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Archive for the ‘Oncolytic virus & OncoViro-Therapy’ Category


LIVE Tweets via @pharma_BI and by @AVIVA1950 for August 29 and August 30, 2016 of CHI’s 4th IMMUNO-ONCOLOGY SUMMIT – Oncolytic Virus Immunotherapy Track, Marriott Long Wharf Hotel – Boston

Curator: Aviva Lev-Ari, PhD, RN

 

  1. Aviva Lev-Ari‏@AVIVA1950  8m8 minutes ago

Real Time Coverage and eProceedings of Presentations on August 29 and August 30, 2016 CHI’s 4th IMMU… https://pharmaceuticalintelligence.com/2016/09/01/real-time-coverage-and-eproceedings-of-presentations-on-august-29-and-august-30-2016-chis-4th-immuno-oncology-summit-oncolytic-virus-immunotherapy-track/ … via @Pharma_BI

 

  1. Stephen J Williams‏@StephenJWillia2  5h5 hours ago

LIVE CONSIDERATIONS IN DESIGNING IMMUNOTHERAPY COMBINATIONS @CHI #IOSUMMIT #immunotherapy @AVIVA1950 https://pharmaceuticalintelligence.com/2016/08/30/150-500-830-considerations-in-designing-immunotherapy-combinations-immuno-oncology-summit-august-30-31-2016-marriott-long-wharf-hotel-boston-ma/ … via @Pharma_BI

  1. Stephen J Williams‏@StephenJWillia2  5h5 hours ago

PANEL DISCUSSION: ONCOLYTIC IMMUNOTHERAPY IN THE ERA OF CHECKPOINT BLOCKADE #IOSUMMIT #immunotherapy https://pharmaceuticalintelligence.com/2016/08/29/430-829-panel-discussion-oncolytic-immunotherapy-in-the-era-of-checkpoint-blockade-immuno-oncology-summit-august-29-30-2016-marriott-long-wharf-hotel-boston-ma/ … via @Pharma_BI

  1. Aviva Lev-Ari‏@AVIVA1950 9m9 minutes ago

Real Time Coverage and eProceedings of Presentations on August 29 and August 30, 2016 CHI’s 4th IMMU… https://pharmaceuticalintelligence.com/2016/09/01/real-time-coverage-and-eproceedings-of-presentations-on-august-29-and-august-30-2016-chis-4th-immuno-oncology-summit-oncolytic-virus-immunotherapy-track/ … via @Pharma_BI

 

  1. Stephen J Williams‏@StephenJWillia2  5h5 hours ago

LIVE CONSIDERATIONS IN DESIGNING IMMUNOTHERAPY COMBINATIONS @CHI #IOSUMMIT #immunotherapy @AVIVA1950 https://pharmaceuticalintelligence.com/2016/08/30/150-500-830-considerations-in-designing-immunotherapy-combinations-immuno-oncology-summit-august-30-31-2016-marriott-long-wharf-hotel-boston-ma/ … via @Pharma_BI

  1. Stephen J Williams‏@StephenJWillia2  5h5 hours ago

LIVE UNDERSTANDING MECHANISMS OF ACTION @IMMUNO-ONC SUMMIT#IOSUMMIT #immunotherapy @Aviva1950 @CHI https://pharmaceuticalintelligence.com/2016/08/29/live-955-1200-829-understanding-mechanisms-of-action-immuno-oncology-summit-august-29-30-2016-marriott-long-wharf-hotel-boston-ma/ … via @Pharma_BI

  1. Aviva Lev-Ari‏@AVIVA1950  Aug 30

#IOSUMMIT Plenary Keynotes TUESDAY 4:00PM – 5:30PM| AUGUST 30 @CHI‘s IMMUNO-ONCOLOGY SUMMIT, https://pharmaceuticalintelligence.com/2016/08/30/plenary-keynotes-tuesday-400pm-530pm-august-30-chis-immuno-oncology-summit-marriott-long-wharf-hotel-in-boston/ … via @Pharma_BI

  1. Aviva Lev-Ari‏@AVIVA1950 Aug 30

#IOSummit 1:50 – 5:00 8/30 CONSIDERATIONS IN DESIGNING IMMUNOTHERAPY COMBINATIONS @IMMUNO-ONCOLOGY https://pharmaceuticalintelligence.com/2016/08/30/150-500-830-considerations-in-designing-immunotherapy-combinations-immuno-oncology-summit-august-30-31-2016-marriott-long-wharf-hotel-boston-ma/ … via @Pharma_BI

 

  1. Aviva Lev-Ari‏@AVIVA1950  Aug 30

#IOSummit 1:15 – 3:15 8/30 TUMOR NEOANTIGENS FOR PERSONALIZED IMMUNOTHERAPY @IMMUNO-ONCOLOGY SUMMIT – https://pharmaceuticalintelligence.com/2016/08/30/115-500-830-tumor-neoantigens-for-personalized-immunotherapy-immuno-oncology-summit-august-30-31-2016-marriott-long-wharf-hotel-boston-ma/ … via @Pharma_BI

 

  1. Aviva Lev-Ari‏@AVIVA1950  Aug 29

#IOSummit 4:30 8/29 PANEL DISCUSSION: ONCOLYTIC IMMUNOTHERAPY IN THE ERA OF CHECKPOINT BLOCKADE https://pharmaceuticalintelligence.com/2016/08/29/430-829-panel-discussion-oncolytic-immunotherapy-in-the-era-of-checkpoint-blockade-immuno-oncology-summit-august-29-30-2016-marriott-long-wharf-hotel-boston-ma/ … via @Pharma_BI

 

  1. Aviva Lev-Ari‏@AVIVA1950  Aug 29

Stephen Russell of Mayo Clinic:#IOSummit – oncolytic therapy (OT) IS THE MAIN EVENT immune therapies will be used in conjunction with OT

2 retweets1 like

 

  1. Aviva Lev-Ari‏@AVIVA1950  Aug 29

#IOSummit LIVE 1:30 – 4:30 8/29 BIOMARKERS AND IMPROVING VIRUS ACTIVITY – AUGUST 29-30… https://pharmaceuticalintelligence.com/2016/08/29/live-130-430-829-biomarkers-and-improving-virus-activity-immuno-oncology-summit-august-29-30-2016-marriott-long-wharf-hotel-boston-ma/ … via @Pharma_BI

 

  1. Aviva Lev-Ari‏@AVIVA1950  Aug 29

#IOSummit LIVE 8:25 – 9:30 8/29 REALIZING THE POTENTIAL OF ONCOLYTIC VIRUS IMMUNOTHERAPY https://pharmaceuticalintelligence.com/2016/08/29/825-930-829-realizing-the-potential-of-oncolytic-virus-immunotherapy-immuno-oncology-summit-august-29-30-2016-marriott-long-wharf-hotel-boston-ma/ … via @Pharma_BI

 

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Real Time Coverage and eProceedings of Presentations on August 29 and August 30, 2016 CHI’s 4th IMMUNO-ONCOLOGY SUMMIT – Oncolytic Virus Immunotherapy Track

Curator: Aviva Lev-Ari, PhD, RN

Aviva Lev-Ari, PhD, RN,

Founder, LPBI Group & Editor-in-Chief

http://pharmaceuticalintelligence.com

Streamed LIVE @ Marriott Long Wharf Hotel in Boston

Leaders in Pharmaceutical Business intelligence (LPBI) Group

covered in Real Time the IMMUNO-ONCOLOGY SUMMIT using Social Media

http://www.immuno-oncologysummit.com/uploadedFiles/Immuno_Oncology_Summit/Agenda/16/2016-The-Immuno-Oncology-Summit-Brochure.pdf

Plenary Keynotes TUESDAY | AUGUST 30 4:00PM – 5:30PM @CHI’s IMMUNO-ONCOLOGY SUMMIT, Marriott Long Wharf Hotel in Boston

https://pharmaceuticalintelligence.com/2016/08/30/plenary-keynotes-tuesday-400pm-530pm-august-30-chis-immuno-oncology-summit-marriott-long-wharf-hotel-in-boston/

1:50 – 5:00 8/30 CONSIDERATIONS IN DESIGNING IMMUNOTHERAPY COMBINATIONS @IMMUNO-ONCOLOGY SUMMIT – AUGUST 30-31, 2016 | Marriott Long Wharf Hotel – Boston, MA

https://pharmaceuticalintelligence.com/2016/08/30/150-500-830-considerations-in-designing-immunotherapy-combinations-immuno-oncology-summit-august-30-31-2016-marriott-long-wharf-hotel-boston-ma/

1:15 -2:00 8/30 SELECTING PD-L1/PD-1 IMMUNOTHERAPY COMBINATIONS: Rational Combination Cancer Immunotherapy @IMMUNO-ONCOLOGY SUMMIT – AUGUST 30-31, 2016 | Marriott Long Wharf Hotel – Boston, MA

https://pharmaceuticalintelligence.com/2016/08/30/115-200-830-selecting-pd-l1pd-1-immunotherapy-combinations-rational-combination-cancer-immunotherapy-immuno-oncology-summit-august-30-31-2016-marriott-long-wharf-hotel-b/

1:15 – 3:15 8/30 TUMOR NEOANTIGENS FOR PERSONALIZED IMMUNOTHERAPY @IMMUNO-ONCOLOGY SUMMIT – AUGUST 30-31, 2016 | Marriott Long Wharf Hotel – Boston, MA

https://pharmaceuticalintelligence.com/2016/08/30/115-500-830-tumor-neoantigens-for-personalized-immunotherapy-immuno-oncology-summit-august-30-31-2016-marriott-long-wharf-hotel-boston-ma/

AUGUST 30 8:30 am TRANSLATIONAL AND CLINICAL UPDATES

https://pharmaceuticalintelligence.com/2016/08/30/august-30-830-am-translational-and-clinical-updates/

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

https://pharmaceuticalintelligence.com/2016/08/29/430-829-panel-discussion-oncolytic-immunotherapy-in-the-era-of-checkpoint-blockade-immuno-oncology-summit-august-29-30-2016-marriott-long-wharf-hotel-boston-ma/

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

https://pharmaceuticalintelligence.com/2016/08/29/live-130-430-829-biomarkers-and-improving-virus-activity-immuno-oncology-summit-august-29-30-2016-marriott-long-wharf-hotel-boston-ma/

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

https://pharmaceuticalintelligence.com/2016/08/29/live-955-1200-829-understanding-mechanisms-of-action-immuno-oncology-summit-august-29-30-2016-marriott-long-wharf-hotel-boston-ma/

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

https://pharmaceuticalintelligence.com/2016/08/29/825-930-829-realizing-the-potential-of-oncolytic-virus-immunotherapy-immuno-oncology-summit-august-29-30-2016-marriott-long-wharf-hotel-boston-ma/

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Plenary Keynotes TUESDAY | AUGUST 30 4:00PM – 5:30PM @CHI’s IMMUNO-ONCOLOGY SUMMIT, Marriott Long Wharf Hotel in Boston

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

Plenary Keynotes TUESDAY | AUGUST 30

4:00 Personalized, NeoantigenBased Immunotherapy

Edward Fritsch, Ph.D., Chief Technology Officer, Neon Therapeutics, Inc.

Multiple lines of evidence have demonstrated the critical role that Neoantigens have in the immune response to cancer and the availability of next-generation sequencing to identify personal, neoantigen-creating mutations has opened the door to directly enhance the power and breadth of host immunity to overcome this deadly disease.

  • Yervoy approved for melanoma ipilimumab
  • ipilimumab and Nivolumab combination
  • Cancer Vaccine for infections disease – PREVENTIVE NOT TREATMENT HPV
  • CLASSES OF TUMOR ANTIGENS CT many tumors: Methylation pattern
  • Selectively expressed: Melanomas
  • Over expressed antigens – some tumor

Personalized

Scientific Advance I:

  • Tumor DNA sequences: Kras, PIK3CA, FBXW7
  • Somatic mutations potential to generate neoantigens
  • Neoantigents: Native antigens (mage) vs NEOANTIGENS 0 tumor specific Antigens

Scientific Advance II:

  • Ipilimumab
  • anti PL-1
  • single neoantigen reactive CD4+ T cell clone mediates tumor rejection in adoptive therapy

A Neoantigen Vaccine – The Opportunity

  • T -cell capable of tumor infiltration

DFCI/Broad Institute: Tumor procurement, Target selection Personal caccine manufacturing Vaccine administration

  • Identify targets: accuracy, epitope features multipla epitopes
  • Personalised GMP manufacturing – 20 long peptide regulatory acceptance, time and cost

FDA approval:

  • High risk Melanoma (IIIB/C; IVM1a)
  • cancer with documented immune responsiveness
  • 12 patients enrolled – Vaccine prepared for 8, 6 dosed
  • Immunological Responses: DeNovo – detectable directly ex-vivo: ICS Primarily CD4+ Poly-functional
  • CD8+ Responses – 1 Pre-stim: Pre vs 16 weeks after
  • Immunizing peptide (IMP)

NEON Therapeutics, Inc.:

  • Personalized Neoantigens vs Shared Neoantigens
  • Vaccines vs T-Cells
  • Moving into Advanced Metastatic disease — COmbination Checkpoint blockade
  1. immediate response
  2. synergies by combination therapy
  3. Neoantigets

 

4:30 Merck Sasso 

Emerging Innate Immune Targets for enhancing 

  • Additional component of the Immune system
  1. Combination of Checkpoint inhibitors – Targeting functionality of T-Cells
  2. Standard of care moving to Goal State by Check point blocade
  3. Monoclonal antibodies blocking PD-1 and CTLA4
  4. Immunogenic cell death
  5. Effectors that promote cross presentation of antigens
  6. recruitment of T cells
  7. reversing the pathways driving a repressing tumor environment

MERCK – Keytruda

Study with Dinociclib – Immunogenic Cell Death – induced by Radiation, combined with CTLA4  – median response overall survival – 20 month

MORE OPTIONS:

  • OV therapies – enhance tumor Combination:
  1. TVEC +Keytruda – disease control 68%
  2. CAVATAK +Keytruda
  3. CAVATAK + pembrolizumab
  • TLR agonism
  1. Two Phase I in melanoma
  2. TC-1 Anti-IL-10 MK-1966 induced by SD-101
  3. Innate Immune Triggers against Pathogens and Damaged selt

 

  • STING agonism
  1. DNA Sensing cGAS/STING – another approach to viral mechanism for Cancer
  2. Non-nuclear dsDNA is a ‘danger
  3. DMXAA – can’t stimulate HUman only moth STING pathway
  • RNA – RIG like receptors –
  1. leveraging anti-viral Mechanisms to eliminate Tumors 
  2. Activation of RIG-like receptor

SHARED MECHANISMS: INFgamma, TNF alpha

  • TLR9
  • RIG-I
  • STING
  • Oncolytic viruses

Summary

  • Merck – Keytruda – will be combined with different strategies to leverage innate immunity in combination with traditional T cell approaches
  • expend beyond T cell
  • limitation of checkpoint blockade therapies can be due to aberrant T cell localization and the suppressive microenvironment of the tumor

 

5:00 Reading Tea Leaves: The Dilemma of Prediction and Prognosis in Immunotherapy

Morganna Freeman, D.O., Associate Director, Melanoma & Cutaneous Oncology Program, The Angeles Clinic and Research Institute

With the rapid expansion of immunotherapeutics in oncology, scientifically significant advances have been made with both the depth and duration of antitumor responses. However, not all patients benefit, or quickly relapse, thus much scientific inquiry has been devoted to appropriate patient selection and how such obstacles might be overcome. While more is known about potential biomarkers, accurate prognostication persists as a knowledge gap, and efforts to bridge it will be discussed here.

  • CD8+ T cell – Tumor — Imune Priming — CHeckpoint Inhibition  CD8+
  • execution is complex
  • predict who will benefit from what treatment
  • Patient and Tumor Profiling
  1. Tcell Prining: TILs, PDL1, IDO, Tcell anergy Treg- Ovarian cancer: CD8+ TILs
  2. microenvironment – immuno-scoring
  3. Immune competence -flow, biomarkers CyTOF – Mass Flow Cytometry
  4. mutation burden – chemo + Vaccine – longer time to progression
  5. mictoenvironment – Tumor Profiling
  6. tumor adaptation – serum ULBP2 NKligand – independent predictor of prognosis in Stage I-III
  7. Predictive Genomic Analysis – Immune SIgnature of Response to CHeckPoint Blockage – liquid biopsy
  8. Neoantigens: Allows analysis of T cell
  9. Multispectral imaging – Immune cell phenotypes visualized and quantified simultaneously – improve TME immune suppression, TIL harvest potential, location of the T celle impact prognosis
  10. Immune monitoring: Pre intervation vs Post Intervention
  11. Tumor heterogeneity: Cancer progression and metastasis, clinical resistance
  12. Intervention Assessments: Tissue marker of Blood which one is the best to use
  13. Cloonal Tracking: Quantifying Tumor
  14. ImmunoPET – anti CD8 immune-PET sensitive of tumor infiltrating
  15. Transcriptomic Signature: IPRES (innate PD-1 resistence) can be induced by MAPKi, furthe account for poor response – due to immune depletion
  16. Tests and immuno-toxicity, Translation to POC
  17. Data assimilation
  18. Ideal BioMarkers related to Mechanism of Action – multivariant scoring systems
  19. Gender differences, BMI differences, Age difference  — IN RESPONDING TO IMMUNOTHERAPY IN IMMUNO ONCOLOGY

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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

http://pharmaceuticalintelligence.com

Streaming LIVE @ Marriott Long Wharf Hotel in Boston

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

  • Phase I Intravenous
  1. VCN-01 – Pancreatic Cancer (IV)
  2. VCN-01 – Pancreatic Cancer (IT)
  3. 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
  1. systemic administration in mice
  2. 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. 1.2 DEATH OF LIVER METASTESIS
  2. REOLYSIN – ON LIVER METASTASIS = cross BBB, genetics: Ras Pathway defects
  3. REO 013: Liver metastasiss in REOLYSIN Monotherapy treated Pt
  4. RNA Transcription yes with REOLYSIN
  5. Post cycle 6 – vs. Post cycle 2 (radiation) vs. Pre-Treatment:
  6. Randomized Tumor-Specific Data: REOLYSIN/carboplatin/Paclitaxel/Combinations
  7. 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
  1. Does not work on Melanoma – it is IV and does not get to skin,
  2. 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:
  1. Adenovirus
  2. retrovirus – infect cancer cells and persists – unique RRV – Retroviral Replicating Vector – NOT lytic
  3. armed with 5-FC – CNS fungus infection – used for glioblastoma
  4. tumor produce his own drug after fungal infection
  5. RRV-CD reservoir  +5FC – become part of the CNS – continue infected cycle multiple times
  6. RRV – mediated Prodrug Survival 300 days without
  7. Immune activation, virus not immunogenic, T-cells vs Tumor Burden T-cells and B- cells infiltration causing decrease in tumor burden
  8. MDSC vs CD4 helper cells  vs CD8 cytotoxic cell
  9. Naive control vs Previosly cured at 30 days
  10. Anti tumor immunity – immunized T cells
  11. immunized unfractionated spleen cells
  12. RRV Administered — RRV spread through tumor
  13. High Grade Glioma (HGG) :
  14. 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 
  1. No vector
  2. IV
  3. Surgery intracranial local administration
  4. dose ascalation on 303 patients
  5. 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)
  1. PROVENCE
  2. Xtandi – Medivation bought by Pfizer
  • Head room vs cost
  • OV are diverse and have specific requirements
  1. 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
  1. MV – CEA – secreted from
  2. 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

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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

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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

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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

 

 

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