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


Cancer Cell Therapy: Global Start up Acquisitions in Oncolytic Viruses (OV) Therapeutics – a Pipeline of 70 OVs in Clinical Development and another 95 in Preclinical Programs

 

Reporter: Aviva Lev-Ari, PhD, RN

 

September 2018 

  • Boehringer Ingelheim is buying ViraTherapeutics in $244M deal

Boehringer Ingelheim joins the crowd and goes all-in on oncolytic viruses, buying ViraTherapeutics in $244M deal

https://endpts.com/boehringer-ingelheim-joins-the-crowd-and-goes-all-in-on-oncolytic-viruses-buying-viratherapeutics-in-244m-deal/?utm_medium=email&utm_campaign=Thursday%20September%2013%202018&utm_content=Thursday%20September%2013%202018+CID_61414a80a0003abe24ea7e26fafb3eab&utm_source=ENDPOINTS%20emails&utm_term=Boehringer%20Ingelheim%20joins%20the%20major%20league%20players%20with%20a%20buyout

 

May 2018

  • J&J executed one of its classic billion-dollar deals to buy BeneVir.

J&J’s Janssen to Acquire BeneVir for $1 Billion

May 09, 2018
By Pharmaceutical Technology Editors

Janssen Biotech, part of Janssen Pharmaceutical Companies, a subsidiary of Johnson & Johnson (J&J), announced on May 2, 2018 that it has entered into a definitive agreement to acquire BeneVir Biopharm (BeneVir), a biotechnology company specializing in the development of oncolytic immunotherapies.

BeneVir is a portfolio company and subsidiary of HC2 Holdings’ Pansend Life Sciences, which is focused on developing healthcare technologies and products. Benevir uses a proprietary T-Stealth Oncolytic Virus Platform to engineer oncolytic viruses tailored to infect and eliminate cancer cells.

Under the terms of the agreement, Janssen will make an upfront cash payment of $140 million at closing of the transaction, plus additional contingent payments of up to $900 million based on achievement of certain predetermined milestones. The total amount of all payments could exceed $1 billion if all milestones are met. The closing of the transaction is subject to customary closing conditions, including clearance under the Hart-Scott-Rodino Antitrust Improvements Act. The transaction, which was facilitated by J&J Innovation, is expected to close in the second quarter of 2018.

SOURCE

http://www.pharmtech.com/jj-s-janssen-acquire-benevir-1-billion-0

 

May 2018

  • A recent study from the Cancer Research Institute found 69 OVs in clinical development and another 95 in a preclinical program.

New Report on the Global Landscape of Cancer Cell Therapy Highlights Robust International Pipeline Marked by Rapid Growth

  • A comprehensive, neutral analysis of the global cancer cell therapy landscape
  • 753 cancer cell therapies in the global development pipeline, with 375 in clinical studies
  • 350 new cancer cell therapies have entered the global development pipeline since Sep. 2017, an 87% increase in less than 7 months
  • 113 targets are being pursued in 7 different classes of cell therapies

NEW YORK, May 25, 2018—The Cancer Research Institute (CRI) announced today the publication of a report that provides a comprehensive, independent analysis of the global landscape of cancer cell therapies, including all agents from preclinical to post-market stages. This report provides a quantitative and current overview of the cancer cell therapy field, reveals the unparalleled speed of the field’s expansion, highlights exciting innovations in the development pipeline, and advises strategies to advance the field as a whole.

The report, titled “The Global Landscape of Cancer Cell Therapy,” appeared online today in Nature Reviews Drug Discovery, a premium journal from Nature Publishing Group and an authoritative source of information in drug discovery and development. This report, which expands on CRI’s previously published landscape analysis of the entire field of immuno-oncology, highlights the geographic distribution of cancer cell therapies worldwide and identifies the dominant presence of CAR T therapies in the cancer cell therapy space.

“The quantitative analyses from this report reveal unprecedented enthusiasm and innovation in the global cell therapy pipeline,” said Jill O’Donnell-Tormey, Ph.D., chief executive officer and director of scientific affairs at the Cancer Research Institute.

“In addition to traditional powerhouses of drug development such as the United States or European countries, many other countries, especially China, have significant presence in this space,” noted Jun Tang, Ph.D., a senior research analyst for the CRI Anna-Maria Kellen Clinical Accelerator program and first author on the report.

To access the interactive dashboard of the report, visit the CRI website at cancerresearch.org/io-cell-therapy.

Reference
Tang J. et al. Global landscape of cancer cell therapy. Nature Reviews Drug Discovery. 25 May 2018. doi:10.1038/nrd.2018.74

SOURCE

https://www.cancerresearch.org/news/2018/global-landscape-of-cancer-cell-therapy-report

 

February 2018

  • Merck’s R&D chief Roger Perlmutter — who steered the T-Vec deal at Amgen — bagged Viralytics for $394 million.
FEBRUARY 21, 2018 / 4:29 AM / 7 MONTHS AGO

Merck to buy virus-based cancer drug firm Viralytics for $394 million

(Reuters) – U.S. drugmaker Merck & Co (MRK.N), already one of the leaders in the hot area of cancer immunotherapy, said on Wednesday it had agreed to buy Viralytics VLA.AX for 502 million Australian dollars ($394 million) to expand its pipeline in the sector.

Merck will pay 1.75 Australian dollars per share for the Sydney-based biotech company, which uses viruses to infect and kill cancer cells.

The idea is to cause cancer cells to rupture and die, while also stimulating a wider immune system response in the body.

SOURCE

https://www.reuters.com/article/us-viralytics-m-a-merck-co/merck-to-buy-virus-based-cancer-drug-firm-viralytics-for-394-million-idUSKCN1G50ZN

 

Hum Vaccin Immunother. 2018; 14(4): 839–846.
Published online 2018 Feb 22. doi:  10.1080/21645515.2017.1412896
PMCID: PMC5893211
PMID: 29420123

Talimogene laherparepvec: First in class oncolytic virotherapy

ABSTRACT

Oncolytic viruses represent a novel drug class in which native or modified viruses mediate tumor regression through selective replication within and lysis of tumor cells as well as induction of systemic antitumor immunity capable of eradicating tumor at distant, uninjected sites. Talimogene laherparepvec (TVEC) is a type I herpes simplex virus genetically modified to preferentially replicate in tumor cells, enhance antigen loading of MHC class I molecules and express granulocyte-macrophage colony-stimulating factor to increase tumor-antigen presentation by dendritic cells. It is presently the only oncolytic virus approved by the FDA with an indication for advanced melanoma based upon improved durable response rate in a randomized, phase III trial. Clinical trials are underway in melanoma investigating TVEC as neoadjuvant monotherapy and in combination with checkpoint inhibitors for unresectable disease as well as in an array of other malignancies. It is appropriate to review TVEC’s biology mechanism of action, clinical indication and future directions as a prototype of the burgeoning class of oncolytic viruses.

SOURCE

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5893211/

October 2015 

  • Amgen’s landmark approval of T-Vec, the world’s first marketed oncolytic virus.

FDA approves cancer-killing cold sore virus as therapy for late-stage melanoma

October 28, 2015, University of Utah Health Sciences
melanoma
Melanoma in skin biopsy with H&E stain — this case may represent superficial spreading melanoma. Credit: Wikipedia/CC BY-SA 3.0

The U.S. Food and Drug Administration announced on Oct. 27 that it has approved, for the first time, an oncolytic (cancer-killing) viral therapy in the United States. The drug was approved for use against late-stage melanoma, a deadly skin cancer that can be difficult to treat.

The approval came as the result of a recent Phase III study, which showed that more patients with late-stage melanoma, treated with a herpes cold sore virus designed to kill , had a better response when compared to a different treatment. Robert Andtbacka, M.D., from Huntsman Cancer Institute at the University of Utah and Howard L. Kaufman, M.D., from Rutgers Cancer Institute of New Jersey, led the multisite study, published May 26 online in the Journal of Clinical Oncology.

SOURCE

https://medicalxpress.com/news/2015-10-fda-cancer-killing-cold-sore-virus.html

 

Additional Sources

T Cell Engineering Breakthrough Sidesteps Need for Viruses in Gene-Editing
UCSF News Center | Pete Farley | July 11, 2018

With Faster, Cheaper, More Precise Technique, Authors Say It’s ‘Off to the Races’ Toward New Cell

The basic unit of life. The number of cells in a living organism ranges from one (e.g. yeast) to quadrillions (e.g. blue whale). A cell is composed of four key macromolecules that allow it to function (protein, lipids, carbohydrates, and nucleic acids). Among other things, cells can build and break down molecules, move, grow, divide, and die.

” aria-describedby=”tt”>CellTherapies

In an achievement that has significant implications for research, medicine, and industry, UC San Francisco scientists have genetically reprogrammed the human immune cells known as T cells without using Virus

An infectious entity that can only persist by hijacking a host organism to replicate itself. Has its own genome, but is technically not considered a living organism. Viruses infect all organisms, from humans to plants to microbes. Multicellular organisms have sophisticated immune systems that combat viruses, while CRISPR systems evolved to stop viral infection in bacteria and archaea.

” aria-describedby=”tt”>viruses to insert DNA

Abbreviation of deoxyribonucleic acid, a long molecule that encodes the information needed for a cell to function or a virus to replicate. Forms a double-helix shape that resembles a twisted ladder. Different chemicals called bases, abbreviated as A, C, T, and G, are found on each side of the ladder, or strand. The bases have an attraction for each other, making A stick to T while C sticks to G. These rungs of the ladder are called base pairs. The sequence of these letters is called the genetic code.

” aria-describedby=”tt”>DNA. The researchers said they expect their technique — a rapid, versatile, and economical approach employing CRISPR

Pronounced “crisper.” An adaptive immune system found in bacteria and archaea, co-opted as a genome engineering tool. Acronym of “clustered regularly interspaced short palindromic repeats,” which refers to a section of the host genome containing alternating repetitive sequences and unique snippets of foreign DNA. CRISPR-associated surveillance proteins use these unique sequences as molecular mugshots as they seek out and destroy viral DNA to protect the cell.

” aria-describedby=”tt”>CRISPR Gene

A segment of DNA that encodes the information used to make a protein. Each gene is a set of instructions for making a particular molecular machine that helps a cell, organism, or virus function.

” aria-describedby=”tt”>gene-editing technology — to be widely adopted in the burgeoning field of cell therapy, accelerating the development of new and safer treatments for Cancer

A type of disease caused by uncontrolled growth of cells. Cancerous cells may form clumps or masses known as tumors, and can spread to other parts of the body through a process known as metastasis.

” aria-describedby=”tt”>cancer, autoimmunity, and other diseases, including rare inherited disorders.

The new method, described in the July 11, 2018 issue of Nature, offers a robust molecular “cut and paste” system to rewrite Genome

The entire DNA sequence of an organism or virus. The genome is essentially a huge set of instructions for making individual parts of a cell and directing how everything should run.

” aria-describedby=”tt”>genome sequences in human T cells. It relies on electroporation, a process in which an electrical field is applied to cells to make their membranes temporarily more permeable. After experimenting with thousands of variables over the course of a year, the UCSF researchers found that when certain quantities of T cells, DNA, and the CRISPR “scissors” are mixed together and then exposed to an appropriate electrical field, the T cells will take in these elements and integrate specified genetic sequences precisely at the site of a CRISPR-programmed cut in the genome.

“This is a rapid, flexible method that can be used to alter, enhance, and reprogram T cells so we can give them the specificity we want to destroy cancer, recognize infections, or tamp down the excessive immune response seen in autoimmune disease,” said UCSF’s Alex Marson, MD, PhD, associate professor of microbiology and immunology, member of the UCSF Helen Diller Family Comprehensive Cancer Center, and senior author of the new study. “Now we’re off to the races on all these fronts.”

But just as important as the new technique’s speed and ease of use, said Marson, also scientific director of biomedicine at the Innovative Genomics

The study of the genome, all the DNA from a given organism. Involves a genome’s DNA sequence, organization and control of genes, molecules that interact with DNA, and how these different components affect the growth and function of cells.

” aria-describedby=”tt”>Genomics Institute, is that the approach makes it possible to insert substantial stretches of DNA into T cells, which can endow the cells with powerful new properties. Members of Marson’s lab have had some success using electroporation and CRISPR to insert bits of genetic material into T cells, but until now, numerous attempts by many researchers to place long sequences of DNA into T cells had caused the cells to die, leading most to believe that large DNA sequences are excessively toxic to T cells.

SOURCE

https://innovativegenomics.org/news/t-cell-engineering-breakthrough-sidesteps-viruses/

 

Cancer Res. 2016 Aug 15; 76(16): 4627–4636.

Published online 2016 Jun 3. doi:  10.1158/0008-5472.CAN-15-3455

PMCID: PMC5295843

CAMSID: CAMS5780

PMID: 27261504

Design and Reporting of Targeted Anticancer Preclinical Studies: A Meta-Analysis of Animal Studies Investigating Sorafenib Antitumor Efficacy

James Mattina,1 Nathalie MacKinnon,1 Valerie C. Henderson,1 Dean Fergusson,2 andJonathan Kimmelman

 

Other 17 related articles published in this Online Scientific Journal include the following:

https://pharmaceuticalintelligence.com/category/oncolytic-virus-oncoviro-therapy/

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Emerging STAR in Molecular and Cell Biology, Synthetic Virology and Genomics: Clodagh C. O’Shea: ChromEMT – Visualizing 3D chromatin structure


Emerging STAR in Molecular Biology, Synthetic Virology and Genomics: Clodagh C. O’Shea: ChromEMT – Visualizing 3D chromatin structure

 

Curator: Aviva Lev-Ari, PhD, RN

 

On 8/28/2017, I attend and covered in REAL TIME the CHI’s 5th Immune Oncology Summit – Oncolytic Virus Immunotherapy, August 28-29, 2017 Sheraton Boston Hotel | Boston, MA

https://pharmaceuticalintelligence.com/2017/08/28/live-828-chis-5th-immune-oncology-summit-oncolytic-virus-immunotherapy-august-28-29-2017-sheraton-boston-hotel-boston-ma/

 

I covered in REAL TIME this event and Clodagh C. O’Shea talk at the conference.

On that evening, I e-mailed my team that

“I believe that Clodagh C. O’Shea will get the Nobel Prizebefore CRISPR

 

11:00 Synthetic Virology: Modular Assembly of Designer Viruses for Cancer Therapy

Clodagh_OShea

Clodagh O’Shea, Ph.D., Howard Hughes Medical Institute Faculty Scholar; Associate Professor, William Scandling Developmental Chair, Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies

Design is the ultimate test of understanding. For oncolytic therapies to achieve their potential, we need a deep mechanistic understanding of virus and tumor biology together with the ability to confer new properties.

To achieve this, we have developed

 

Clodagh O’Shea’s Talk In Real Time:

On Twitter:

Engineer Adenovirus Caspids prevent Liver uptake and Sequestration – Natural Ad5 Therapies C. O’Shea, HHDI

Scientist’s Profile: Clodagh C. O’Shea

http://www.salk.edu/scientist/clodagh-oshea/

EDUCATION

BS, Biochemistry and Microbiology, University College Cork, Ireland
PhD, Imperial College London/Imperial Cancer Research Fund, U.K.
Postdoctoral Fellow, UCSF Comprehensive Cancer Center, San Francisco, U.S.A

VIDEOS

http://www.salk.edu/scientist/clodagh-oshea/videos/

O’Shea Lab @Salk

http://oshea.salk.edu/

AWARDS & HONORS

READ 

Clodagh C. O’Shea: ChromEMT: Visualizing 3D chromatin structure and compaction in interphase and mitotic cells | Science

http://science.sciencemag.org/content/357/6349/eaag0025

and 

https://www.readbyqxmd.com/keyword/93030

Clodagh C. O’Shea

In Press

Jul 27, 2017 – Salk scientists solve longstanding biological mystery of DNA organization

Sep 22, 2016 – Clodagh O’Shea named HHMI Faculty Scholar for groundbreaking work in designing synthetic viruses to destroy cancer

Oct 05, 2015 – Clodagh O’Shea awarded $3 million to unlock the “black box” of the nucleus

Aug 27, 2015 – The DNA damage response goes viral: a way in for new cancer treatments

Apr 12, 2013 – Salk Institute promotes three top scientists

Oct 16, 2012 – Cold viruses point the way to new cancer therapies

Aug 25, 2010 – Use the common cold virus to target and disrupt cancer cells?

Oct 22, 2009 – Salk scientist receives The Sontag Foundation’s Distinguished Scientist Award

May 15, 2008 – Salk scientist wins 2008 Beckman Young Investigator Award

Mar 24, 2008 – Salk scientist wins 2007 Young Investigator’s Award in Gene Therapy for Cancer

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LIVE – 8/29 – CHI’s Oncolytic Virus Immunotherapy and ADOPTIVE CELL THERAPY, August 28-29, 2017 Sheraton Boston Hotel | Boston, MA


LIVE – 8/29 – CHI’s Oncolytic Virus Immunotherapy and ADOPTIVE CELL THERAPY, August 28-29, 2017 Sheraton Boston Hotel | Boston, MA

ANNOUNCEMENT

Leaders in Pharmaceutical Business Intelligence (LPBI) Group will cover the event in

REAL TIME

Aviva Lev-Ari, PhD, RN will be streaming live from the floor of the Sheraton Hotel in Boston on August 28 and August 29, 2017

@pharma_BI

@AVIVA1950

#IOSummit

http://www.immuno-oncologysummit.com/imx-content.aspx?id=158189

http://www.immuno-oncologysummit.com/Oncolytic-Virus-Immunotherapy/

http://www.immuno-oncologysummit.com/T-Cell/

 

TUESDAY, AUGUST 29

7:00 am Registration

7:25 Breakout Discussion Groups with Continental Breakfast

ONCOLYTICS IN AN ERA OF COMBINATION THERAPIES

8:25 Chairperson’s Opening Remarks

Matthew Mulvey, Ph.D., CEO, BeneVir Biopharm, Inc.

8:30 Rationale for Oncolytic Viruses as the Backbone of Combination Immunotherapy Regimens

Robert Coffin, PhD., Co-founder and CEO, Replimune

Oncolytic viruses (OVs) mediate anti-tumor activity through direct cell lysis and induction of host anti-tumor immunity. The ability to attract and activate T cells within the tumor microenvironment and induce interferon release suggests that OVs could be used as the backbone in combination immunotherapy strategies designed to promote anti-tumor immunity. Emerging clinical data is demonstrating significant improvement in studies of melanoma, and further clinical development for other cancers is anticipated.

9:00 FEATURED PRESENTATION: Developing Tumor-Specific Immunogene (T-Sign) Combination Immunotherapies by Arming the Oncolytic Group B Adenovirus Enadenotucirev

Brian_ChampionBrian R. Champion, Ph.D., CSO, Psioxus Therapeutics Ltd.

We have developed a broadly applicable platform system, based on the potent chimeric oncolytic adenovirus enadenotucirev (EnAd), for directing the selective localized production of a combination of immunotherapeutic agents within tumors following systemic dosing, while minimizing the potential for systemic off-target effects of such combination approaches. The presentation will highlight recent data supporting both the platform and specific T-SIGn virus candidates.

9:30 T-Stealth Technology Promotes Synergy between Oncolytic Viruses and Immuno-Stimulatory Agents

Matt_MulveyMatthew Mulvey, Ph.D., CEO, BeneVir Biopharm, Inc.

BeneVir is developing an OV platform based on T-Stealth Technology, which hides infected cells from anti-viral T-cells. This allows an OV to complete its replication program, produce progeny viruses, and spread in the tumor microenvironment despite a robust anti-viral T-cell response. In immune-competent murine tumor models, regimens that simultaneously combine immuno-stimulatory agents with T-Stealth armed OV show efficacy. However, there is no effect on tumor burden in these models when simultaneous combination regimens utilize a “Visible” OV that does not encode T-Stealth Technology. BeneVir’s lead OV will enter a Phase I trial in solid tumors in Q2 2018.

10:00 Poster Presentation: Neural Stem Cell Mediated Oncolytic Virotherapy for Ovarian Cancer

Jennifer Batalla, Graduate Student, Karen Aboody Laboratory Irell & Manella Graduate Program

10:30 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing

11:15 What Does It Take to Cure Glioblastoma; Combinations Plus?

Samuel_RabkinSamuel D. Rabkin, Ph.D., Professor, Neurosurgery, Massachusetts General Hospital and Harvard Medical School

We will discuss combination therapies for glioblastoma in representative preclinical models, involving oncolytic herpes simplex viruses (oHSV), cytokine expression, and immune checkpoint inhibitors. OHSV induce anti-tumor immunity and can be armed with therapeutic transgenes. The complex multicomponent strategy illustrates both the difficulty in treating non-immunogenic tumors and the opportunities in coupling immunovirotherapy with other immunotherapeutic approaches.

  1. GBM highly Immunosuppressive Cancer
  2. Impairment of MHC Class I presentation
  3. CG80, CD86 – down regulation of co-stimulatory molecule, Kb MHC I Db MHC I NKligand
  4. oHSV induces anti-tumor immunity
  5. armed with immune modulatory transgenes
  6. Immune checkpoint inhibitors can reduce immunosuppression in tumor and boost immune response
  7. Targeting Cancer Stem cells – permissive to cure – (GSC) Model (005)

11:45 Oncolytic Virus-Induced Rad51 Degradation: Synergy with Poly(Adp-Ribose) Polymerase Inhibitors in Treating Glioblastoma

Jianfang_NingJianfang Ning, Ph.D., Instructor, Neurosurgery, Massachusetts General Hospital, Harvard Medical School

Oncolytic herpes simplex virus (oHSV) sensitized glioblastoma stem cells (GSCs) to poly(ADP-ribose) polymerase inhibitors (PARPis), irrespective of their PARPi sensitivity through selective proteasomal degradation of key DNA damage response protein, Rad51, mediating the combination effects. This synthetic lethal-like interaction increased DNA damage, apoptosis, and cell death in vitro and in vivo. Combined treatment of mice bearing PARPi-sensitive or -resistant GSC-derived brain tumors greatly extended survival compared to either agent alone.

  1. DNA Demage: SIngle strand break, double strand break, bulky sdducts, base mismatch insertion/deletion, base alkalation
  2. PARP inhibition
  3. PARPi combination with anti-cancer – PARPi and oHSV increase apoptosis and DNA damage
  4. Genetic engineering of oHSV confers cancer PARPi-selectivity and PARPi-resistant GSCs
  5. Rad51
  6. oHSV inhibits HR
  7. oHSV-induces proteasomal degradation of Rad51 mediates  – Rad51-silencing abrogates the synergy between PARPi and oHSV
  8. infiltration: Intracelebral vs Intra-tumor
  9. Induction of aptosis and DNA demage in brain tumors in vivo
  10. oHSV – selective disruptor of DDR – penetrates BBB,

12:15 pm Close of Oncolytic Virus Immunotherapy

 

Cambridge Healthtech Institute’s 4th Annual

Adoptive T Cell Therapy

Delivering CAR, TCR, and TIL from Research to Reality
August 29 – 30, 2017 | Sheraton Boston | Boston, MA

 

Greater understanding of T cell biology as well as promising patient outcomes have led to immunotherapies accelerating at an unprecedented pace. With multiple engineered receptors making an impact, many biotech and pharma companies are already entering clinical trials in a race to get to market. However, with the end goal being the same – improved patient outcomes – there is still work to be done. Cambridge Healthtech Institute’s Fourth Annual Adoptive T Cell Therapy event will focus on the steps needed to deliver CAR, TCR, and TIL therapies to the patient by examining emerging science, autologous immune cell products, and allogenic immune cell products. Overall, this event will address clinical progress, case studies, and critical components to make adoptive T cell therapy work.

 

Final Agenda

TUESDAY, AUGUST 29

12:00 pm Registration

PART I: WHAT’S NEW IN ADOPTIVE CELL THERAPY

 

KEYNOTE SESSION

1:15 Chairperson’s Opening Remarks

Kite Pharma was acquired by Gilead on 8/28/2017

http://www.businessinsider.com/why-gilead-bought-kite-pharma-for-12-billion-2017-8

1:20 Building Better T Cell Therapies: The Power of Molecular Profiling

Mark Bonyhadi, Ph.D., Head, Research and Academic Affairs, Juno Therapeutics

Chimeric antigen receptor (CAR)-T cells are a promising new modality for cancer immunotherapy and many variants are rapidly being developed across the immuno-oncology space for haematological and solid tumor malignancies. The field has displayed enormous promise, however the rules governing which attributes drive efficacy are still being learned. Here, we present early insights from transcriptomic and epigenetic profiling of CAR-T cells describing how cell state may play an important role.

1:50 Tricked-Out Cars, the Next Generation of CAR T Cells

Richard Morgan, Ph.D., Vice President, Immunotherapy, Bluebird Bio

Genetically-engineered CAR T cells are designed to supplement a patient’s immune system and can be further engineered to survive and overcome immune evasion mechanisms employed by tumors. We found that addition of a PI3-kinase inhibitor during manufacturing enriched for memory-like CAR T cells without complicated cell sorting procedures. These methodologies, combined with synthetic biology and gene editing, can be considered for the further development of CAR T cell technology.

2:20 SPEAR T Cells for Solid Tumor Therapy

Mark Dudley, Ph.D., Senior Vice President, Bioprocessing, Adaptimmune

Adoptive cell transfer with gene modified T lymphocytes is effective for some advanced cancer indications. Specific peptide engineered antigen receptor (SPEAR) T cells that recognize the NY-ESO-1 cancer-testes antigen have shown promise in early phase trials for melanoma, multiple myeloma, and synovial sarcoma. Combination therapies and product improvements are being explored, and a registration trial is planned. Numerous tumor antigen candidates predicted from proteomic and HTS analysis of tumor specimen NAS have been used to generate new SPEAR T cells. T cells targeting MAGE-A10, MAGE-A4, and AFP are approved for initial evaluation in clinical trials in new solid tumor indications in 2017. A robust manufacturing platform that generates multiple SPEAR products for exploratory registration studies will be discussed. Challenges in scaling out successful autologous cell therapies and opportunities for implementing automation and improving T cell products will be assessed.

Miltenyi_Biotec2:50 The Generation of Lentiviral Vector-Modified CAR-T Cells Using an Automated Process

Boro DropulicBoro Dropulic, Ph.D., General Manager and CSO, Lentigen Technology, Inc.

Participants will learn about: 1) How Lentiviral vectors are a proven robust technology to genetically modify cells 2) The Development of a large-scale lentiviral vector manufacturing process using a chemically defined, serum free suspension bioreactors 3) How automation using the CliniMACS Prodigy is a robust and cost effective method to generate patient specific CAR-T cells 4) The design and testing of CAR constructs – factors that influence in vivo efficacy 5) How automation provides options for the manufacture of CAR-T cell products: Centralized vs Decentralized models.

  1. Very stealth – no genotoxicity
  2. efficient transduction
  3. HIV vector, AIDS
  4. Implementation of suspention Serum-Free Chemically-dependent
  5. USA cGMP
  6. Generic and novel CD19 CAR-T LV – demonstrated target-specisif lysis in vivo, eliminated Raji tumors in vivo in mice
  7. Patients achieveing neagtive remission

3:20 Refreshment Break in the Exhibit Hall with Poster Viewing

 

4:00 PLENARY KEYNOTE SESSION

4:00 Regulatory and Scientific Considerations for Cancer Vaccines and Adoptive Cellular Immunotherapy

Graeme E. Price, Ph.D., Research Microbiologist, Gene Transfer & Immunogenicity, FDA CBER

Cell and Gene therapy including therapeutic vaccines and cellular immunotherapy products are evaluated at FDA’s Center for Biologics Evaluation and Research in the Office of Tissues and Advanced Therapies (OTAT) previously known as Office of Cellular, Tissue and Gene Therapies. I will discuss current general regulatory and scientific considerations in the regulation of therapeutic cancer vaccines and cellular immunotherapy. In addition, research activities in OTAT will be summarized.

  1. Fast track designation – Eligible: (AA) (PR)
  2. (FT)
  3. Breakthrough Therapy (BT) Multidisciplinary Meeting
  4. Accelerated Approval (AA) will include Post-Marketing Requirement (PMR) for a confirmatory study: Biomarkers
  5. Priority Review (PR)
  6. Common Reasons for BTDR Denial: appropriateness
  1. Adoptive T Cell Therapies – Gene modified T Cells
  2. Complex Manufacturing Process
  3. Typical CAR construct: Complex Vector Design: SIgnal 1 + SIgnal @2012pharmaceuticalCD19 IND Applications
  4. Product Characterization in Immunotherapy: demonstrate comparability, quality of growth factors and cells

CART-T Cells: Safety Issues and Concerns:

FDA Pilot CAR T-cell DB Project Objectives: CMC and Clinical Safety

SOURCES on FDA Website

 

4:45 Market Access and Reimbursement for Immuno-Oncology Drugs in Today’s Healthcare System

Gergana Zlateva, Ph.D., Vice President, Payer Insights and Access, Oncology, Pfizer

Now that immunotherapies have hit the market, with the promise of more to come, the healthcare system will need to establish standards for cost and reimbursement of immuno-oncology agents. This talk will address how the healthcare marketplace can prepare for the adoption of novel pricing and reimbursement models to increase patient access to immunotherapies. Establishing the value of IO therapies to payers and HTAs will also be addressed in the context of pricing and evidence generation.

Click here for keynote biographies

# of Treatment Options:

Investigational COumpounds for NSCLC: Cytotoxin, Targeted tx, Immunotherapy: Marketed, Pre/Reg, Phase III, Phase II

COST of Oncology & Supportive Care Cost Globally

  1. Efficacy, Safety, Relative Efficacy, Relative Value (Cost-Benefit Analysis), Budget Impact (# of candidates for a given budget)
  2. Value of Immuno-Oncology – Assessment:
  1. ICER (Evidence Reports),
  2. OSCO Value Framework),
  3. NCCN (Evidence Blocks),
  4. DrugPricingLab (Oncology Drug Abacus), Memorial Sloan Kettering
  1. Triple Aim/ Institute for HC Improvement 2008
  2. HC Services
  3. Pharmaceuticals: Financial-based
  4. Value based in the US: Medicaid Best price, Medicare part B, 340B, anti-kickback statues
  5. Specific to Oncology:
  6. PFS, OS, HR, CR – not captured in medical claims data
  7. Outcomes Agreements: Genetech – Priority Health Outcomes-Based Pilot

 

 

5:30 Welcome Reception in the Exhibit Hall with Poster Viewing

5:30 Dinner Short Course Registration*

SC1: Bioinformatics for Immuno-Oncology and Translational Research

SC2: Microbiome in Immuno-Oncology

*Separate registration required, please click here for more information.

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LIVE – 8/28 – CHI’s 5th Immune Oncology Summit – CHI’s 4th Oncolytic Virus Immunotherapy, August 28-29, 2017 Sheraton Boston Hotel | Boston, MA


LIVE – 8/28 – CHI’s 5th Immune Oncology Summit – Oncolytic Virus Immunotherapy, August 28-29, 2017 Sheraton Boston Hotel | Boston, MA

ANNOUNCEMENT

Leaders in Pharmaceutical Business Intelligence (LPBI) Group will cover the event in

REAL TIME

Aviva Lev-Ari, PhD, RN will be streaming live from the floor of the Sheraton Hotel in Boston on August 28 and August 29, 2017

@pharma_BI

@AVIVA1950

#IOSummit

 

http://www.immuno-oncologysummit.com/Oncolytic-Virus-Immunotherapy/

 

MONDAY, AUGUST 28

7:30 am Registration & Morning Coffee

LATEST UPDATES AND FUTURE DIRECTIONS IN ONCOLYTIC VIRUS IMMUNOTHERAPY

8:25 Chairperson’s Opening Remarks

Brian R. Champion, Ph.D., CSO, Psioxus Therapeutics Ltd.

  • Virus: Design, Selection, Pre-Clinical Testing

8:30 KEYNOTE PRESENTATION: Engineering and Bio-Selection to Optimize an Oncolytic Virus Platform

John_BellJohn Bell, Ph.D., Senior Scientist, Center for Innovative Cancer Research, Ottawa Hospital Research Institute

Oncolytic viruses are therapeutics that are designed or selected to specifically infect and destroy cancer cells. There are multiple strategies that can be employed to create viruses that replicate in and kill tumors; however, one common feature of malignant cells is that they lack a potent anti-viral response. I will discuss the molecular basis for these defects, how best to exploit them to create tumor killing therapeutics and strategies to improve manufacturing output of oncolytic viruses from manufacturing cell lines based upon these principles.

Oncolytic Viruses (OV)

  • Anti Vascular, Selective Oncolytic Replicating Cancer Gene Therapy Immune Adjuvant
  • OV selective to Tumor cells  – selectivity of OV – Cellular Anti-Viral Responses and Malignant Evolution-Incompatibilite?
  • p53, Ras, Rb, Wnt, PTEN, VPV, E6/E7, VEGF, FGF2
  • OV Therapy – exploits Cancer biology – Cellular Antiviral Responses – multiple pathologically activated Pathways
  • Bio-Selection of Optimal Oncolytic Virus Strains
  • Maraba Oncolytic Virus Platform – Rhabdovirus Structure, Life cycle, Key Features: no genotoxicity. Systemic Theraphy for Metastatic Cancer: Lang Tumours, Targeted Infection, Tumour Clearance
  • Viccinia Virus as systemic Therapeutics – PexaVec (Sillajen, Transgene)
  • How do SYStemically delivered Oncolytic Viruses ENTER tumours? – selective infection of tumor vascular EndothelialCells – response to cell proliferation
  • In ovarian cancer
  • Localized infection affects microenvironment – cytokines – nano string analysis 2 days post IV Infection — increase in PD-1 expression
  • personalized InSitu Vaccine
  • Oncolytic Herpes Virus expressing activation of T-Cells
  • Effects are Stochastic and unpredictable
  • OV — T-Cell Vaccine: COmbine principles of Vaccinology and OVTherapy
  • adivo virus  + Maraba-Tumour Ag–>> ptoduced TCell Responses: Prime Immune analysis –>> Boost immune analysis: %IFNgCD8+ T Cells – Days Post engraftment
  • Patient Heterogeniety: Immunr stimulating Activity Gene thHerapy

IMPROVING THE TARGETING AND EFFICACY OF ONCOLYTIC VIRUSES

9:00 Tumor Selective HSV-Based Oncolytic Vectors for Treatment of GBM

Paola_GrandiPaola Grandi, Ph.D., Senior Research Director, Immunology/Virology, Oncorus, Inc.

Oncorus oHSV is controlled by certain microRNAs (miRNAs) that are present in healthy cells, but absent in cancer cells. Typically, miRNAs regulate the ability of classical messenger RNA (mRNAs) to be translated into protein or promote the degradation of mRNAs. By engineering miRNA binding sites into essential viral genes, oHSV replication and cellular destruction is prevented in healthy cells. Since cancer cells lack these specific miRNAs, Oncorus oHSV is free to replicate in and destroy them.

  • Harnessing the body’s power to fight tumors – Developing Best-in-class Next-Gen oHSV Vectors to trigger Immune response
  • Infection of Tumor cells >> Oncolysis –>>
  • Glioblastoma Multiforme: Lead Candidate -ONCR-001 – when armed with immune modulatoring payloads, shows more promising results: Vehicle: Oncorus Unarmed oHSV (matrix modification); Armed oHSV (matrix modification +xx)
  • Insertion of miR-Target Cassettes Controls Expression of Essential  Viral Genes and Payloads
  • Proof of Concept: no neurotoxicity of miR controlled virus after intracrenial injection, WT HSV-1 fatal
  • Multiple-miR Attenuation nenables pursuit of Cancer beyond Brain (Liver)
  • Robust Neurovirulence Factor: Attenuates neurotoxicity; Inhibits autophagy by binding to Beclin-1; Inhibit IDO: indirect regulation – IDO expands, recruits and activates MDSCs, converts trytophan to kynurenine production stimulated by IFNgamma
  • Targeted Viral Entry for replication – remove portion of native gD gene and insert EDFR binding domain
  • Receptor Engineering: WIld type, gD
  • EGFR retargeted vector: Tumor Volume vS Days after virus injection – Intracranial HSV injection in normal and in GBM mice
  • Enhanced Viral Spreading: Control vs EGFR-retargeted vs Matrix Modified Payload  + EGFR-retargeted (Immune Modulatory)  – TUMOUR VOLUME reduced the most for MatrixModified Payload + EGFR-retargeted
  • T-cells, NK cells,
  • ONCR-001 IND in GBM anticipated H2 2018

TD2 tagline9:30 Coffee Break

10:00 WO-12, a Multi-Mechanistic Immuno-Oncolytic Therapy

Steve_ThorneSteve H. Thorne, CSO, Western Oncolytics Ltd.

The next generation of oncolytic viruses will likely combine multiple genetic modifications (transgenes and viral genetic alteration) that act to synergistically target tumors through multiple mechanisms. In particular, approaches that (i) enhance systemic delivery and viral spread within and between tumors, (ii) activate a potent anti-tumor T-cell response, and (iii) modify the tumor microenvironment to enhance the activity of both the viral therapy and other therapies would produce additional benefits. The Western Oncolytics platform and its lead product WO-12 aim to achieve these goals. WO-12 has demonstrated enhanced activity in preclinical models and will soon enter clinical testing.

  • 2015 IMLYGIC becomes first approved OV in US [1904 – Rabies Virus Vaccination, live non-attenuated virus Egypt 101 Virus, Cancer 1952]
  • Viral replication inhibited – Normal cell SPARED
  • Tumor Lysis – Virus spread – Vaccinia
  • Next Generation Vectors modify tumor microenvironmentaddition of transgenes can enahnce activity
  • Expression of combinations of multiple Tx transgenes and viral modifications
  • WO-12 Design – Vaccinia Virus
  1. surface deglycosylation – does not effect infectivity and reduces TLR2 ligand activation
  2. HPGD Insertion – # of anti-viral CTL after vaccination of naive BALB/c mice with different vectors: Increase in WR.TK-TRIF
  3. TRIF Insertion
  4. TK & C12L Deletions
  • Optimizing immune activation – increase systemic anti tumor CTL response while reducing anti-viral: Reduced anti-viral: Tumor Volume/days after virus
  • Re-directing TLP Activation to enhance cell mediated immune responses
  • Immunogenic cell death and IFN response leading to a primarily
  • Overcoming immunosuppression – Resistance to oncolytic virus correlates with higher @ of myeloid derived suppressor cells (MDSC) in tumor
  • Expression of murine HPGD decreases MDSC and T-regs in the Tumor
  • Targeting of PGE2
  • % Survival vs Day after Treatment and Tumor Volume vs Day of Treatment
  • Pre-clinical Efficacy – nWO-12 – Avoid antiviral Immunity and immune suppression
  • IV (intra-venous) Delivery vs IT (intra-tumor) Delivery

10:30 Pepticrad, a Novel Oncolytic Virus-Based Therapeutic Cancer Vaccine

Sari_PeseonenSari Pesonen, Vice President, Clinical Development, Valo Therapeutics, Finland

PeptiCRAd (Peptide-coated Conditionally Replicating Adenovirus) is an innovative and unique way of combining two clinically proven cancer immunotherapy approaches: an oncolytic adenovirus and a cancer-specific peptide vaccine, to take advantage of the best features of both technologies. The idea is straightforward: to use immunogenic virus as active carrier of tumor-specific peptides to direct the immune system to specifically target and kill cancer cells.

  • PeptiCARd
  1. Oncolytic Adenovirus (negative charge)
  2. Tumor-specific  Peptides (positive charge)
  3. Patient-specific Treatment – OV highly immunogenic –>>> Peptide Vaccine ANti-tumor immunity is high and anti-virus immunity is low
  4. OV are potential Cancer Vaccine/Immunotherapy candidates
  • Genetic engineering for increased tumor specificity
  • hig immunogenicity may help breaking cancer-driven immune tolerance
  • limitation of OV is that they trigger a strong anti-virus immunity and only weak anti-tumor immune response in Cancer patients
  • Per-existing immunity to OV potentiates its Therapeutic efficacy
  1. Virus replication
  2. 3 of T-regs in tumor
  3. #of T-cell in Tumor
  4. # CD4, CD8
  1. Triple negative BR CA
  2. Malignant Melanoma
  3. NSCLC

 

11:00 Synthetic Virology: Modular Assembly of Designer Viruses for Cancer Therapy

Clodagh_OSheaClodagh O’Shea, Ph.D., Howard Hughes Medical Institute Faculty Scholar; Associate Professor, William Scandling Developmental Chair, Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies

Design is the ultimate test of understanding. For oncolytic therapies to achieve their potential, we need a deep mechanistic understanding of virus and tumor biology together with the ability to confer new properties. To achieve this, we have developed combinatorial modular genome assembly (ADsembly) platforms, orthogonal capsid functionalization technologies (RapAd) and replication assays that have enabled the rational design, directed evolution, systematic assembly and screening of powerful new vectors and oncolytic viruses.

  • Future Cancer therapies to be sophisticated as Cancer is
  • Targer suppresor pathways (Rb/p53)
  • OV are safe their efficacy ishas been limited
  • MOA: Specify Oncolytic Viral Replication in Tumor cells Attenuate – lack of potency
  • SOLUTIONS: Assembly: Assmble personalized V Tx fro libraries of functional parts
  • Adenovirus – natural & clinical advantages
  • Strategy: Technology for Assmbling Novel Adenovirus Genomes using Modular Genomic Parts
  • E1 module: Inactives Rb & p53
  • core module:
  • E3 Module Immune Evasion Tissue targeting
  • E4 Module Activates E2F (transcription factor TDP1/2), PI3K
  • Adenovirus promoters for Cellular viral replication __ Tumor Selective Replication: Novel Viruses Selective Replicate in RB/p16
  • Engineering Viruses to overcome tumor heterogeneity
  • Target multiple & Specific Tumor Cel Receptors – RapAd Technology allows Re-targeting anti Rapamycin – induced targeting of adenovirus
  • Virus Genome: FKBP-fusion FRB-Fiber
  • Engineer Adenovirus Caspids that prevent Liver uptake and Sequestration – Natural Ad5 Therapies 
  • Solution: AdSyn335 Lead candidat AdSyn335 Viruses targeting multiple cells
  • Engineering Mutations that enhanced potency
  • Novel Vector: Homes and targets
  • Genetically engineered PDX1 – for Pancreatic Cancer Stroma: Early and Late Stage

11:30 Adenovirus-based virotherapy for disseminated disease

David T. Curiel, MD, PhD., Distinguished Professor of Radiation Oncology, D=rector, Biologic Therapeutics Center, Washington University

Effective virotherapy for disseminated neoplastic disease required precise =umor targeting. The unique molecular plasticity of adenovirus offers the p=tential to achieve the tumor selectivity required for virotherapy for meta=tatic disease.

  • OV for DIsseminated Neoplastic DIsease
  • Vector Targetinc:
  1. Restrict gene expression
  2. mitigate liver sequestration
  3. Transduction Targeting – integrin binding ligand capsid protein hexon HVR7 Chimerism basis of vector PLUS Transcriptional Targeting works synergistic – modification of Adenovirus Fiber Protein
  4. Replacement of Adenovirus Fiber with T4 Fibritin – Caspid dysthesis AdB2 cmvLuc
  5. Camelid sdAb Retargeting of Adenovirus – A robust technology CRAd-Based Tumor Selectivity
  6. Targeting Tumor cutotoxicity

12:00 pm Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

12:30 Session Break

ONCOLYTICS IN DEVELOPMENT: UPDATE ON MAJOR CLINICAL AND PRECLINICAL THERAPIES

1:25 Chairperson’s Remarks

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

1:30 Stroma Targeting Strategies for Oncolytic Virotherapy

Daniel Katzman, PhD., CEO, Unleash Immuno Oncolytics

  • Clinical Trials: OV in Clinical Development – 35 Trials Meyer Oncology 2017
  • Malignant Cells + Tumor Associated Stromal Cells
  • normal stroma are different thn Tumor activated stromaLateralization
  • SPARC is overexpressed in malignant and tumor associated stromal cells
  • SPARC is a key regulator of proliferation
  • number Cell type E4 copies ng DNA ratio/Hours after viral infection or /Days post injection

2:00 Development of OV Immunotherapy Using a Novel Preclinical GBM Model

Hiroshi_NakashimaHiroshi Nakashima, Ph.D., Instructor, Neuroscience, Brigham and Women’s Hospital

Mechanism of action of the Oncolytic virus includes direct tumor killing and vaccine adjuvant. Since OV immunotherapy is emerge to apply in incurable glioblastoma multiforme (GBM) for the durable therapeutic effects, our new glioma mouse model will provide new opportunity to evaluate the combined OV therapies that work under the patient-mimicked immunological condition.

  • Immunotherapy for TX of GBMs: Controlled Neurovirulence, defective to generate DNA resource
  • Next generation of oHSV: Efficacy and Safety – GADD34 enhances expression
  • Combination CheckPoint – PD-1 Aband OV: Tumor progression with T-Cell exhaustion Pro-tumor immunity- specific to tumor-antigen can mimic disease condition in GBM Patients
  • and the timing of Immunotherapy in GBM models
  • Antigen exposure & Tumor Growth: Acute infection, Naive, Chronic infection
  • Antigen persistence, temporal Antigen exposure, no antigen experience
  • PD-1 expression is high in brain-infiltrating GP33+ CTLs
  • Blocking PD-1 rescued mice with exhausted T-cells from GBM
  • Development of PD-1 blockade armed oHSV.
  • Cross-talk between brain-infiltrating anti- and pro-tumor immune cells
  • GP33 vs CD44
  • Limitation of PD-1 Blockade to Cure- suggesting other pre-tumor immunity contributes to suppress anti-tumor immunity

2:30 Pexa-Vec: A Multi-Mechanistic Immunotherapeutic Modulator of the Tumor Microenvironment

Naomi De Silva, Associate Director, Preclinical Science, Sillajen Biotherapeutics, Inc.

Pexa-Vec (pexastimogene devacirepvec, JX-594) is an oncolytic and immunotherapeutic vaccinia virus, engineered to preferentially infect tumor cells, disrupt vasculature, and stimulate anti-tumor immune responses. A Phase III trial evaluating Pexa-Vec in the treatment of advanced primary liver cancer is underway.

  • Broad Tropism – Infection and uptake to multiple receptor targets
  • Vaccinia CD31 and CD8 and Granzyme B Positive in Metastatic Pancreatic Cancer – Oncolytic vaccinia targets tumor endothelial vasculature
  • Anti-tumor responses important for eradication of malignancies
  • Pexa-Vec increases T cells infiltration into tumors
  • Oncolytic Vaccinia increases PD-L1 expression
  • Combination of Oncolytic Vaccinia anf anti-PD-1 antibody decreases tumor growth
  • Pexa-Vec’s ability to induce anti-tumor immune response
  • Future study: Pexa-Vec in combination with checkpoint inhibitor CRC

TD2 tagline3:00 Refreshment Break

3:30 Designing Clinical Trials to Elucidate Oncolytic Virus Mechanisms-of-Action

Caroline_BreitbachCaroline Breitbach, Ph.D., Vice President, Translational Development, Turnstone Biologics

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.

  • Local effect: Cell Lysis
  • Systemic: Immune response
  • Turning Maraba (MG1) into T Cell Immunotherapy – ability to engage memory T cells to generate durable secondary immune response
  • MG1 Mechanism of DIrect T Cell Induction
  • Biology of T cell boosting:
  1. Virus infects follicualr B Cells
  2. Bcells provide virus to dendritic cells to present antigen
  3. DCT Prime – 9 days interval: Prime immune analysis
  4. DAy 14 boost induction
  5. Immune Boost in Tumor Greater in Improved Survival
  6. % survival vs days post treatment
  7. PK and viremia: Day 1,5,9,14, 11 days after dose #2
  8. Immunogenic Markers: Chemokines, Cytokines, Markers of Attack
  9. Evidence for Robust IMMUNE RESPONSE: HIGHEST RESPONDERS for self antigen
  10. Pembrolizumab Trial Design:Positive MAGE-A3 expressing tumors
  11. MG1 OV: systemic delivery and targeted metastatic tumor site

CMC, SCALE-UP AND COMMERCIAL MANUFACTURING

4:00 Development of an Attenuated Oncolytic Influenza a Virus Expressing Mycobacterial ESAT-6 Protein

Michael Bergmann, M.D., Ph.D., CMO, Vacthera

We have expressed ESAT-6 in a partial NS1-deletion influenza virus. ESAT-6 expressing viruses were associated with lower levels of NF-kB activating as compared to empty viral vectors. ESAT-6 expressing viruses led to higher titers in eggs up to 1010 TCID50. ESAT-6 expressing deletion viruses were still attenuated when applied to the upper respiratory tract of mice. Intra-tumoral application of virus into B16 melanoma significantly delayed tumor growth.

  • Influenza A Virus (ESAT6 expressing partial NS1 deletion virus) – Lytic, Small RNA, Stable – live virus vaccine – infection affects Trypsin cleavage site, Elastase cleavage site
  • Conditionally replicating  – tumor ablation in PKR of INF-Defective Tumors
  • Cytokine stimulation: CD14+ CD56+ CD19+
  • Cytokine – IL15 – increased Intra tumor T-Cells and NK cells
  • Virus titers are lost during purification
  • AIM: Effective virus optimized for growth, genetic stability
  • H1N1
  • TLR2 inhibits TLR signaling in pmacrophageg
  • Viral Input in ptoduction makes Oncolytics effect depend on amount of virus
  • TB Vaccine TB/FLU-04 BCG-vaccinated healthy adults – Nasal Cytokine prduction
  • Growth optimized viruses can be generated and appear to be safe – Onlcolytic influenza

4:30 Testing and Characterization of Oncolytic Viruses

Jerrod_DenhomJerrod Denham, Ph.D., Principal & Senior Consultant, Dark Horse Consulting

Testing and characterization of oncolytic viruses typically follow the current principles for the majority of gene therapy product critical quality attributes. There are specific challenges with respect to adventitious agent safety testing and viral clearance studies. This presentation will walk through examples of how these challenges were resolved.

  • Vaccinia, HSV-1, Adeno
  • Cell QA: Cell counts, viability, identity. purity, potency,safety, stability
  • Cell Production Process (CPP): Cells, virus, Plasmids, materials, equipment,settings test methods
  • Experimental design for space cintrol
  • Cell bank vs
  • cGMP: Virus Bank – Master Virus Bank,Working Virus Bank
  • Process Characterization: Mycoplasma & Endotoxin, sterility, pH, Metabolic Analysis, Viability, Vell Counts, visual inspection
  • Unit Operation: Steile filter, concentrate, polish, purify
  • Phase III: Drug substance: Formulate, bulk drug – fill & finish–>>> drug product
  • Validation of Pre-Phase 3 manufacturing
  • Clinical Lot: at least one batch: Bulk cell harvest, Final Drug Product
  • Safety testing: Bovine, Porcine virus
  • Adventitious Virus Testing: In Vitro Assay vs In Vivo Assay
  • Neutralization: Agent for Neutralization – what if it does not work? Mock product

5:00 End of Day

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Funding Oncorus’s Immunotherapy Platform: Next-generation Oncolytic Herpes Simplex Virus (oHSV) for Brain Cancer, Glioblastoma Multiforme (GBM)


Funding Oncorus’s Immunotherapy Platform: Next-generation Oncolytic Herpes Simplex Virus (oHSV) for Brain Cancer, Glioblastoma Multiforme (GBM)

Reporter: Aviva Lev-Ari, PhD, RN

 

Series A  Funding in July 2016 and in December 2016

Jul 20, 2016 at 2:19 PM

SOURCE

http://medcitynews.com/2016/07/qa-ceo-oncorus-just-raised-57m-battle-cancer/?rf=1

 

MPM Capital

MPM Capital, which has around $2 billion in assets, is already working with drugmakers on funding healthcare startups. This  includes a venture fund it closed last year at $400 million that included Novartis ($NVS) Astellas Pharma as investors.

http://www.fiercebiotech.com/biotech/ubs-raises-471m-for-a-new-kind-cancer-research-fund

(with equal contributions from MPM BV2014 and the Oncology Impact Fund), and included Deerfield Management, Arkin Bio Ventures, Celgene, Inc., Excelyrate Capital, Long March Investment Fund and MPM’s SunStates Fund.

  1. MPM BV2014  – OIF will co-invest with MPM’s BV2014 venture fund in private oncology company investments.

http://finance.yahoo.com/news/mpm-launches-471-million-social-194500117.html

  1. MPM Oncology Impact Fund (OIF)

https://www.ft.com/content/b5e1e678-0c6a-11e6-b0f1-61f222853ff3

 

 

COINVESTORS:

 

SOURCE

http://medcitynews.com/2016/07/qa-ceo-oncorus-just-raised-57m-battle-cancer/?rf=1

http://www.finsmes.com/2016/07/immuno-oncology-company-oncorus-completes-57m-series-a-financing.html

 

December 15, 2016

 

Oncorus®, Inc. Announces Additional Series A Financing Support From Astellas Venture Management LLC (AVM)

 

Oncorus Management – “We are thrilled to have AVM join this outstanding group of high-quality investors.

http://www.oncorus.com/board-of-directors

 

 

Finer serves on Oncorus’s Board of Directors along with:
– Luke Evnin, Ph.D., MPM Capital co-founder and Chairman,
– Briggs Morrison, CEO, Syndax;
– Cameron Wheeler, Ph.D., Principal, Deerfield Management; and,
– Alon Lazarus, Ph.D., Biotech Investment Manager, Arkin Bio Ventures.

This additional funding will help advance our immunotherapy platform as we discover innovative new therapies which we hope will be of benefit to patients in need and the physicians who treat them,” said Dr. Finer.

 

Oncorus licensed certain patent rights from the University of Pittsburgh based upon the work of renowned scientists Joseph Glorioso III, Ph.D., and Paola Grandi, Ph.D., who will join Oncorus’s Scientific Advisory Board.

The company will invest in researching and developing oncolytic viral constructs which will move through preclinical development and ultimately into clinical trials. Currently, the company’s lead candidate is in preclinical development for GBM. The company will also expand and improve its technology platform and accelerate the development of pipeline programs in other forms of cancer.

 

About AVM Astellas Venture Management LLC., based in Menlo Park, California, is a corporate venture capital of Astellas Pharma Inc. (“API”), headquartered in Tokyo, Japan. For over 15 years, AVM has been making strategic investments to achieve its mission to explore emerging innovative companies, which have potential to become API’s collaboration partners in R&D. For more information, please visit the website at www.astellasventure.com.

About Oncorus, Inc. Oncorus, Inc. is an early-stage biotechnology company developing a next-generation immunotherapy platform of oncolytic viruses to treat several types of cancer, including highly malignant and aggressive cancers. A leader in corporate philanthropy, Oncorus has taken a pledge to donate a portion of product sales revenue to fund promising cancer research and to support cancer care in the developing world. The company is located in Kendall Square, Cambridge, Massachusetts. Visit www.oncorus.com, for more information.

 

SOURCE

https://static1.squarespace.com/static/574456597c65e4f329ea6950/t/5852b919d1758eb23d44fdd1/1481816345729/Oncorus+Series+A+Astellas+Press+Release+FINAL+12-15-16.pdf

http://www.oncorus.com/news-items/2016/12/15/oncorus-inc-announces-additional-series-a-financing-support-from-astellas-venture-management-llc

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Meeting report: Cambridge Healthtech Institute’s 4th Annual Immuno-Oncology SUMMIT: Oncolytic Virus Immunotherapy Stream – 2016


Meeting report: Cambridge Healthtech Institute’s 4th Annual Immuno-Oncology SUMMIT: Oncolytic Virus Immunotherapy Stream – 2016

Reporter: David Orchard-Webb, PhD

 

Cambridge Healthtech Institute’s 4th Annual Immuno-Oncology SUMMIT took place August 29-September 2, 2016 at the Marriott Long Wharf Boston, MA. The following is a synthesis of the Oncolytic Virus Immunotherapy stream.

 

Biomarkers

 

Biomarkers for patient selection in clinical trials is an important consideration for developing cancer therapeutics and immunotherapeutics such as oncolytic viruses in particular. Howard L. Kaufman, M.D., discussed the development of biomarkers for oncolytic virus efficaciousness and patient selection focusing on Imlygic (HSV-1). An important consideration for any viral therapy is the presence or absence of the receptors that the virus uses to gain entry to the cell. For example HSV-1 utilises Nectin and HVEM cell surface receptors and their expression levels on a patient’s tumour will influence whether Imlygic can gain entry and replicate in tumours. In addition he reported that B-RAF mutation facilitates Imlygic infection and that MEK inhibitors sensitise melanoma cell lines to Imlygic. Stephen Russell also presented data on the mathematical modelling of Vesicular Stomatitis Virus (VSV) tumour spread and the development of a companion diagnostic based on gene expression profiling to predict patients whose tumours will be readily infected.

 

The immune reaction triggered by oncolytic viruses is important to monitor. Howard L. Kaufman discussed immunogenic cell death and stated that oncolytic viruses trigger immunity through the release of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). He reported that immunosuppressive Tregs, PDL1 and IDO expression were associated with anti-cancer CD8+ T cell infiltration. Imlygic also promoted the tumour infiltration of monocytes which depending on the context may either be immunosuppressive or beneficial through recruiting natural killer (NK) cells. This highlights the importance of combining Imlygic with other immune modulating therapeutics that can modulate the immunosuppressive cells and messengers that are present in the tumour environment. He discussed the finding that high mutation burden is a marker for response to immune checkpoint inhibition (such as CTLA and PD1) and suggested that due to the fact that oncolytic viruses release tumour associated antigens (TAA) during cell lysis this may also be a predictive marker for oncolytic viral therapy immune response. Supporting this notion Stephen Russell reported that a patient that underwent complete remission of multiple myeloma plasmacytomas in response to a measles virus oncotherapy had a very high mutational burden.

 

Targeting the tumour stroma with adenoviral vectors

 

VCN Biosciences SL is a privately-owned company focused in the development of new therapeutic approaches for tumors that lack effective treatment”. Manel Cascalló presented data from an ongoing phase I, multi-center, open-label dose escalation study of intravenous administration of VCN-01 oncolytic adenovirus with or without intravenous gemcitabine and Abraxane® in advanced solid tumors. Patients were selected based on low anti-Ad levels. Manel highlighted the problems of the pancreatic cancer matrix which limit intratumoral virus spread and also reduces chemotherapy uptake and tumour lymphocyte infiltration. VCN-01 expresses hyaluronidase to degrade the extracellular matrix and is administered intravenously. Liver tropism is reduced by replacement of the heparan sulfate glycosaminoglycan putative-binding site KKTK of the fiber shaft with an integrin-binding motif RGDK. VCN-01 replicates only in Rb tumour suppressor pathway dysregulated cancers, achieved through genetic modification of the E1A protein. In previous mouse xenograft studies of pancreatic and melanoma tumours VCN-01 showed efficaciousness in intratumoral spread, degradation of hyaluronan, and evidence of sensitisation to chemotherapy. The mouse models suggested that strategies that further target other major components of the ECM such as collagen and stromal cells may increase VCN-01 efficaciousness further [1]. The phase I trial supported safety and demonstrated that when administered intravenously VCN-01 reached the pancreatic tumour and replicated. In combination with gemcitabine and Abraxane® neutropenia was observed earlier than with chemotherapy alone. This is suggestive of increased efficaciousness of the chemotherapeutics as would be expected if a greater effective concentration reached the tumour. Biopsies suggested that VCN-01 shifted the balance of immune cells towards CD8+ T cells and away from immunosuppressive Treg.

 

Adenovirus tumor-specific immunogene (T-SIGn) Therapy

 

PsiOxus Therapeutics Ltd develops novel therapeutics for serious diseases with a particular focus upon cancer”. Brian Champion discussed the application EnAd a chimeric Ad11p/Ad3 adenovirus which retains the Ad11 receptor usage (CD46 and DSG2). PsiOxus are developing Membrane-integrated T-cell Engagers (MiTe) proteins delivered via EnAd. These MiTe proteins are expressed at the cancer cell surface and engage with and activate T-cells. Their lead candidate NG-348 showed promising T-cell activation in vitro.

 

Vaccinia virus – overcoming the immunosuppressive cancer microenvironment

 

David Kirn provided a recent history of the oncolytic virus field and provided an overview of the validation of vaccinia virus over the period 2007-14 stating that it can produce cancer oncolysis, induce an immune response, and result in angiogenic ablation.

 

Western Oncolytics develops novel therapies for cancer”. Steve Thorne discussed strategies to mitigate the immunosupressive environment encountered by oncolytic viruses. He presented data from models of tumours resistant to vaccinia oncolytic virus that Treg, and myeloid-derived suppressor cell (MDSC) numbers were higher whereas CD8+ T-cell levels were lower than in a sensitive model. He elaborated on a strategy of targeting the PGE2 pathway in order to reduce MDSC numbers entering the tumour microenvironment. He demonstrated that vaccinia virus expressing HPGD has reduced levels of MDSC in target tumours.

 

Transgene (Euronext: TNG), part of Institut Mérieux, is a publicly traded French biopharmaceutical company focused on discovering and developing targeted immunotherapies for the treatment of cancer and infectious diseases”. Eric Quéméneur presented preclinical data on Transgene’s oncolytic vaccinia virus TG6002 which expresses a chimeric bifunctional enzyme which converts the nontoxic prodrug 5‐FC into the toxic metabolites 5‐FU and 5‐FUMP. This allows systemic delivery of the non-toxic prodrug chemotherapy with activation at tumours infected with the Vaccinia oncolytic virus. The virus plus prodrug combination was effective against all of the solid tumour cell lines tested. In addition the combination was effective against glioblastoma cancer stem-like cells. In pancreatic and colorectal cancer cell line models the vaccinia prodrug combination was synergistic or additive when combined with additional chemotherapeutics. In immunocompetent mouse models TG6002 increased the Tumour Teff/Treg ratio indicative of a shift from an immunosuppressive to an immunocompetent microenvironment. Furthermore in mouse models TG6002 induced an abscopal response.

 

Vesicular Stomatitis Virus (VSV) – A single shot cure for cancer?

 

Vyriad strives to develop potent, safe and cost-effective cancer therapies in areas of unmet need”. Stephen Russell presented his position that oncolytic viruses could be a single shot cure for cancer. He emphasised the point that in oncolytic viral therapy the initial dose will be the most effective due to the relatively low levels of neutralising antibodies present and therefore defining the optimal dose is critical. The trend is for increased initial dose. Two IND’s have been accepted by the FDA, one for measles virus and the other for VSV.

 

John Bell described using VSV to deliver Artificial microRNAs (amiRNAs) to tumours. It was demonstrate that a VSV delivering ARID1A amiRNA was synthetic lethal when combined with EZH2 (methyl transferase) inhibition. He postulated that oncolytic viruses can be used to create factories of therapeutic amiRNAs transmitted throughout the tumour by exosomes.

 

HSV-1 an update on immune checkpoint combinations

 

Amgen was the first company to launch an FDA approved (October 2015) oncolytic virus, trade name Imlygic, which was developed by the UK based company Biovex. Jennifer Gansert gave a background on Imlygic and presented new data on combination with the CTLA4 inhibitor Ipilimumab. In mouse models abscopal response in contralateral tumours was 100% when a single tumour was treated with Imlygic combined with systemic delivery of anti-CTLA4. A Phase 1b clinical trial to test the combination in unresectable melanoma patients was completed and published in 2016. Fifty percent of the patients had durable response for greater than 6 months and 20% of the patients had ongoing complete response after a year of follow-up. Overall 72% of patients has controlled disease (no progression). In addition Amgen is recruiting for a phase III trial of the anti-PD1 Pembrolizumab in combination with Imlygic for unresectable stage IIIB to IVM1c melanoma.

 

Virttu is a privately held biotechnology company, which has pioneered the development of oncolytic viruses for treating cancer”. Joe Connor discussed Seprehvir an oncolyic virus based on HSV-1 like Imlygic which is in clinical trials for which 100 patients have been treated to date. The trial data indicate that Seprehvir induces CD8+ T cell infiltration and activity as well as a novel anti-tumour immune response against select antigens such as Mage A8/9. Preclinical investigations focus on combination with checkpoint inhibitor antibodies, CAR-T targeted to GD2, and synergies with targeted therapies on the mTOR/VEGFR signalling axes.

 

Reovirus – an update

 

Oncolytics Biotech Inc. is a clinical-stage oncology company focused on the development of oncolytic viruses for use as cancer therapeutics in some of the most prevalent forms of the disease”. Brad Thompson provided an update on REOLYSIN®, Oncolytics Biotech’s proprietary T3D reovirus. Highlights included concluding the first checkpoint inhibitor and REOLYSIN® study in patients with pancreatic cancer and preparing for registration study in multiple myeloma.

 

Maraba virus – privileged antigen presentation in splenic B cell follicles

 

Turnstone Biologics is developing “a first-in-class oncolytic viral immunotherapy that combines a bioselected and engineered oncolytic virus to directly lyse tumors with a potent vaccine technology to drive tumor-antigen specific T-cell responses of unprecedented magnitude”. Caroline Breitbach described Maraba MG1 Oncolytic Virus which was isolated from Brazilian sand flies. Their lead candidate is an MG1 virus expressing the tumour antigen MAGE-A3. In mouse models a combination of adenovirus-MAGE-A3 and MG1-MAGE-A3 in a prime-boost regimen produced extremely robust CD8+ T cell responses. It is thought that a privileged antigen presentation in splenic B cell follicles maximizes the T cell responses. A phase I/II trial is enrolling patients to test the adenovirus-MAGE-A3 and MG1-MAGE-A3 prime-boost regimen in patients with MAGE‐A3 positive solid tumours for which there is no life prolonging standard therapy.

 

Oncolytic virus manufacturing

 

Anthony Davies of Dark Horse Consulting Inc. reviewed the manufacturing hurdles facing oncolytic viruses and pointed out that thus far adenovirus is the gold standard. He discussed isoelectric focusing for virus manufacturing, process flow and the procurement of key raw materials. He emphasized the importance of codifying analytical methods, and the statistical design of experiments (DOE) for optimal use of finite resources.

 

Mark Federspiel described the difficulties associated with measles virus manufacturing which include the large pleomorphic size (100-300nm) which cannot be filter sterilized efficiently due to shear stress. As a result aseptic conditions must be maintained throughout the manufacturing process. There are also issues with genomic contamination from infected cells. He described improved manufacturing bioprocesses to overcome these limitations using the HeLa S3 cell line. Using this cell line resulted in less residual genomic DNA than the standard however it was still relatively high compared to vaccine production. There is still much room for improvement.

 

REFERENCES
Rodríguez-García A, Giménez-Alejandre M, Rojas JJ, Moreno R, Bazan-Peregrino M, Cascalló M, Alemany R. Safety and efficacy of VCN-01, an oncolytic adenovirus combining fiber HSG-binding domain replacement with RGD and hyaluronidase expression. Clin Cancer Res. 2015 Mar 15;21(6):1406-18. Doi: 10.1158/1078-0432.CCR-14-2213. Epub 2014 Nov 12. PubMed PMID: 25391696.

 

Other Related Articles Published In This Open Access Online Journal Include The Following:

https://pharmaceuticalintelligence.com/2016/07/15/agenda-for-oncolytic-virus-immunotherapy-unlocking-oncolytic-virotherapies-from-science-to-commercialization-chis-4th-annual-immuno-oncology-summit-august-29-30-2016-marriott-lo/

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

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/

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

https://pharmaceuticalintelligence.com/2016/09/01/live-tweets-via-pharma_bi-and-by-aviva1950-for-august-29-and-august-30-2016-of-chis-4th-immuno-oncology-summit-oncolytic-virus-immunotherapy-track-marriott-long-wharf-hotel/

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LIVE 9/20 2PM to 5:30PM New Viruses for Therapeutic Gene Delivery at CHI’s 14th Discovery On Target, 9/19 – 9/22/2016, Westin Boston Waterfront, Boston


LIVE 9/20 2PM to 5:30PM New Viruses for Therapeutic Gene Delivery at CHI’s 14th Discovery On Target, 9/19 – 9/22/2016, Westin Boston Waterfront, Boston

http://www.discoveryontarget.com/

http://www.discoveryontarget.com/crispr-therapies/

Leaders in Pharmaceutical Business Intelligence (LPBI) Group is a

Media Partner of CHI for CHI’s 14th Annual Discovery on Target taking place September 19 – 22, 2016 in Boston.

In Attendance, streaming LIVE using Social Media

Aviva Lev-Ari, PhD, RN

Editor-in-Chief

http://pharmaceuticalintelligence.com

#BostonDOT16

@BostonDOT

 

COMMENTS BY Stephen J Williams, PhD

Gene Therapy Breakthroughs

New Strategies for Better Specificity and Delivery

 

2:05  Chairman’s Remarks

Joseph Gold, Ph.D. Director Manufacturing Center for Biomedicine and Genetics, Beckman Research Institute City of Hope

 

 

ALS  

 

Canavan disease: progressive fatal neurologic disorder that begins in infancy and don’t make it past teenage years

 

They have been named a PACT Center Production Assistance for Cell Therapy where you can apply for a project grant.  Applicable for startups up to larger mature companies

www.pactgroup.net

 

They do a standard panel of tests for viral infections.

They work with investigators or companies at all stages of manufacturing processes.

 

@BeckmanInst

@cityofhope

 

2:15 Large-Scale Production of Cell Therapies for Regenerative Medicine

Joseph Gold, Ph.D. Director Manufacturing Center for Biomedicine and Genetics, Beckman Research Institute

 

2:45  Directed Evolution of New Viruses for Therapeutic Gene Delivery

David Schaffer, Ph.D.  Professor of Chemical and Biomolecular Engineering, BioEngineering, Molecular and Cell Biology and Neuroscience;

 

AAV is very safe as many people already infected with it

 

Retinal:  AAV may be too large to get through layers of the eye, problems; subretinal injections and damage or retinal detachment.  Then they used their whole library in an in-vivo screen (as hard to recapitulate the multi cell layers of the retina).  

 

Cystic Fibrosis

 

Brain and Spinal Cord:  Sanfilippo B trial  8 holes drilled into skull followed by 16 AAV injections

 

They started a spinout 4D Molecular Therapeutics

 

4:25 Lentiviral Vectors for Gene Therapy

 

Munapaty Swani, Ph.D. Texas Tech Health Science Center

 

 

4:55 AAV Capsid Design

Miguel Seria Esteves, PhD Associate Professor Neurology, Gene Therapy Center University of Massachusetts Medical School

 

-AAV replication dependent no known human disease with native AAV

 

Huntington’s Disease

12:45 PM Screening with shRNA and CRISPR

Ryan Raver, PhD Global Product Manager, Functional Genomics, MilliporeSigma

  1. RNAi -KD
  2. CRISPR-Cas9 – KO

NEW STRATEGIES FOR BETTER SPECIFICITY AND DELIVERY

2:05 Chairperson’s Remarks

Joseph Gold, Center for Biomedicine and Genetics Beckman Research Institute, City of Hope

2:15 Large Scale Production of cell Therapies for Regenerative Medicine: COmbination Cell and Gene Therapy products

Joseph Gold, Center for Biomedicine and Genetics Beckman Research Institute, City of Hope

  1. Almost Xeno free
  2. defined
  3. very good reproducibility
  4. high purity and yield:

Combination cell/gene therapy products at COH

  1. CAR T CCR5-inactivated CD34+ HSPC – Target: AIDS

2. HIV resistance with engineering CCR5-negative blood stem cells: gene KO by ZFNs

3. Glioblastoma

4.  In vivo activity of transduced NSCs: Assay consideration – viability, sterility, mycobatom,

5.  ALS: degeneration of neurones

6.  Canavan Disease – Y.Shi – ASPA gene mutations cause Canavan disease

Strategy: autologous iPSC-derived, modified neural progenitors: DIferentiate to neural progenitors

Gene therapy: Correction (Off-taregt effects, correct individual cell lines)  or Over expression (Copy number, selection, transduce iPSC)

 

2:45 Directed Evolution of New Viruses for Therapeutic Gene Delivery

David Schaffer, Ph.D., Professor of Chemical and Biomolecular Engineering, Bioengineering, Molecular and Cell Biology, and Neuroscience; Director, Berkeley Stem Cell Center, University of California, Berkeley

Adeno-associated viral (AAV) vectors have been increasingly successful in clinical trials; however, viruses face many delivery barriers that limit their efficacy for most disease targets. We have developed directed vector evolution – the iterative genetic diversification of a viral genome and functional selection for desired properties – to engineer novel, optimized AAV vectors for efficient, selective delivery for a range of tissue and disease targets.

Gene Delivery

  1. neutralization of pre-esisting antibodies
  2. target tissue – deep penetration
  3. Inefficient transduction to target cells
  4. target specific cells

Fitness as Therapy – virus evolutionary: Tropism and immunity

Lung- Cystic Fibrosis (mucus production amplifies (enhanced transduction) due to MAC3 translation error) – Gene Therapy – cilia function to restore ability to clear mucos: Variant evolved on Human airway epithelia – AA  particles

  1. AAV2>>> AAV%>> T mutation

Brain and Spinal Cord

  1. Scull – 8 drills followed by 16 AAV injections
  2. Spinal cord: injuction in muscle

Synthetic version of AAV — Engineered AAV for enhanced Retrograde Transport

Summary

 

3:15 Sponsored Presentation (Opportunity Available)

3:45 Refreshment Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced

4:25 Lentiviral Vectors for Gene Therapy

Manjunath N. Swamy, MD, Professor of Biomedical Sciences and Co-DIrector of the Center of Emphasis in Infectious Diseases. Paul L Foster School of Medicine, Texas Tech University Health Science Center

 

4:55 AAV Caspid Engineering

Miguel Sena Esteves, Ph.D., Associate Professor, Department of Neurology, Gene Therapy Center, University of Massachusetts Medical School

Adeno-associated virus vectors have become the leading platform for development of in vivo gene therapies for neurological diseases. We have developed new AAV vectors for widespread gene delivery to the CNS through vascular infusion in adult animals through peptide grafting and in vivo library selection. These new neurotropic AAVs have achieved CNS-wide silencing of gene expression using gene-specific microRNAs.

Huntington’s Disease > 40 CAG vs <26 CAG in normal – Peptide grafting of AAV vectors for CNS

Next generation of AAV vectors for CNS 

neural transduction after vascular delivery

Conclusion

New capsids with improved CNS tropism

19 alanines modifies the CNS tropism of AAV9 variants

Chimeric caspids identified from in vivo screens

 

5:25 Welcome Reception in the Exhibit Hall with Poster Viewing

 

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