity is the target for patient therapy

Reporter: Aviva Lev-Ari, PhD, RN

August 24, 2016 |
SOURCE

RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS


Chest Radiation Therapy causes Collateral Damage to the Human Heart

Reporter: Aviva Lev-Ari, PhD, RN

“Radiation therapy for some forms of cancer involves a large dose of radiation to the chest,” says Milind Desai, MD, Director of Cardiovascular Imaging Research at Cleveland Clinic. “The heart can suffer collateral damage as a result.”

Guideposts for identification

The key to identifying true radiation-associated heart disease, says Dr. Desai, is later injury — whether constrictive pericarditis, coronary artery disease, valvular disease or conduction abnormalities. He adds that the prevalence of radiation-associated heart disease is difficult to ascertain, due in part to its considerable latency, although it appears to be increasing.

Risk factors for radiation-associated heart disease include:

  • Total radiation dose > 20-35 Gy
  • Doses > 2 Gy/day
  • Increased volume of heart irradiated
  • Younger age
  • Time since exposure
  • Concomitant cardiotoxic chemotherapy
  • Other cardiovascular risk factors (diabetes mellitus, smoking)
  • Radiation source (cobalt)

SOURCE

Radiation Heart Disease: A Few Learnings on a Diverse, Daunting Entity

Heart Surgery to a Damaged Heart by Radiation

Patients undergoing cardiothoracic surgery at Cleveland Clinic over a three-year period had a 2.5-fold elevated mortality risk if they had a history of malignancy requiring chest irradiation compared with matched controls who underwent the same surgery but did not have a history of malignancy or chest irradiation. Most of the patients with the cancer history had had either

  • Breast cancer (53 percent) or
  • Hodgkin lymphoma (27 percent).
Long-Term Survival of Patients With Radiation Heart Disease Undergoing Cardiac Surgery

A Cohort Study

Willis Wu, Ahmad Masri, Zoran B. Popovic, Nicholas G. Smedira, Bruce W. Lytle, Thomas H. Marwick, Brian P. Griffin and Milind Y. Desai

Alternative treatment approaches, including transcatheter aortic valve replacement or other percutaneous interventions, may be more appropriate after identifying risk.

 

Other related articles published on this Open Access Online Scientific Journal include the following:

Cardio-oncology and Onco-Cardiology Programs: Treatments for Cancer Patients with a History of Cardiovascular Disease

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/08/cardio-oncology-and-onco-cardiology-programs-treatments-for-cancer-patients-with-a-history-of-cardiovascular-disease/

 

Series A: e-Books on Cardiovascular Diseases

Series A Content Consultant: Justin D Pearlman, MD, PhD, FACC

VOLUME THREE

Etiologies of Cardiovascular Diseases:

Epigenetics, Genetics and Genomics

http://www.amazon.com/dp/B018PNHJ84

by  

Larry H Bernstein, MD, FCAP, Senior Editor, Author and Curator

and

Aviva Lev-Ari, PhD, RN, Editor and Curator

https://pharmaceuticalintelligence.com/biomed-e-books/series-a-e-books-on-cardiovascular-diseases/volume-three-etiologies-of-cardiovascular-diseases-epigenetics-genetics-genomics/

 

  • Cardiovascular Diseases, Volume Three: Etiologies of Cardiovascular Diseases: Epigenetics, Genetics and Genomics, on Amazon since 11/29/2015

http://www.amazon.com/dp/B018PNHJ84

onepagecvdseriesaflyervol1-4

 

 

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