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Lectures by The 2017 Award Recipients of Warren Alpert Foundation Prize in Cancer Immunology, October 5, 2017, HMS, 77 Louis Paster, Boston

Reporter: Aviva Lev-Ari, PhD, RN

Article ID #242: LIVE: Lectures by The 2017 Award Recipients of Warren Alpert Foundation Prize in Cancer Immunology, October 5, 2017, HMS, 77 Louis Paster, Boston. Published on 9/8/2017

WordCloud Image Produced by Adam Tubman

Top, from left: James Allison and Lieping Chen. Bottom, from left: Gordon Freeman, Tasuku Honjo (NOT ATTENDED), Arlene Sharpe.

Aviva Lev-Ari, PhD, RN was in attendance and covered this event LIVE

The 2017 Warren Alpert Foundation Prize has been awarded to five scientists for transformative discoveries in the field of cancer immunology.

Collectively, their work has elucidated foundational mechanisms in cancer’s ability to evade immune recognition and, in doing so, has profoundly altered the understanding of disease development and treatment. Their discoveries have led to the development of effective immune therapies for several types of cancer.

The 2017 award recipients are:

  • James Allison, professor of immunology and chair of the Department of Immunology, The University of Texas MD Anderson Cancer Center – Immune checkpoint blockage in Cancer Therapy strictly Genomics based drug
  1. 2017 FDA approved a genomics based drug
  2. and co-stimulatory signals
  3. CTLA-4 blockade, CD28, AntiCTLA-4 induces regression of Transplantable Murine tumor
  4. enhance tumor-specific immune response
  5. Fully antibody human immune response in 10,000 patients – FDA approved 2011
  6. Metastatic melanoma – 3 years survival, programmed tumor death, PD-1, MHC-A1
  7. Ipi/Nivo vs. Ipi – combination – 60% survival vs Ipi alone
  8. Anti CTA4 vs Anti-PD-1
  9. responsive T cell population – MC38 TILs
  10. MC38 Infiltrating T cell populations: T-reg, CD4, Effector, CD8, NKT/gamma-delta
  11. Checkpoint blockage modulates infiltrating T cell population frequencies
  12. T reg correlated with Tumor growth
  13. Combination therapy lead to CURE survival at 80% rate vs CTAL-4 40% positive outcome

Not Attended — Tasuku Honjo, professor of immunology and genomic medicine, Kyoto University – Immune regulation of Cancer Therapy by PD-1 Blockade

 

  • Lieping Chen, United Technologies Corporation Professor in Cancer Research and Professor of immunobiology, of dermatology and of medicine, Yale University – Adoptive Resistance: Molecular Pathway t Cancer Therapy – focus on solid tumors
  1. Enhancement – Enhance normal immune system – Co-stimulation/Co-inhibition Treg, and Cytokines, adoptive cell therapy, Lymphoid organs stores
  2. Normalization – to correct defective immune system – normalizing tumor immunity, diverse tumor escape mechanisms
  3. Anti-PD therapy: regression of large solid tumors: normalizing tumor immunity targeting tumor microenvironment: Heterogeneity, functional modulation, cellular and molecular components – classification by LACK of inflamation, adaptive resistance, other inhibitory pathways, intrinsic induction
  4. avoid autoimmune toxicity,
  5. Resetting immune response (melanoma)
  6. Understad Resistance: Target missing resistance or Adaptive resistance Type II= acquired immunity
  • Gordon Freeman, professor of medicine, Dana-Farber Cancer Institute, Harvard Medical School – PD-L1/PD-1 Cancer Immunotherapy
  1. B7 antibody
  2. block pathway – checkpoint blockage, Expand the T cells after recognition of the disease. T cell receptor signal, activation, co -stimulatory: B71 molecule, B72 – survival signals and cytokine production,.Increased T cell proliferation,
  3. PDL-1 is a ligand of PD 1. How T cell die? genes – PD1 Gene was highly expressed,
  4. Interferon gamma upregulate PD-L1 expression
  5. Feedback loop Tumor – stimulating immune response, interferon turn off PD1
  6. PD-L1 and PD-L2 Expression: Interferom
  7. Trancefuctor MHC, B7-2
  8. PD-L! sisgnat inhibit T-cell activation: turn off Proliferation and cytokine production — Decreasing the immune response
  9. T cell DNA Content: No S-phase devided cell
  10. PD-L1 engagement of PD-1 results in activation : Pd-1 Pathway inhibits T Cell Actiivation – lyposite motility,
  11. Pd-L2 is a second ligand for PD-1 and inhibits T cell activation
  12. PDl-1 expression: BR CA, Ovarian, Colonol-rectal, tymus, endothelial
  13. Blockage of the Pathway – Immune response enhanced
  14. Dendritic cells express PD-L1, PD-L2 and combination of Two, Combination was best of all by increase of cytokine production, increasing the immune response.
  15. PD-L1 blockade enhanced the immune response , increase killing and increased production of cytokines,
  16. anti-tumor efficacy of anti-PD-1/Pd-L1
  17. Pancreatic and colono-rector — PD-L, PDL1, PDL2 — does not owrkd.
  18. In menaloma: PD-1 works better than CYLA-4
  19. Comparison of Targeted Therapy: BRAF TKI vs Chemo high % but short term
  20. Immunotherapy – applies several mechanism: pre-existing anti-therapy
  21. Immune desert: PD=L does not work for them
  22. COMBINATION THERAPY: BLOCK TUMOR INVASION THEN STIMULATE IMMUNE RESPONSE — IT WILL WORK
  23. PD blockage + nutrients and probiotic
  24. Tumor Genome Therapy
  25. Tumore Immuno-evasion Score
  26. Antigens for immune response – choose the ones
  27. 20PD-1 or PD-L1 drugs in development
  28. WHO WILL THE DRUG WORK FOR?

 

  • Arlene Sharpe, the George Fabyan Professor of Comparative Pathology, Harvard Medical School; senior scientist, department of pathology, Brigham and Women’s Hospital – Multi-faceted Functionsof the PD-1 Pathway
  1. function of the pathway: control T cell activation and function of maintain immune tolerance
  2. protect tissues from damage by immune response
  3. T cell dysfunction during cancer anf viral infection
  4. protection from autoimmunity, inflammation,
  5. Mechanism by which PD-1 pathway inhibits anti-tumor immunity
  6. regulation of memoryT cell responce of PD-1
  7. PD-1 signaling inhibit anti-tumor immunity
  8. Compare: Mice lacking CD8-Cre- (0/5) cleared vs PD-1-/-5/5 – PD-1 DELETION: PARTIAL AND TIMED: DELETION OF PD-1 ON HALF OG TILS STARTING AT DAY 7 POSTTUMOR IMPLANTATION OF BOTH PD-1 AND PD-1 TILS: – Tamoxifen days 7-11
  9. Transcription profile: analysis of CD8+ TILs reveal altered metabolism: Fatty Acid Metabolism vs Oxidative Phosphorylation
  10. DOes metabolic shift: WIld type mouth vs PD-1-/_ P14: analyze Tumor cell killingPD-1-/- enhanced FAO increases CD8+ T cell tocicity
  11. Summary: T cell memory development and PD-1: T effectors vs T cell memory: Primary vs Secondary infection: In the absent of PD-1, CD8+ T cels show increase expansion of T cells
  12. INFLUENZA INFECTION: PRIMARY more virus in lung in PD-1 is lacking
  13. Acute infection: PD-1 controls memory T cell differentiation vs PD-1 increase expansion during effector phase BUT impaired persistence during memory phase: impaired cytokine production post re-challenge
  14. PD-1 immunotherapy work for patients with tumor: Recall Response and Primary response
  15. TIL density Primary vs Long term survivor – 5 days post tumor implantation – rechallenged long term survival
  16. Hot tumor vs Cold tumor – Deletion of PD-1 impairs T memory cell development

Opening Remarks: George Q. Daley, MD, PhD, DEAN, HMS

  • Scientific collaboration check point – avoid the body attacking itself, sabotaging the immune system
  • 1987 – Vaccine for HepB
  • Eight of the awardees got the Nobel Prize

 

Moderated by Joan Brugge, PhD, HMS, Prof. of Cell Biology

  • Evolution of concepts of Immunotherapy: William Coley’s Toxin streptoccocus skin infection.
  • 20th century: Immuno-surveilence, Immune response – field was dead in 1978 replaced by Immunotherapy
  • Rosenberg at NIH, high dose of costimulatory molecule prevented tumor reappearanceantbody induce tumor immunity–>> immune theraphy by check point receptor blockade – incidence of tumor in immune compromised mice – transfer T cell
  • T cell defficient, not completely defficient, self recognition of tumor,
  • suppress immmune – immune evasion
  • Michael Atkins, MD, Detupy Director, Georgetown-Lombardi, Comprehensive Cancer Center Clinical applications of Checkpoint inhibitors: Progress and Promise
  1. Overwhelm the Immune system, hide, subvert, Shield, defend-deactivating tumor trgeting T cells that ATTACK the immune system
  2. Immune system to TREAT the cancer
  3. Monotherapy – anti PD1/PD-L1: Antagonist activity
  4. Evading immune response: prostate, colcn
  5. MMR deficiency
  6. Nivolumab in relaped/Refractory HODGKIN LYMPHOMAS – over expression of PD-L1 and PDL2in Lymphomas
  7. 18 month survival better with Duv in Lung cancer stage 3 – anti PD-1- adjuvant therapy with broad effectiveness
  8. Biomarkers for pD-L1 Blockage
  9. ORR higher in PD-L1
  10. Improve Biomarkers: Clonality of T cells in Tumors
  11. T-effector Myeloid Inflammation Low – vs Hogh:
  12. Biomarker Model: Neoantigen burden vs Gene expression vs CD8+
  13. Tissue DIagnostic Labs: Tumor microenveironmenr
  14. Microbiome
  15. Combination: Nivo vs Nivo+Ipi is superior: DETERMINE WHEN TO STOP TREATMENT
  16. 15/16 stopped treatment – Treatment FREE SURVIVAL
  17. Sequencing with Standard Therapies
  18. Brain metastasis – Immune Oncology Therapy – crosses the BBB
  19. Less Toxic regimen, better toxicity management,
  20. Use Immuno therapy TFS
  21. combination – survival must be justified
  22. Goal: to make Cancer a curable disease vs cancer becoming a CHronic disease

Closing Remarks: George Q. Daley, MD, PhD, DEAN, HMS

The honorees will share a $500,000 prize and will be recognized at a day-long symposium on Oct. 5 at Harvard Medical School.

The Warren Alpert Foundation, in association with Harvard Medical School, honors trailblazing scientists whose work has led to the understanding, prevention, treatment or cure of human disease. The award recognizes seminal discoveries that hold the promise to change our understanding of disease or our ability to treat it.

“The discoveries honored by the Warren Alpert Foundation over the years are remarkable in their scope and potential,” said George Q. Daley, dean of Harvard Medical School. “The work of this year’s recipients is nothing short of breathtaking in its profound impact on medicine. These discoveries have reshaped our understanding of the body’s response to cancer and propelled our ability to treat several forms of this recalcitrant disease.”

The Warren Alpert Foundation Prize is given internationally. To date, the foundation has awarded nearly $4 million to 59 scientists. Since the award’s inception, eight honorees have also received a Nobel Prize.

“We commend these five scientists. Allison, Chen, Freeman, Honjoand Sharpe are indisputable standouts in the field of cancer immunology,” said Bevin Kaplan, director of the Warren Alpert Foundation. “Collectively, they are helping to turn the tide in the global fight against cancer. We couldn’t honor more worthy recipients for the Warren Alpert Foundation Prize.”

The 2017 award: Unraveling the mysterious interplay between cancer and immunity

Understanding how tumor cells sabotage the body’s immune defenses stems from the collective work of many scientists over many years and across multiple institutions.

Each of the five honorees identified key pieces of the puzzle.

The notion that cancer and immunity are closely connected and that a person’s immune defenses can be turned against cancer is at least a century old. However, the definitive proof and demonstration of the steps in this process were outlined through findings made by the five 2017 Warren Alpert prize recipients.

Under normal conditions, so-called checkpoint inhibitor molecules rein in the immune system to ensure that it does not attack the body’s own cells, tissues and organs. Building on each other’s work, the five award recipients demonstrated how this normal self-defense mechanism can be hijacked by tumors as a way to evade immune surveillance and dodge an attack. Subverting this mechanism allows cancer cells to survive and thrive.

A foundational discovery made in the 1980s elucidated the role of a molecule on the surface of T cells, the body’s elite assassins trained to seek, spot and destroy invaders.

A protein called CTLA-4 emerged as a key regulator of T cell behavior—one that signals to T cells the need to retreat from an attack. Experiments in mice lacking CTLA-4 and use of CTLA-4 antibodies demonstrated that absence of CTLA-4 or blocking its activity could lead to T cell activation and tumor destruction.

Subsequent work identified a different protein on the surface of T cells—PD-1—as another key regulator of T cell response. Mice lacking this protein developed an autoimmune disease as a result of aberrant T cell activity and over-inflammation.

Later on, scientists identified a molecule, B7-H1, subsequently renamed PD-L1, which binds to PD-1, clicking like a key in a lock. This was followed by the discovery of a second partner for PD-1—the molecule PD-L2—which also appeared to tame T-cell activity by binding to PD-1.

The identification of these molecules led to a set of studies showing that their presence on human and mouse tumors rendered the tumors resistant to immune eradication.

A series of experiments further elucidated just how tumors exploit the interaction between PD-1 and PD-L1 to survive. Specifically, some tumor cells appeared to express PD-L1, essentially “wrapping” themselves in it to avoid immune recognition and destruction.

Additional work demonstrated that using antibodies to block this interaction disarmed the tumors, rendering them vulnerable to immune destruction.

Collectively, the five scientists’ findings laid the foundation for antibody-based therapies that modulate the function of these molecules as a way to unleash the immune system against cancer cells.

Antibody therapy that targets CTLA-4 is currently approved by the FDA for the treatment of melanoma. PD-1/PD-L1 inhibitors have already shown efficacy in a broad range of cancers and have been approved by the FDA for the treatment of melanoma; kidney; lung; head and neck cancer; bladder cancer; some forms of colorectal cancer; Hodgkin lymphoma and Merkel cell carcinoma.

In their own words

“I am humbled to be included among the illustrious scientists who have been honored by the Warren Alpert Foundation for their contributions to the treatment and cure of human disease in its 30+ year history.  It is also recognition of the many investigators who have labored for decades to realize the promise of the immune system in treating cancer.”
        -James Allison


“The award is a great honor and a wonderful recognition of our work.”
         Lieping Chen



I am thrilled to have made a difference in the lives of cancer patients and to be recognized by fellow scientists for my part in the discovery of the PD-1/PD-L1 and PD-L2 pathway and its role in tumor immune evasion.  I am deeply honored to be a recipient of the Alpert Award and to be recognized for my part in the work that has led to effective cancer immunotherapy. The success of immunotherapy has unleashed the energies of a multitude of scientists to further advance this novel strategy.”
                                        -Gordon Freeman


I am extremely honored to receive the Warren Alpert Foundation Prize. I am very happy that our discovery of PD-1 in 1992 and subsequent 10-year basic research on PD-1 led to its clinical application as a novel cancer immunotherapy. I hope this development will encourage many scientists working in the basic biomedical field.”
-Tasuku Honjo


“I am truly honored to be a recipient of the Alpert Award. It is especially meaningful to be recognized by my colleagues for discoveries that helped define the biology of the CTLA-4 and PD-1 pathways. The clinical translation of our fundamental understanding of these pathways illustrates the value of basic science research, and I hope this inspires other scientists.”
-Arlene Sharpe

Previous winners

Last year’s award went to five scientists who were instrumental in the discovery and development of the CRISPR bacterial defense mechanism as a tool for gene editing. They were RodolpheBarrangou of North Carolina State University, Philippe Horvath of DuPont in Dangé-Saint-Romain, France, Jennifer Doudna of the University of California, Berkeley, Emmanuelle Charpentier of the Max Planck Institute for Infection Biology in Berlin and Umeå University in Sweden, and Virginijus Siksnys of the Institute of Biotechnology at Vilnius University in Lithuania.

Other past recipients include:

  • Tu Youyou of the China Academy of Chinese Medical Science, who went on to receive the 2015 Nobel Prize in Physiology or Medicine with two others, and Ruth and Victor Nussenzweig, of NYU Langone Medical Center, for their pioneering discoveries in chemistry and parasitology of malaria and the translation of their work into the development of drug therapies and an anti-malarial vaccine.
  • Oleh Hornykiewicz of the Medical University of Vienna and the University of Toronto; Roger Nicoll of the University of California, San Francisco; and Solomon Snyder of the Johns Hopkins University School of Medicine for research into neurotransmission and neurodegeneration.
  • David Botstein of Princeton University and Ronald Davis and David Hogness of Stanford University School of Medicine for contributions to the concepts and methods of creating a human genetic map.
  • Alain Carpentier of Hôpital Européen Georges-Pompidou in Paris and Robert Langer of MIT for innovations in bioengineering.
  • Harald zur Hausen and Lutz Gissmann of the German Cancer Research Center in Heidelberg for work on the human papillomavirus (HPV) and cancer of the cervix. Zur Hausenand others were honored with the Nobel Prize in Physiology or Medicine in 2008.

The Warren Alpert Foundation

Each year the Warren Alpert Foundation receives between 30 and 50 nominations from scientific leaders worldwide. Prize recipients are selected by the foundation’s scientific advisory board, which is composed of distinguished biomedical scientists and chaired by the dean of Harvard Medical School.

Warren Alpert (1920-2007), a native of Chelsea, Mass., established the prize in 1987 after reading about the development of a vaccine for hepatitis B. Alpert decided on the spot that he would like to reward such breakthroughs, so he picked up the phone and told the vaccine’s creator, Kenneth Murray of the University of Edinburgh, that he had won a prize. Alpert then set about creating the foundation.

To award subsequent prizes, Alpert asked Daniel Tosteson (1925-2009), then dean of Harvard Medical School, to convene a panel of experts to identify scientists from around the world whose research has had a direct impact on the treatment of disease.

SOURCE

https://hms.harvard.edu/news/warren-alpert-foundation-honors-pioneers-cancer-immunology

Koch Institute Immune Engineering Symposium on October 16 & 17, 2017, Kresge, MIT

Reporter: Aviva Lev-Ari, PhD, RN

 

Koch Institute Immune Engineering Symposium on October 16 & 17, 2017.

 

Summary: Biological, chemical, and materials engineers are engaged at the forefront of immunology research. At their disposal is an analytical toolkit honed to solve problems in the petrochemical and materials industries, which share the presence of complex reaction networks, and convective and diffusive molecular transport. Powerful synthetic capabilities have also been crafted: binding proteins can be engineered with effectively arbitrary specificity and affinity, and multifunctional nanoparticles and gels have been designed to interact in highly specific fashions with cells and tissues. Fearless pursuit of knowledge and solutions across disciplinary boundaries characterizes this nascent discipline of immune engineering, synergizing with immunologists and clinicians to put immunotherapy into practice.

SPEAKERS:

Michael Birnbaum – MIT, Koch Institute

Arup Chakraborty – MIT, Insititute for Medical Engineering & Sciences

Jianzhu Chen – MIT, Koch Institute

Jennifer R. Cochran – Stanford University

Jennifer Elisseeff – Johns Hopkins University

K. Christopher Garcia – Stanford University

George Georgiou – University of Texas at Austin

Darrell Irvine – MIT, Koch Institute

Tyler Jacks – MIT, Koch Institute

Doug Lauffenburger – MIT, Biological Engineering and Koch Institute

Wendell Lim – University of California, San Francisco

Harvey Lodish – Whitehead Institute and Koch Institute

Marcela Maus – Massachusetts General Hospital

Garry P. Nolan – Stanford University

Sai Reddy – ETH Zurich

Nicholas Restifo – National Cancer Institute

William Schief – The Scripps Research Institute

Stefani Spranger – MIT, Koch Institute

Susan Napier Thomas – Georgia Institute of Technology

Laura Walker – Adimab, LLC

Jennifer Wargo – MD Anderson Cancer Center

Dane Wittrup – MIT, Koch Institute

Kai Wucherpfennig – Dana-Farber Cancer Institute

Please contact ki-events@mit.edu with any questions.

SOURCE

From: Koch Institute Immune Engineering Symposium <ki-events@mit.edu>

Reply-To: <ki-events@mit.edu>

Date: Friday, September 8, 2017 at 9:06 AM

To: Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu>

Subject: Reminder – Register Today

 

Announcing our 10th e-Book on Amazon.com – 1st day, 9/4/2017

Editor-in-Chief: Aviva Lev-Ari, PhD, RN

 

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The Immune System, Stress Signaling, Infectious Diseases and Therapeutic Implications: VOLUME 2: Infectious Diseases and Therapeutics and VOLUME 3: The Immune System and Therapeutics (Series D: BioMedicine & Immunology) Kindle Edition – on Amazon.com since 9/4/2017

by Larry H. Bernstein (Author), Aviva Lev-Ari (Author), Stephen J. Williams (Author), Demet Sag (Author), Irina Robu (Author), Tilda Barliya (Author), David Orchard-Webb (Author), Alan F. Kaul (Author), Danut Dragoi (Author), Sudipta Saha (Editor)

https://www.amazon.com/dp/B075CXHY1B

 

Product details

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  • Publisher:Leaders in Pharmaceutical Business Intelligence (LPBI) Group; 1 edition (September 4, 2017)
  • Publication Date:September 4, 2017
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Cleveland Clinic: Change at the Top,  Tomislav “Tom” Mihaljevic, M.D., as its next CEO and President to succeed Toby Cosgrove, M.D., effective Jan. 1, 2018

Reporter: Aviva Lev-Ari, PhD, RN

 

Cleveland Clinic’s Board of Governors and Board of Directors unanimously selected Dr. Mihaljevic based on the unanimous recommendation of a nomination committee chaired by Mr. Rich that conducted an extensive review of potential successors. Drs. Cosgrove and Mihaljevic will work on a transition process together through the end of the year. As of Jan. 1, 2018, Dr. Mihaljevic will assume the full duties of president and CEO, while Dr. Cosgrove will move to an advisory role to be determined by the Board of Directors and Dr. Mihaljevic.

A native of Croatia and a naturalized American citizen, Dr. Mihaljevic earned his medical degree from the University of Zagreb, before moving to the United States in 1995 to join Brigham and Women’s Hospital in Boston. He moved to Cleveland Clinic in 2004 as a cardiothoracic surgeon specializing in minimally invasive and robotically assisted cardiac surgeries – particularly robotic mitral valve repair – complex valve operations and reoperations, heart failure surgery, and heart transplantation. He helped to build Cleveland Clinic into the world’s largest robotic practice.

Dr. Mihaljevic has been on the editorial review board for prestigious medical journals. He is the author or co-author of more than 145 articles in medical and peer-reviewed scientific journals, and is the author of a numerous textbook chapters on robotic and minimally invasive mitral valve surgery, and heart valve disease. In 2005, Dr. Mihaljevic received a patent for a novel cardioscopy system for minimally invasive cardiac surgery. He earned the Cleveland Clinic Innovation Award in both 2006 and 2007.

Dr. Mihaljevic, 53, joined Cleveland Clinic in 2004 as a cardiothoracic surgeon specializing in minimally invasive and robotically assisted cardiac surgeries. Since 2015, Dr. Mihaljevic has served as CEO of Cleveland Clinic Abu Dhabi, overseeing the hospital’s strategy and operations as the first US multispecialty hospital to be replicated outside of North America, including directly managing the hospital’s Patient Experience and Strategy & Business Development programs.

Tomislav Mihaljevic, M.D. 

“Dr. Mihaljevic brings a depth of experience, first as an innovative, world-class surgeon and more recently as a hospital executive focused on healthcare quality and safety, patient experience and business strategy,” said Robert E. Rich Jr., chair of Cleveland Clinic’s Board of Directors. “By nearly every measure – quality, accessibility, finances, innovation, reputation – Cleveland Clinic has made unprecedented strides since Dr. Cosgrove became CEO and president in 2004. Following in his footsteps would be challenging for anybody, but Dr. Mihaljevic has the background, skills and vision to move Cleveland Clinic forward to even greater heights.”

SOURCE

https://newsroom.clevelandclinic.org/2017/09/01/tomislav-mihaljevic-m-d-named-cleveland-clinic-ceo-president/

 

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Cardiovascular Complications: Death from Reoperative Sternotomy after prior CABG, MVR, AVR, or Radiation; Complications of PCI; Sepsis from Cardiovascular Interventions

Author, Introduction and Summary: Justin D Pearlman, MD, PhD, FACC, and Article Curator: Aviva Lev-Ari, PhD, RN

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Less is More: Minimalist Mitral Valve Repair: Expert Opinion of Prem S. Shekar, MD, Chief, Division of Cardiac Surgery, BWH – #7, 2017 Disruptive Dozen at #WMIF17

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Call for the abandonment of the Off-pump CABG surgery (OPCAB) in the On-pump / Off-pump Debate, +100 Research Studies

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Writer and Caurator: Larry H. Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/06/28/effect-on-endovascular-carotid-artery-repair-outcomes-of-the-cmms-high-risk-criteria/

 

Open Abdominal Aortic Aneurysm (AAA) repair (OAR) vs. Endovascular AAA Repair (EVAR) in Chronic Kidney Disease (CKD) Patients –  Comparison of Surgery Outcomes

Writer and Curator: Larry H. Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/06/28/the-effect-of-chronic-kidney-disease-on-outcomes-after-abdominal-aortic-aneurysm-repair/

 

 

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

Article ID #241: Emerging STAR in Molecular and Cell Biology, Synthetic Virology and Genomics: Clodagh C. O’Shea: ChromEMT – Visualizing 3D chromatin structure. Published on 8/31/2017

WordCloud Image Produced by Adam Tubman

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

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

  • 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.

Clodagh O’Shea’s Talk In Real Time:

  • 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
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

  • 2016 Howard Hughes Medical Institute Faculty Scholar
  • 2014 W. M. Keck Medical Research Program Award
  • 2014 Rose Hills Fellow
  • 2011Science/NSF International Science & Visualization Challenge, People’s Choice
  • 2011 Anna Fuller Award for Cancer Research
  • 2010, 2011, 2012 Kavli Frontiers Fellow, National Academy of Sciences
  • 2009 Sontag Distinguished Scientist Award
  • 2009 American Cancer Society Research Scholar Award
  • 2008 ACGT Young Investigator Award for Cancer Gene Therapy
  • 2008 Arnold and Mabel Beckman Young Investigator Award
  • 2008 William Scandling Assistant Professor, Developmental Chair
  • 2007 Emerald Foundation Schola

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

Novartis’ Kymriah (tisagenlecleucel), FDA approved genetically engineered immune cells, would charge $475,000 per patient, will use Programs that Payers will pay only for Responding Patients

Curator: Aviva Lev-Ari, PhD, RN

 

UPDATED on 9/1/2017:

This Pioneering $475,000 Cancer Drug Comes With A Money-Back Guarantee

Novartis defends the eye-popping price of its pioneering gene therapy with arguments about its $1 billion expenditure—and novel “value-based” pricing.

https://www.fastcompany.com/40461214/how-novartis-is-defending-the-record-475000-price-of-its-pioneering-gene-therapy-cancer-drug-car-t-kymriah

 

On 8/30/2017 we wrote:

FDA has approved the world’s first CAR-T therapy, Novartis for Kymriah (tisagenlecleucel) and Gilead’s $12 billion buy of KitePharma, no approved drug and Canakinumab for Lung Cancer (may be?)

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/08/30/fda-has-approved-the-worlds-first-car-t-therapy-novartis-for-kymriah-tisagenlecleucel-and-gileads-12-billion-buy-of-kite-pharma-no-approved-drug-and-canakinumab-for-lung-cancer-may-be/

 

The Price for the Treatment was published on 8/31/2017, a Value-based Pricing Payment Model of a $475,000 per patient charge for the responding patients after ONE month of treatment. Novartis says it takes an average of 22 days to create the therapy, from the time a patient’s cells are removed to when they are infused back into the patient. Kymriah will initially be available at 20 U.S. hospitals within a month, Novartis says. Eventually, 32 total sites will offer the therapy. 

CAR-T gained national attention three years ago when Carl June, a researcher at the University of Pennsylvania, used to put a young girl’s acute lymphoblastic leukemia. Genetically altering the girl’s immune cells had made her deathly ill, but June had used a Roche drug, Actemra, to treat the side effects. She lived, and the results were published in The New England Journal of Medicine. Novartis bought the rights to the Penn treatment for just $20 million up front.

Pharma Buying the right to use from an Academic Institution is a known route to leap frog the R&D lengthy process of Drug discovery.

“I’ve told the team that resources are not an issue. Speed is the issue,” says Novartis’ Chief Executive Joseph Jimenez, told Forbes in a cover story about the work then.

The FDA calls this CAR-T therapy treatment, made by Novartis, the “first gene therapy” in the U.S. The therapy is designed to treat an often-lethal type of blood and bone marrow cancer that affects children and young adults. The FDA defines gene therapy as a medicine that “introduces genetic material into a person’s DNA to replace faulty or missing genetic material” to treat a disease or medical condition. This is the first such therapy to be available in the U.S., according to the FDA.

Two gene therapies for rare, inherited diseases have already been approved in Europe.

To further evaluate the long-term safety, Novartis is also required to conduct a post-marketing observational study involving patients treated with Kymriah.

The FDA granted Kymriah Priority Review and Breakthrough Therapy designations. The Kymriah application was reviewed using a coordinated, cross-agency approach. The clinical review was coordinated by the FDA’s Oncology Center of Excellence, while CBER conducted all other aspects of review and made the final product approval determination.

The FDA granted approval of Kymriah to Novartis Pharmaceuticals Corp. The FDA granted the expanded approval of Actemra to Genentech Inc.

FDA commissioner Scott Gottlieb in a statement.

“We’re entering a new frontier in medical innovation with the ability to reprogram a patient’s own cells to attack a deadly cancer,” 

“Kymriah is a first-of-its-kind treatment approach that fills an important unmet need for children and young adults with this serious disease,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research (CBER). “Not only does Kymriah provide these patients with a new treatment option where very limited options existed, but a treatment option that has shown promising remission and survival rates in clinical trials.”

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm574058.htm

The Protocol

A patient’s T cells are extracted and cryogenically frozen so that they can be transported to Novartis’s manufacturing center in New Jersey. There, the cells are genetically altered to have a new gene that codes for a protein—called a chimeric antigen receptor, or CAR. This protein directs the T cells to target and kill leukemia cells with a specific antigen on their surface. The genetically modified cells are then infused back into the patient.

In a clinical trial of 63 children and young adults with a type of acute lymphoblastic leukemia, 83 percent of patients that received the CAR-T therapy had their cancers go into remission within three months. At six months, 89 percent of patients who received the therapy were still living, and at 12 months, 79 percent had survived.

https://www.technologyreview.com/s/608771/the-fda-has-approved-the-first-gene-therapy-for-cancer/?utm_campaign=add_this&utm_source=email&utm_medium=post

CAR-T Therapies: Product/Molecules/MOA under Development:

  • Similar CAR-T treatments were being developed at other institutions including
  • Memorial Sloan-Kettering Cancer Center,
  • Seattle Children’s Hospital, and
  • The National Cancer Institute.
  • The Memorial and Seattle work was spun off into a startup called Juno Therapeutics, which has fallen behind. Juno Therapeutics ended a CAR-T study earlier this year after patients died from cerebral edema, or swelling in the brain.
  • The NCI work became the basis for the product being developed by Kite Pharma. Kite Pharma, which is awaiting FDA approval for its CAR-T therapy to treat a form of blood cancer in adults, was this week bought out by Gilead in a deal worth $11.9 billion.

On 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

TUESDAY, AUGUST 29 – I covered in Real Time the talk on Juno Therapeutics: Building Better T Cell Therapies: The Power of Molecular Profiling by Mark Bonyhadi, Ph.D., Head, Research and Academic Affairs, Juno Therapeutics

https://pharmaceuticalintelligence.com/2017/08/29/live-829-chis-oncolytic-virus-immunotherapy-and-adoptive-cell-therapy-august-28-29-2017-sheraton-boston-hotel-boston-ma/

 

Precision Medicine is Costly and not a Rapid manufacturing process

All of the CAR-T products are expensive to make, and must be manufactured on an individual basis for each new patient from the patient’s own T-cells, a type of white blood cells, a process that takes weeks.

  • How quickly companies can speed up manufacturing.
  • Kymriah will be manufactured at a facility in Morris Plains, N.J.
  • CAR-T technology, which has so far been used only in patients with blood cancers that have not been cured by other treatments, can be used earlier in the disease or for solid tumors: Breast, Prostate, Melanomas.

https://www.forbes.com/sites/matthewherper/2017/08/30/fda-approves-novartis-treatment-that-alters-patients-cells-to-fight-cancer/#2aecb25b4400

Prediction How Patients will Far Well – Researchers use a big-data approach to find links between different genes and patient survival.

https://www.technologyreview.com/s/608666/a-cancer-atlas-to-predict-how-patients-will-fare/?set=

A pathology atlas of the human cancer transcriptome

+ See all authors and affiliations

Science  18 Aug 2017:
Vol. 357, Issue 6352, eaan2507
DOI: 10.1126/science.aan2507

Modeling the cancer transcriptome

Recent initiatives such as The Cancer Genome Atlas have mapped the genome-wide effect of individual genes on tumor growth. By unraveling genomic alterations in tumors, molecular subtypes of cancers have been identified, which is improving patient diagnostics and treatment. Uhlen et al. developed a computer-based modeling approach to examine different cancer types in nearly 8000 patients. They provide an open-access resource for exploring how the expression of specific genes influences patient survival in 17 different types of cancer. More than 900,000 patient survival profiles are available, including for tumors of colon, prostate, lung, and breast origin. This interactive data set can also be used to generate personalized patient models to predict how metabolic changes can influence tumor growth.

FDA has approved the world’s first CAR-T therapy, Novartis for Kymriah (tisagenlecleucel) and Gilead’s $12 billion buy of Kite Pharma, no approved drug and Canakinumab for Lung Cancer (may be?)

Curator: Aviva Lev-Ari, PhD, RN

 

UPDATED on 12/10/2019

For an ‘acquisitive’ Gilead, 2020 will be key test for CAR-T plans

Success for Kite, which O’Day made an independent unit, is critical for Gilead. Not only did the California biotech invest a large sum to buy the CAR-T specialist, it’s the most notable bet made on a future outside of drugs for HIV and hepatitis C.

Sentiment on Wall Street has begun to turn against the wisdom of Gilead’s choice, doubting CAR-T will live up to the promise envisioned by O’Day’s predecessors. One analyst went so far as to include the acquisition among the five most value-destroying biopharma deals of the past decade.

Commercially, sales of Yescarta have grown to $334 million through the first nine months of the year, up from $183 million during the same period last year. Still, marketing CAR-T has proved challenging, with hurdles in reimbursement and in-hospital administration particularly acute.

The coming year could prove consequential in shifting Kite’s trajectory higher.

Within the next few weeks, Gilead will ask regulators to approve its second CAR-T cell therapy, a variation of its currently cleared leukemia and lymphoma treatment Yescarta that’s manufactured differently.

new site in Europe coming online next year could substantially cut times down for Yescarta delivery there, Shaw said. (Globally, Novartis appears better positioned, with sites in Switzerland and France as well as partnerships in China, Japan and Australia.)

Automation of what’s now a mostly manual process will play an important role in CAR-T’s future too, according to Shaw.

“If we get our autologous cell therapy automated very well, you could imagine one day it could be at point of care,” she said. “We don’t want to be disrupted by someone else doing that.”

Disruption could also come in the form of allogeneic cell therapies, which are constructed using donor T cells rather than autologous treatments that use a patient’s own. Numerous clinical hurdles have made that approach more difficult but companies like Allogene — founded by former Kite executives — are moving ahead.

SOURCE

https://www.biopharmadive.com/news/gilead-kite-car-t-christi-shaw-dealmaking/568767/

 

UPDATED on 5/3/2019

Gilead Sciences tapped new CEO Daniel O’Day in part because of his cancer expertise. But he’s not planning to lead the company’s oncology ramp-up alone.

The Roche veteran intends to bring on a CEO for Gilead’s Kite unit, responsible for key CAR-T drug Yescarta. The new chief will report to O’Day and operate Kite as a separate business unit, JPMorgan analyst Cory Kasimov wrote in a Thursday note to clients.

RELATED: Gilead, looking for cancer sales, swipes Roche pharma chief Daniel O’Day for CEO post

Gilead acquired Kite in 2017 for $12 billion as its hepatitis C revenues, once its bread and butter, crashed. But so far, both Yescarta and Novartis’ rival CAR-T player, Kymriah, have struggled, thanks to a mix of reimbursement and manufacturing challenges.

Kite underperformed expectations once again in the first quarter, with Yescarta’s $96 million in sales for the period checking in below Wall Street consensus of $105 million.

O’Day doesn’t expect to see that trend continue, though. On Gilead’s earnings conference call, he “proclaimed his confidence in cell therapy, noting that it was a critical element of the company’s long term strategy,” Kasimov wrote.

Getting Gilead’s commercial business in order is just one of O’Days three main priorities as he settles into the CEO role, though. After taking the reins March 1, he decided to zero in on strengthening Gilead’s pipeline, in part through M&A. And he’ll also be making organizational tweaks to “ensure the right people are in the right place,” as Kasimov put it.

Gilead is “continuing to scan the entirety” of the M&A landscape and “acknowledges they will continue to ‘look at late stage pipeline,’” while keeping an eye on the company’s areas of expertise—oncology, HIV and hepatitis B and nonalcoholic steatohepatitis, Jefferies analyst Michael Yee wrote to his own clients. And the Big Biotech will be “accelerating internal” candidates in addition to adding bolt-on buys.

RELATED: Gilead executives predict patience—and some deal scouting—from new CEO Daniel O’Day

Unsurprisingly, analysts trained their attention on the call to O’Day’s strategy comments, and “there were literally minimal to no questions about financials,” Yee noted. But that doesn’t mean Gilead turned in a bad quarter. On the contrary, the first quarter was “fairly clean,” he wrote, with revenues of $5.28 billion meeting expectations and earnings per share of $1.76 topping forecasts by 15 cents.

New HIV hotshot Biktarvy stole the show on the revenue side, blowing the $648 million consensus prediction out of the water with $793 million in quarterly sales.

In the quarter, “about 80% of Biktarvy revenue came from switches with 25% from dolutegravir-containing regimens in the U.S.,” Kasimov wrote, referencing key combinations from Gilead’s HIV archrival, GlaxoSmithKline.

SOURCE

 

UPDATED on 9/7/2017

Here’s the inside account of Gilead’s 11-week sprint to its $12B Kite buyout – ENDPOINTS NEWS

UPDATED on 8/31/2017

Gilead-Kite: A New Transformative Deal For Biotech, AUG 30, 2017

Gilead has made a big bet on new technology in Kite’s immunotherapy platforms and has reduced the number of credible large players in the space.

With a reputation for intense diligence and dynamism in its business development efforts, Gilead’s management team will only bolster the immunotherapy field as it prepares to face off with Novartis, its immediate competitor, and enters squarely in the province of Merck and Bristol Myers Squibb, two of the leaders in immuno-oncology.

Gilead has reinvented the transformative transaction for the sector.

https://www.forbes.com/sites/stephenbrozak/2017/08/30/gilead-kite-a-new-transformative-deal-and-maybe-the-new-future-of-healthcare-deals/#fc64fca65d49

 

I attended this week the 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

 

The following talks on 8/29/2017 presented the frontier of CAR-T Therapies and Technologies from lab to bed side:

  • Building Better T Cell Therapies: The Power of Molecular Profiling

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

  • Tricked-Out Cars, the Next Generation of CAR T Cells

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

  • The Generation of Lentiviral Vector-Modified CAR-T Cells Using an Automated Process

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

I covered this event in Real Time for the Press

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

https://pharmaceuticalintelligence.com/2017/08/29/live-829-chis-oncolytic-virus-immunotherapy-and-adoptive-cell-therapy-august-28-29-2017-sheraton-boston-hotel-boston-ma/

 

One year ago we published the following:

What does this mean for Immunotherapy? FDA put a temporary hold on Juno’s JCAR015, Three Death of Celebral Edema in CAR-T Clinical Trial and Kite Pharma announced Phase II portion of its CAR-T ZUMA-1 trial

https://pharmaceuticalintelligence.com/2016/07/09/what-does-this-mean-for-immunotherapy-fda-put-a-temporary-hold-on-jcar015-three-death-of-celebral-edema-in-car-t-clinical-trial-and-kite-pharma-announced-phase-ii-portion-of-its-car-t-zuma-1-trial/

 

SOURCE

Is Canakinumab the Next Viagra?

In this Revolution and Revelation, Milton Packer explains how safety data can sometimes trump a primary endpoint

by Milton PackerAugust 30, 2017

https://www.medpagetoday.com/Blogs/RevolutionandRevelation/67605

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

Reporter: Aviva Lev-Ari, PhD, RN

 

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.

  • Oncolytic HSV (oHSV) Strategy
  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)
  • H-Ras V12 lentiviruses; AKT act
  • TP53+/- nestin-Cre mice
  • oHSV-mCherry
  • Interferon Gamma
  • Strategy – Combination: Check inhibitors PLUS IL12 –>>> Immune response
  • oHSV G47 – Clinical trials in Japan
  • Deletion ICP6
  • IL-12 – Pro-inflammatory cytokine
  • promote proliferation of activated T- and NK cells
  • Expression on G47 delta Prolongs survival
  • Immune Checkpoint Inhibitors: PD-1;PD-L1 (bind to receptor PD-1); TCR–MHC
  • Anti CTLA-4 (Ipilimumab)
  • Strategy: anti-CTLA4+G47delta-IL12 – improve survival – cure after 80 days survival 90% by 120 days – cured mice are protected from tumor re-challenge 
  • Macropahge (Innate immune for GBM) Infiltration M! and M2
  • Triple Combination Therapy
  • Depletion of CD4 Abrogates all therapies: CD4
  • Depletion of CD8 Abrogates all therapies: CD8
  • Depletion/Inhibition abrogate Triple Therapy – Depletion ALters other Immune Cell Types: Clod – increase
  • Combination Viro-Immunotherapy: Deletion of CD 4+, CD8+ or macrophage – multiple cell types are involved and need selection for Model efficacy

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.

  • DNA damage response (DDR): guardian of genome maintenance
  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.

  • Evolution of T cells Therapy for cancer: LAK and CAR-T: TIL, NK, DLI, T reg TCR CAR (I) CAR (II)
  • Technologies:Flow cytometry, Cytokine measurement, Function, RNA expression –
  • next generation Technology: RNAseq, ATACseq, Single-cell analysis, ML, CyTOF, BigDAta algorithms
  • Outcomes
  • CAR Technology
  • T-Cell Signaling to create artificial molecules
  • Rapamycin-resistant allogenic T cells
  • T cell gene : IFN-gamma vs IL6
  • Lineage potential, differentiation cell expression T6, T12
  • T cell less well defined after CAR-T production – CHange in activation/Ag experience over the CAR-T production process
  • MST – Minimum Spanning Tree: CAR expression in sub-populations may vary in constructs with different endo-domains
  • CAR signaling may vary in construct that contain different endo-domains
  • Antigen stimulation in vitro: Extract RNA,
  • CAR Ag on T cell transcriptional profile: Process — >> Antigen Stimulation –>> Final Product, Drug Product + Ag Stimulation
  • Epigenetic profiling
  • Does cell state predict response potential?Gene accessibility vs % cytokine x hours after production completed
  • Interrogating cell state across the genome: gene regulation networks
  • Leveraging “big data”: hetegogeniety of cells and cellular types/age Hyperparameter optimization

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.

  • Hme malignancy CART: anti-CD19 or anti-BCMA Cart (Promicing Targett for Multiple Myeloma (MM) cells
  • Stable disease, PR, VGPR, CR/sCR
  • Clinical response: Time to response and identification of of dose(s)
  • Overcoming solid tumor microenvironment
  • Manipulatinf T cell lineage via PI3Ki-AKT Pathway ia a Rheostat for T cell Differentiation
  • APC, CD8 – T cell Placticity self revnewal long lived vs terminal no renewal
  • Phenotypic differences in cells grown in bb007; il2, IL2 = bb007, IL-7 +IL-15 vs CyTOF
  • Comparison: Vehicle vs IL-2 culture vs IL-7 + IL-15 Culture vs IL-2 + IL-15
  • DARIC: Drug Regulated Antigen Receptor Technology
  • Genome Edit CRISPR – megaTAL Expertise: Broad range od potential protein
  • Dustructive Gene HDR – Knock0Out Gene vs Knock-IN
  • Multiplex: 3 megaTAL multiplex Editing
  • TCRalpha locus – gene editing: HDR generated CAR T cells have equiv phenotype as LV-CAR-T cells
  • Cytotoxicity vs Cytokine production
  • TGFbeta receptor – A chimeric TGF Beta receptor (CTBR) replaces endogenous
  • CTBR12 signal converter enhances activity of CAR T cells: STAT activation; Gene expression changes; Enhanced Tumor Cell Killing
  • Synthetic Biology plays a greater role

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.

  • MAGE-A-10 TCR: ‘X-scan’ Specificity Analysis: TCR peptide recognition
  • Clinical efficacy of SSPEAR T-cells : Melanoma, synovial sarcoma and multiple myeloma
  • Antigen expression and prior lymphodepletion explored in pitol trial, results presented at ASCO 2017.
  • Open Trials: HCC, Uretrial Cancer
  • SOlid Tumors: MAGE-A4 SPEAR T-cells
  • Product supply forclinical trials
  • SPEAR T cell manufacturing: Platform process – continuous upgrade of unit operations: Apheresis, Activation and LV Trunsduction, Expansion and polarization, harvest and formulation, INFUSE
  • Media Optimization vs Programming T-Cells
  • P2: Cryopreserve: Total nucleated cells vs Days of growth in culture–>> optimal results at 14 days, One Product not like others: NYESO T-Cell expansion
  • Process 1 vs Process 2 – 80% of batches dramatic change
  • Manufacturing Lifecycle – Exploratory phase INDs: Academic vs Industry vs Pivotal/Commercial
  • Industry: CRO, CMO, Stable documented, slow change control, audit facilities and QA, scalable and transferrable
  • Pivotal/Commercial

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.

  • Lentiviral vectors (LV)
  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
  • Improving CAR-T function: Geometry and Binding – CD19
  • 4-1BB co-stimulation T-Cells: production of anti CD22 CAR-T cells
  • Dose level: Effective dose: 1×10 tot the power of 6
  • Biospecific CD19-CD20 targeting CAR T cells in Adult Leukemia – expression of primary cells
  • Tumor eliminated — >>> Tumor selected for escape –>>> analysis of escape strategy
  • POC: cell processing facilities integrate  -cell manufacturing with ANALYTICS
  • Hospital Pharmacy Annex for Apheresis & Infusion Unit
  • Vector design, Media and conditions, Isolation of beads
  • Optimal time-point for LV – T cell cultivation from patient cells: Health DOnot vs Patient material
  • T cell phynotype – 14 day phynotype
  • Cell-Factory come online in late 2017, generic products – CAR19 LV

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.

  • Office of Tissue and Advanced Therapies ( OTAT) [Previously Office of Cellular, Tissue and Gene Theraphies]
  • Oncology Center of Excellence (OCE) – Cancer MoonShot
  • OTAT – Regulated Products
  • Cancer Vaccines and Immunotherapy Products
  • Gene Therapies and Gene Modified Cancer Vaccines and Immunotherapy Products: Vectors, Cancer Vaccines, CART
  • Biologic Agents and Adjuvants: Dendritic Cells, Tumor antigens, Antibody tumor antibody
  • Oncology Product Approval: phases
  • FDA Safety and Innovation Act (FDASIA) – law 2012
  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
  • 21st Century Cures Act, becomes law in 12/2016. – REGENERATIVE Medicine Advanced Therapy (RMAT): 60 days to respond. RMAT Benefit Designation
  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
  • products with multiple active components: Identity and potency – TESTING for
  • Personalized products: Autologous cancer vaccines – if not cryopreserved

CART-T Cells: Safety Issues and Concerns:

  • Cytokine Release Syndrom
  • Neurologic Toxicity +/- CRS: Cerebral edema, Infections, Long term

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

  • If Data to small – risk can’t be assess
  • confidential data analysis
  • Identify safety trends across INDs

SOURCES on FDA Website

  • Cell and Gene Therapy Guidances

 

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

  • 83% of survival gains in Cancer – attributed to treatment , including Medicines
  • In past 5 years, 22 tumor types ahve new medicines for

# 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:
  • Median Survival
  • long term benefit
  • utility gain post progression
  • relationships : PFS and OS: Redefined wiht OS = redefined with IO
  • FRAMEWORKS in Oncology for assessment of Cost of Treatments:
  1. ICER (Evidence Reports),
  2. OSCO Value Framework),
  3. NCCN (Evidence Blocks),
  4. DrugPricingLab (Oncology Drug Abacus), Memorial Sloan Kettering
  • OPDIVO: HTA Reimbursement Decision BY Agency By Country
  • Promise of Combination Therapies: AntiPD-1/PD-L1 MAb – Study by companion agent
  • PATIENT Perspective: Multiple Combinations, Multiple Indications, Longer Treatment, Better Chance to Fight Cancer, Increase cost of therapy
  • Putting Patient FIRST: Evidence vs Access: Stop treating decisions, Intermittent treatment, side effect mgm, adherence
  • Combination Therapy vs Standard of Care ifs different than Combination vs. Agent 1, Agent 2, Agent 3 – all the variations
  • Payers will reimburse One party not three parties – if the combination is a three drugs from three vendors
  • VALUE-Based Agreements in Oncology:
  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
  • Avastin in Lung Cancer
  • Rebates tied to PFS a key endpoint in the Phase 3 PCT

 

 

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.

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

Reporter: Aviva Lev-Ari, PhD, RN

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
  • PeptiCRAd eradicates melanoma tumors
  • PeptiCRAd was the most effective in controlling tumorgrowth >> induced high # of tumor peptide – presenting mature dendritic cells
  • induced systemic tumor-specific CD8+
  • targeting two antigens provides better anti-tumor efficacy
  • Tumor Volume/days after treatment: PeptiCARd (TRP-2 – best efficacy
  • Phase I Clinical Trial with PeptiCRAd – selected indications and checkpoint inhibitor (CPI) combination
  1. Triple negative BR CA
  2. Malignant Melanoma
  3. NSCLC
  • CPI show clinical activity in PT with ongoing anti-tumor immune response
  • local treatment with OV attracts T-cells — Intra-Tumor (IT) OV delivery is superior to systemic route (IV/IA (intra-arterial))

 

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

CHI’s 5th ImmunoModulatory Therapeutic Antibodies for Cancer Conference, August 28-29, 2017 Sheraton Boston Hotel | Boston, MA

Reporter: Aviva Lev-Ari, PhD, RN

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

 

Cambridge Healthtech Institute’s 5th Annual

Immunomodulatory Therapeutic Antibodies for Cancer

Scientific Strategies for Discovering and Developing Novel Immunotherapies and Agents to Improve the Efficacy and Toxicology Profiles of T Cell-Targeted Biotherapeutics
August 28-29, 2017 Sheraton Boston Hotel | Boston, MA

http://www.immuno-oncologysummit.com/Immunomodulatory-Antibodies-Cancer/

 

MONDAY, AUGUST 28

7:30 am Registration & Morning Coffee

8:25 Chairperson’s Opening Remarks

Yan Qu, Ph.D., Senior Principal Scientist, Pfizer

 

8:30 KEYNOTE PRESENTATION: Enabling Effective Immuno-Oncology

Greg_AdamsGregory Adams, Ph.D., CSO, Eleven Biotherapeutics

Checkpoint inhibitors and other immune-oncology agents have shown significant promise in the treatment of a variety of cancers. However, many of these agents are only effective when an existing host immune response has already been induced by other therapeutic approaches. I will discuss strategies that may be used to effectively set the stage for immune-oncology treatments including Eleven BioTherapeutics’ Targeted Protein Therapeutics.

9:00 Immunomodulatory Antibodies – Potentiation by Fc Receptor Engagement

Rony_DahanRony Dahan, Ph.D., Principal Investigator, Immunology, Weizmann Institute of Science, Israel

Immunomodulatory mAbs are revolutionizing cancer treatment due to their clinical effective stimulation of therapeutic anti-cancer immunity. Recent studies demonstrated the importance of the Fc domain of these types of mAbs. Their optimal activity can be critically depended on their ability to engage defined FcgR pathways. I will discuss our recent characterization of these FcgR-dependent mechanisms, and how they can be exploited for introducing second generation Fc-optimized immunomodulatory mAbs.

TD2 tagline9:30 Coffee Break

 

MECHANISMS OF ACTION

10:00 The Role of Metabolism in Immune Response in Tumors: Merging the Past and the Present of Tumor Microenvironment

Allison_BetofAllison S. Betof, M.D., Ph.D., Medical Oncology Fellow, Memorial Sloan Kettering Cancer Center

Tumors are not simply collections of cancer cells that arise in a vacuum; they are instead complex structures composed of blood vessels, immune cells, and other supporting structures that interact, consume oxygen and other nutrients, and produce waste. Tumor metabolism has long been viewed as a therapeutic target. I will discuss recent data on how metabolism influences immunobiology and our group’s approach to harness these interactions to improve therapeutic outcomes.

10:30 PI3Kgamma Is a Molecular Switch that Controls Immune Suppression

Megan_KanedaMegan M. Kaneda, Ph.D., Assistant Project Scientist, University of California, San Diego

Macrophages play critical but opposite roles in inflammation and cancer. We have found that the predominant isoform of PI3K in myeloid cells, PI3Kgamma, controls the switch between immune stimulation and immune suppression. Inhibition of macrophage PI3Kgamma activity promotes an immunostimulatory transcriptional program that restores CD8+ T cell activation and cytotoxicity and synergizes with checkpoint inhibitor therapy to promote tumor regression and extend survival in mouse models of cancer.

11:00 Avelumab (hIgG1 Anti-human PD-L1) Mediates the anti-Tumor Efficacy via Multiple Pathways in Preclinical Models

Yan_QuYan Qu, Ph.D., Senior Principal Scientist, Pfizer

Analysis of PD-L1 expression on various immune subpopulations in human patient samples showed that PD-L1 is enriched on non-T cells. In tumor-bearing mice, the percentage of splenic NK cells was increased with WT avelumab treatment but not with the Fc isotype variant. Avelumab-induced tumor shrinkage, tumor-infiltrating CD8+ T cell increase, and tumor PD-L1+ immature myeloid cell decrease appear to require NK cells, as such changes were abolished upon NK depletion.

ProImmune11:30 Epitope Identification and Clinical Immune Monitoring in Immune Oncology Programs

Emilee KnowltonEmilee Knowlton, Ph.D., Immunology Sales Specialist, ProImmune

 

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

12:30 Session Break

TARGET DISCOVERY FOR NEXT GENERATION IMMUNOTHERAPIES

1:25 Chairperson’s Remarks

Stephen Beers, Ph.D., Associate Professor, Cancer Immunology and Immunotherapy, University of Southampton, United Kingdom

1:30 Functional Characterization of Macaque Fcr and IgG Subtypes

Margie Ackerman, Ph.D., Assistant Professor, Engineering, Dartmouth College

A number of antibody therapies rely on Fc receptor (FcR)-mediated effector functions for optimal activity, prompting the need to understand how native and IgG domains engineered to differentially bind to the human receptors translate in non-human primate (NHP) models. We report characterization of the affinity between an IgG Fc variant panel (including subclass, Fc mutants and glycosylation) and major human and rhesus FcR allotypic variants.

2:00 Utilizing Patient-Derived Organoids and High-Content Imaging for Screening and Characterization of Bispecific Antibodies

Mark_ThrosbyMark Throsby, Ph.D., EVP & CSO, Merus N.V., The Netherlands

This presentation will provide a case study on how panels of patient-derived organoids grown ex-vivo in 3D culture combined with high-content imaging can be applied to bispecific antibody screening. Lead candidate bispecifics were selected targeting the wnt pathway with novel modes of action including immunomodulation.

 

2:30 Discovery and Development Strategies for New Small Molecule Immunotherapies

Nicola_WallisNicola Wallis, Ph.D., Senior Director, Biology, Astex Therapeutics, Ltd.

Small molecules are of interest as immunotherapies as both single agent and combinations, offering the possibility of modulating different aspects of the immune system to biologics. We are exploring targeting a number of different immunomodulatory mechanisms with small molecules derived using fragment-based drug design and will describe examples in this presentation.

TD2 tagline3:00 Refreshment Break

 

IMMUNE SYSTEM PRIMING AND ACTIVATION

3:30 STING Adjuvants for Immune System Priming for Antibody Therapy

Stephen_BeersStephen Beers, Ph.D., Associate Professor, Cancer Immunology and Immunotherapy, University of Southampton, United Kingdom

Successful tumor-targeting antibody approaches appear to rely predominantly on the effector function of Fcγ receptor (FcγR) expressing macrophages. Unfortunately, tumor-associated macrophages (TAM) are frequently poorly cytotoxic, contribute to immune suppression and have suboptimal FcγR expression making treatment less effective. Here we show that STING agonists are able to overcome immunosuppression in the tumour microenvironment effectively reversing the TAM inhibitory FcγR profile and provided strong adjuvant effects to antibody therapy.

4:00 Next-Generation Cancer Vaccines

Daniel_LeveyDaniel L. Levey, Ph.D., Senior Director, Vaccine Research, Agenus

Agenus is advancing two fully synthetic cancer vaccine platforms. The first is based on identification of mutations encoded in the tumor genome while the second relates to a novel class of tumor specific neo-epitopes arising from inappropriate phosphorylation of various proteins in malignant cells. The platforms support the manufacture of both individualized and off-the-shelf cancer vaccines against a range of tumor antigens, increasing the likelihood of immune recognition of tumors.

4:30 Oral T Cell Vaccines Targeting Immune Organs of the Gut for Generating Systemic Antigen Specific T Cells

Marc_MansourMarc Mansour, Ph.D., Chief Business Officer, Vaximm AG

We use attenuated Salmonella typhi Ty21 as a vector to deliver a plasmid encoding antigens of interest via the oral route to Peyer’s patches. The bacteria have built in adjuvant properties and induce cross presentation to produce a systemic T cell response. Monotherapy with a candidate targeting VEGFR2 produced clinical responses in GBM, highlighting the unique properties of this T cell vaccine approach.

5:00 End of Day

 

 

TUESDAY, AUGUST 29

7:25 am Breakout Discussion Groups with Continental Breakfast

Join a breakout discussion group. These are informal, moderated discussions with brainstorming and interactive problem solving, allowing participants from diverse backgrounds to exchange ideas and experiences and develop future collaborations around a focused topic. Details on the topics and moderators are below.

New Understandings of the Mechanisms of Action for Immunomodulatory Antibodies

Moderator: Stephen Beers, Ph.D., Associate Professor, Cancer Immunology and Immunotherapy, University of Southampton, United Kingdom

  • What are we learning about MOA from clinical trial data?
  • Optimizing MOA in next generation immunomodulators
  • The role of effector and receptor engagement
  • MOA and bispecific antibody design
  • Overcoming resistance mechanisms

Target Discovery for Next Generation Immunotherapies

Marc Mansour, Ph.D., Chief Business Officer, Vaximm AG

  • Tumor antigen identification: strengths and weaknesses of different methodologies
  • Drugable IO targets- using macromolecules versus small molecule
  • Novel targets in the tumor microenvironment

NON-RESPONDERS, SIDE EFFECTS AND TOXICOLOGY

8:25 Chairperson’s Opening Remarks

Adam J. Adler, Ph.D., Professor, Immunology, University of Connecticut

8:30 Cancer Immunotherapy with Live-attenuated, Double Deleted Listeria Monocytogenes (LADD) Combination Strategies for the Treatment of Malignant Pleural Mesothelioma

Chan_WhitingChan C. Whiting, Ph.D., Director, Immune Monitoring and Biomarker Development, Aduro Biotech

We are advancing CRS-207, a clinical LADD strain engineered to express mesothelin, in combinations with various modalities for the treatment of malignant pleural mesothelioma.  Data from a Phase 1b study combining CRS-207 with standard chemotherapy demonstrating encouraging clinical and immune responses will be discussed.  An overview of the Phase 2 study design and progress of the CRS-207/Pembrolizumab combination study will also be highlighted.

9:00 Tumor and Class-Specific Patterns of Immune-Related Adverse Events of Immune Checkpoint Inhibitors: A Systematic Review

Aaron_HansenAaron Hansen, M.D., Ph.D., Assistant Professor, Department of Medicine, University of Toronto; Medical Oncologist, Princess Margaret Cancer Center

Through a systematic review, we identified distinct immune related adverse event (irAE) profiles based on tumor type and immune checkpoint inhibitor class (CTLA-4 and PD-1). CTLA-4 inhibitors have a higher frequency of grade 3/4 irAEs. Furthermore, for patients treated with PD-1 inhibitors, those with melanoma had a higher frequency of gastrointestinal and skin irAEs, and lower rate of pneumonitis compared with patients with NSCLC and RCC. Different immune microenvironments may drive histology-specific irAE patterns.

PROTEIN ENGINEERING

9:30 Combination Therapy with PD-1 Blockade Enhances the Antitumor Potency of T Cells Redirected by Novel Bispecific Antibodies

Ken_ChangKen Chang, Ph.D., Vice President, Research and Development, Immunomedics

Novel bispecific antibodies that bind bivalently to tumor antigens and monovalently to CD3 can redirect T cells to kill Trop-2- or CEACAM5-expressing solid cancer cells grown in monolayer cultures at low picomolar concentrations. The antitumor efficacy was demonstrated also in a humanized mouse model and in 3D spheroids generated with cells from TNBC and colonic cancers. Combining anti-PD-1 increased cell death in 3D spheroids and prolonged survival of tumor-bearing animals.

MaxCyte no tagline10:00 Accelerated Production of Immunomodulatory Therapeutic Antibodies & Bispecific Molecules Using Scalable Cell Engineering

James_BradyJames Brady, Ph.D., Vice President, Technical Applications & Customer Support, MaxCyte

Antibodies and antibody-like molecules are a proven means of modulating effective anti-tumor immune responses. MaxCyte’s delivery platform facilitates rapid, fully scalable, high quality transient protein production in the cell line-of-choice, as well as streamlined stable pool and cell line generation enabling accelerated development of relevant immunomodulatory candidates. Case studies will illustrate the identification and development of antibodies, tribodies & bi-specific T cell engaging molecules (BiTEs) using the MaxCyte platform.

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

11:15 A Novel, Dual-Specific Antibody Conjugate Targeting CD134 and CD137 Costimulates T Cells and Elicits Antitumor Immunity

Adam_AdlerAdam J. Adler, Ph.D., Professor, Immunology, University of Connecticut

Combining agonists to different costimulatory receptors can be more effective in controlling tumors compared to individual agonists, but presents logistical challenges and increases the potential for adverse events. We developed a novel immunotherapeutic agent by fusing agonists to CD134 and CD137 into a single biologic, OrthomAb, that potentiates cytokine secretion from TCR-stimulated T cells more potently than non-conjugated CD134 + CD137 agonists in vitro, and reduces tumor growth in vivo.

11:45 Targeted Tissue Delivery Using Caveolae Technology Improves Drug Efficacy

Ruchi_GuptaRuchi Gupta, Ph.D., Team Lead Scientist, MedImmune

Current biotherapeutics focus on the molecular targets expressed on cells/tumors. However, less than 10% of the IV administrated biologics can reach the diseased tissues. Tissue targeting using caveolae proteins can allow for specific delivery to organs of interest. This talk will focus on caveolae technology that shows specific delivery to lungs and kidneys and improves drug efficacy. This targeting holds potential for several diseases including fibrosis, COPD, Infections as well as tumors.

12:15 pm Close of Immunomodulatory Therapeutic Antibodies for Cancer