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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

 

CRISPR Based Research Awarded NHGRI Grants, The University of California, Berkeley’s Doudna will receive $2.1 million and The Broad Institute’s Zhang will receive $1.1 million

Reporter: Aviva Lev-Ari, PhD, RN

2.1.5.4

2.1.5.4   CRISPR Based Research Awarded NHGRI Grants, The University of California, Berkeley’s Doudna will receive $2.1 million and The Broad Institute’s Zhang will receive $1.1 million, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 2: CRISPR for Gene Editing and DNA Repair

UPDATED on 10/10/2017

Gene Editing Market: CRISPR/CAS9 to be the fastest-growing technology segment – 2024

Request for Sample Copy of this Report @ http://bit.ly/2wExTM9

Rising prevalence of cancer, infectious diseases, and other genetic disorders, and growing demand for personalized medicine should stimulate industry expansion. Furthermore, expansion and development in healthcare infrastructure should propel industry demand.

Gene editing market has its extensive application in therapeutic areas of hematology, infectious disease, oncology and muscular diseases. Hematology was recognized as the highest revenue generating segment in 2015, due to extensive use in investigating genetic function in experimental hematology. Infectious disease segment will also follow the robust growth trend with 15.2% CAGR during the forecast timeframe contributing to the overall revenue of over USD 2.5 billion by 2024.

For more information visit @ http://bit.ly/2firtKv

Growth Drivers:

1. Increased funding for genetics research
2. Increased R&D expenditure and growth of biotechnology
3. Increasing demand for synthetic genes
4. Growing use of genetically modified technology
5. Technology advancements

SOURCE

https://www.linkedin.com/groups/1907871/1907871-6322402100114489346?midToken=AQGWu2im3_6Knw&trk=eml-b2_anet_digest_of_digests-hero-11-discussion~subject&trkEmail=eml-b2_anet_digest_of_digests-hero-11-discussion~subject-null-7gtb2~j8lx06xl~ig-nullcommunities~group~discussion&lipi=urn%3Ali%3Apage%3Aemail_b2_anet_digest_of_digests%3BLXMNlwc3Q32rTtwL%2FO%2BYbg%3D%3D

Jennifer Doudna of University of California, Berkeley, and Feng Zhang of the Broad Institute have both received separate grants from the National Human Genome Research Institute (NHGRI) for projects based on CRISPR technology.

Jennifer Doudna will receive $2.1 million to set up and run the Centre for Genome editing and Recording. The centre will address the challenges of accurately interrogating and manipulating DNA sequences in situ “at a scale and level of accuracy and not currently available” by developing technologies based on CRISPR-Cas9 that can “detect, alter and record the sequence and output of the genome in individual cells and tissues,” according to Doudna’s grant proposal.

Feng Zang will receive $1.1 million for a project that aims to develop a suite of tools for the interrogation of RNA based on CRISPR-Cas enzymes that target RNA in a programmable manner.

“Tools for transcript knockdown, translation upregulation, and transcript sensing will be developed, which, together, will enable dissection of genetic circuits in a dynamic, high-throughput manner, accelerating nearly all areas of biomedical science,” Zhang’s grant proposal said.

Doudna and Zhang both say they have the potential to advance the tool’s usefulness for human health purposes.

http://www.frontlinegenomics.com/news/14261/crispr-based-research-awarded-nhgri-grants/

https://www.genomeweb.com/research-funding/jennifer-doudna-feng-zhang-awarded-nhgri-grants-crispr-based-research

Decline in Sperm Count – Epigenetics, Well-being and the Significance for Population Evolution and Demography

Dr. Marc Feldman, Expert Opinion on the significance of Sperm Count Decline on the Future of Population Evolution and Demography

Dr. Sudipta Saha, Effects of Sperm Quality and Quantity on Human Reproduction

Dr. Aviva Lev-Ari, Psycho-Social Effects of Poverty, Unemployment and Epigenetics on Male Well-being, Physiological Conditions affecting Sperm Quality and Quantity

 

Updated on 10/6/2022

“Red states are now less healthy than blue states, a reversal of what was once the case,” Anne Case and Angus Deaton, economists at Princeton, argue in a paper they published in April, “The Great Divide: Education, Despair, and Death.”

Carol Graham, a senior fellow at Brookings, described the erosion of economic and social status for whites without college degrees in a 2021 paper:

From 2005 to 2019, an average of 70,000 Americans died annually from deaths of despair (suicide, drug overdose, and alcohol poisoning). These deaths are concentrated among less than college educated middle-aged whites, with those out of the labor force disproportionately represented. Low-income minorities are significantly more optimistic than whites and much less likely to die of these deaths. This despair reflects the decline of the white working class. Counties with more respondents reporting lost hope in the years before 2016 were more likely to vote for Trump.

2010 Pew Research Center study that examined the effects of the Great Recession on Black and white Americans reported that Black Americans consistently suffered more in terms of unemployment, work cutbacks and other measures, but remained far more optimistic about the future than whites. Twice as many Black as white Americans were forced during the 2008 recession to work fewer hours, to take unpaid leave or switch to part-time, and Black unemployment rose from 8.9 to 15.5 percent from April 2007 to April 2009, compared with an increase from 3.7 to 8 percent for whites.

Despite experiencing more hardship, 81 percent of Black Americans agreed with the statement “America will always continue to be prosperous and make economic progress,” compared with 59 percent of whites; 45 percent of Black Americans said the country was still in recession compared with 57 percent of whites

In “Trends in Extreme Distress in the United States, 1993-2019,” David G. Blanchflower and Andrew J. Oswald, economists at Dartmouth and the University of Warwick in Britain, note that “the proportion of the U.S. population in extreme distress rose from 3.6 percent in 1993 to 6.4 percent in 2019. Among low-education midlife white persons, the percentage more than doubled, from 4.8 percent to 11.5 percent.”

In her 2020 paper, “Trends in U.S. Working-Age Non-Hispanic White Mortality: Rural-Urban and Within-Rural Differences,” Shannon M. Monnat, a professor of sociology at Syracuse University’s Maxwell School, explained that “between 1990-92 and 2016-18, the mortality rates among non-Hispanic whites increased by 9.6 deaths per 100,000 population among metro males and 30.5 among metro females but increased by 70.1 and 65.0 among nonmetro (rural and exurban) males and females, respectively.”

Three economists, David AutorDavid Dorn and Gordon Hanson of M.I.T., the University of Zurich and Harvard, reported in their 2018 paper, “When Work Disappears: Manufacturing Decline and the Falling Marriage Market Value of Young Men,” on the debilitating consequences for working-class men of the “China shock”

There is some evidence that partisanship correlates with mortality rates.

In their June 2022 paper, “The Association Between Covid-19 Mortality and the County-Level Partisan Divide in the United States,” Neil Jay SehgalDahai YueElle PopeRen Hao Wang and Dylan H. Roby, public health experts at the University of Maryland, found in their study of county-level Covid-19 mortality data from Jan. 1, 2020, to Oct. 31, 2021, that “majority Republican counties experienced 72.9 additional deaths per 100,000 people.”

Anne Case wrote in her email, that the United States is fast approaching a point where

Education divides everything, including connection to the labor market, marriage, connection to institutions (like organized religion), physical and mental health, and mortality. It does so for whites, Blacks and Hispanics. There has been a profound (not yet complete) convergence in life expectancy by education. There are two Americas now: one with a B.A. and one without.

SOURCE

 

UPDATED on 2/20/2021

Count Down

How Our Modern World Is Threatening Sperm Counts, Altering Male and Female Reproductive Development, and Imperiling the Future of the Human Race

https://www.simonandschuster.com/books/Count-Down/Shanna-H-Swan/9781982113667

Aside from the decline in sperm counts, growing numbers of sperm appear defective — there’s a boom in two-headed sperm — while others loll aimlessly in circles, rather than furiously swimming in pursuit of an egg. And infants who have had greater exposures to a kind of endocrine disruptor called phthalates have smaller penises, Swan found.

Still, the Endocrine Society, the Pediatric Endocrine Society, the President’s Cancer Panel and the World Health Organization have all warned about endocrine disruptors, and Europe and Canada have moved to regulate them.

Scientists are concerned by falling sperm counts and declining egg quality. Endocrine-disrupting chemicals may be the problem.

Opinion Columnist

https://www.nytimes.com/2021/02/20/opinion/sunday/endocrine-disruptors-sperm.html?campaign_id=45&emc=edit_nk_20210220&instance_id=27333&nl=nicholas-kristof&regi_id=65713389&segment_id=52055&te=1&user_id=edf020ada5f25f6d6c4b0b32ac4a1ee9

 

UPDATED on 2/3/2018

Nobody Really Knows What Is Causing the Overdose Epidemic, But Here Are A Few Theories

https://www.buzzfeed.com/danvergano/whats-causing-the-opioid-crisis?utm_term=.kbJPMgaQo4&utm_source=BrandeisNOW%2BWeekly&utm_campaign=58ada49a84-EMAIL_CAMPAIGN_2018_01_29&utm_medium=email#.uugW6mx1dG

 

Recent studies concluded via rigorous and comprehensive analysis found that Sperm Count (SC) declined 52.4% between 1973 and 2011 among unselected men from western countries, with no evidence of a ‘leveling off’ in recent years. Declining mean SC implies that an increasing proportion of men have sperm counts below any given threshold for sub-fertility or infertility. The high proportion of men from western countries with concentration below 40 million/ml is particularly concerning given the evidence that SC below this threshold is associated with a decreased monthly probability of conception.

1.Temporal trends in sperm count: a systematic review and meta-regression analysis 

Hagai Levine, Niels Jørgensen, Anderson Martino‐Andrade, Jaime Mendiola, Dan Weksler-Derri, Irina Mindlis, Rachel Pinotti, Shanna H SwanHuman Reproduction Update, July 25, 2017, doi:10.1093/humupd/dmx022.

Link: https://academic.oup.com/humupd/article-lookup/doi/10.1093/humupd/dmx022.

2. Sperm Counts Are Declining Among Western Men – Interview with Dr. Hagai Levine

https://news.afhu.org/news/sperm-counts-are-declining-among-western-men?utm_source=Master+List&utm_campaign=dca529d919-EMAIL_CAMPAIGN_2017_07_27&utm_medium=email&utm_term=0_343e19a421-dca529d919-92801633

3. Trends in Sperm Count – Biological Reproduction Observations

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

4. Long, mysterious strips of RNA contribute to low sperm count – Long non-coding RNAs can be added to the group of possible non-structural effects, possibly epigenetic, that might regulate sperm counts.

http://casemed.case.edu/cwrumed360/news-releases/release.cfm?news_id=689

https://scienmag.com/long-mysterious-strips-of-rna-contribute-to-low-sperm-count/

Dynamic expression of long non-coding RNAs reveals their potential roles in spermatogenesis and fertility

Published: 29 July 2017
Thus, we postulated that some lncRNAs may also impact mammalian spermatogenesis and fertility. In this study, we identified a dynamic expression pattern of lncRNAs during murine spermatogenesis. Importantly, we identified a subset of lncRNAs and very few mRNAs that appear to escape meiotic sex chromosome inactivation (MSCI), an epigenetic process that leads to the silencing of the X- and Y-chromosomes at the pachytene stage of meiosis. Further, some of these lncRNAs and mRNAs show strong testis expression pattern suggesting that they may play key roles in spermatogenesis. Lastly, we generated a mouse knock out of one X-linked lncRNA, Tslrn1 (testis-specific long non-coding RNA 1), and found that males carrying a Tslrn1 deletion displayed normal fertility but a significant reduction in spermatozoa. Our findings demonstrate that dysregulation of specific mammalian lncRNAs is a novel mechanism of low sperm count or infertility, thus potentially providing new biomarkers and therapeutic strategies.

This article presents two perspectives on the potential effects of Sperm Count decline.

One Perspective identifies Epigenetics and male well-being conditions

  1. as a potential explanation to the Sperm Count decline, and
  2. as evidence for decline in White male longevity in certain geographies in the US since the mid 80s.

The other Perspective, evaluates if Sperm Count Decline would have or would not have a significant long term effects on Population Evolution and Demography.

The Voice of Prof. Marc Feldman, Stanford University – Long term significance of Sperm Count Decline on Population Evolution and Demography

Poor sperm count appears to be associated with such demographic statistics as life expectancy (1), infertility (2), and morbidity (3,4). The meta-analysis by Levine et al. (5) focuses on the change in sperm count of men from North America, Europe, Australia, and New Zealand, and shows a more than 50% decline between 1973 and 2011. Although there is no analysis of potential environmental or lifestyle factors that could contribute to the estimated decline in sperm count, Levine et al. speculate that this decline could be a signal for other negative changes in men’s health.

Because this study focuses mainly on Western men, this remarkable decline in sperm count is difficult to associate with any change in actual fertility, that is, number of children born per woman. The total fertility rate in Europe, especially Italy, Spain, and Germany, has slowly declined, but age at first marriage has increased at the same time, and this increase may be more due to economic factors than physiological changes.

Included in Levine et al.’s analysis was a set of data from “Other” countries from South America, Asia, and Africa. Sperm count in men from these countries did not show significant trends, which is interesting because there have been strong fertility declines in Asia and Africa over the same period, with corresponding increases in life expectancy (once HIV is accounted for).

What can we say about the evolutionary consequences for humans of this decrease? The answer depends on the minimal number of sperm/ml/year that would be required to maintain fertility (per woman) at replacement level, say 2.1 children, over a woman’s lifetime. Given the smaller number of ova produced per woman, a change in the ovulation statistics of women would be likely to play a larger role in the total fertility rate than the number of sperm/ejaculate/man. In other words, sperm count alone, absent other effects on mortality during male reproductive years, is unlikely to tell us much about human evolution.

Further, the major declines in fertility over the 38-year period covered by Levine et al. occurred in China, India, and Japan. Chinese fertility has declined to less than 1.5 children per woman, and in Japan it has also been well below 1.5 for some time. These declines have been due to national policies and economic changes, and are therefore unlikely to signal genetic changes that would have evolutionary ramifications. It is more likely that cultural changes will continue to be the main drivers of fertility change.

The fastest growing human populations are in the Muslim world, where fertility control is not nearly as widely practiced as in the West or Asia. If this pattern were to continue for a few more generations, the cultural evolutionary impact would swamp any effects of potentially declining sperm count.

On the other hand, if the decline in sperm count were to be discovered to be associated with genetic and/or epigenetic phenotypic effects on fetuses, newborns, or pre-reproductive humans, for example, due to stress or obesity, then there would be cause to worry about long-term evolutionary problems. As Levine et al. remark, “decline in sperm count might be considered as a ‘canary in the coal mine’ for male health across the lifespan”. But to date, there is little evidence that the evolutionary trajectory of humans constitutes such a “coal mine”.

References

  1. Jensen TK, Jacobsen R, Christensen K, Nielsen NC, Bostofte E. 2009. Good semen quality and life expectancy: a cohort study of 43,277 men. Am J Epidemiol 170: 559-565.
  2. Eisenberg ML, Li S, Behr B, Cullen MR, Galusha D, Lamb DJ, Lipshultz LI. 2014. Semen quality, infertility and mortality in the USA. Hum Reprod 29: 1567-1574.
  3. Eisenberg ML, Li S, Cullen MR, Baker LC. 2016. Increased risk of incident chronic medical conditions in infertile men: analysis of United States claims data. Fertil Steril 105: 629-636.
  4. Latif T, Kold Jensen T, Mehlsen J, Holmboe SA, Brinth L, Pors K, Skouby SO, Jorgensen N, Lindahl-Jacobsen R. Semen quality is a predictor of subsequent morbidity. A Danish cohort study of 4,712 men with long-term follow-up. Am J Epidemiol. Doi: 10.1093/aje/kwx067. (Epub ahead of print]
  5. Levine H, Jorgensen N, Martino-Andrade A, Mendiola J, Weksler-Derri D, Mindlis I, Pinotti R, Swan SH. 2017. Temporal trends in sperm count: a systematic review and meta-regression analysis. Hum Reprod Update pp. 1-14. Doi: 10.1093/humupd/dmx022.

SOURCE

From: Marcus W Feldman <mfeldman@stanford.edu>

Date: Monday, July 31, 2017 at 8:10 PM

To: Aviva Lev-Ari <aviva.lev-ari@comcast.net>

Subject: Fwd: text of sperm count essay

Psycho-Social Effects of Poverty, Unemployment and Epigenetics on Male Well-being, Physiological Conditions as POTENTIAL effects on Sperm Quality and Quantity and Evidence of its effects on Male Longevity

The Voice of Carol GrahamSergio Pinto, and John Juneau II , Monday, July 24, 2017, Report from the Brookings Institute

  1. The IMPACT of Well-being, Stress induced by Worry, Pain, Perception of Hope related to Employment and Lack of employment on deterioration of Physiological Conditions as evidence by Decrease Longevity

  2. Epigenetics and Environmental Factors

The geography of desperation in America

Carol GrahamSergio Pinto, and John Juneau II Monday, July 24, 2017, Report from the Brookings Institute

In recent work based on our well-being metrics in the Gallup polls and on the mortality data from the Centers for Disease Control and Prevention, we find a robust association between lack of hope (and high levels of worry) among poor whites and the premature mortality rates, both at the individual and metropolitan statistical area (MSA) levels. Yet we also find important differences across places. Places come with different economic structures and identities, community traits, physical environments and much more. In the maps below, we provide a visual picture of the differences in in hope for the future, worry, and pain across race-income cohorts across U.S. states. We attempted to isolate the specific role of place, controlling for economic, socio-demographic, and other variables.

One surprise is the low level of optimism and high level of worry in the minority dense and generally “blue” state of California, and high levels of pain and worry in the equally minority dense and “blue” states of New York and Massachusetts. High levels of income inequality in these states may explain these patterns, as may the nature of jobs that poor minorities hold.

We cannot answer many questions at this point. What is it about the state of Washington, for example, that is so bad for minorities across the board? Why is Florida so much better for poor whites than it is for poor minorities? Why is Nevada “good” for poor white optimism but terrible for worry for the same group? One potential issue—which will enter into our future analysis—is racial segregation across places. We hope that the differences that we have found will provoke future exploration. Readers of this piece may have some contributions of their own as they click through the various maps, and we welcome their input. Better understanding the role of place in the “crisis” of despair facing our country is essential to finding viable solutions, as economic explanations, while important, alone are not enough.

https://www.brookings.edu/research/the-geography-of-desperation-in-america/?utm_medium=social&utm_source=facebook&utm_campaign=global

 

Shaun Coughlin from UCSF Cardiovascular Research Center to cardio group for the Novartis Institute for Biomedical Research in Cambridge, MA

Reporter: Aviva Lev-Ari, PhD, RN

 

The dean of the UCSF med school, Talmadge King, had this to say in his sendoff today:

Coughlin’s “research discoveries revealed a mechanism by which proteases regulate cellular behaviors including a key mechanism that controls blood platelet activation and clot formation. This work led to a new medical therapy for preventing heart attacks and strokes and has been honored by the American Heart Association’s Basic Science Award in 2003 and its Research Achievement Award in 2014. Among his numerous other awards are the Bristol-Myers Squibb Cardiovascular Research Award and the Distinguished Career Award from the International Society on Thrombosis and Haemostasis.”

SOURCE

https://endpts.com/top-ucsf-scientist-shaun-coughlin-joins-migration-to-big-pharma-leaping-to-novartis

Drug regiment consisting of anti-inflammatories (COX-2) and anti-stress medications (β-Adrenergic Blockade) given before and after surgery could reduce cancer recurrence (biomarkers of metastatic processes)

Reporter: Aviva Lev-Ari, PhD, RN

 

“We found that the drugs were very efficient in reducing biomarkers of metastatic processes,” Prof. Ben-Eliyahu said. “For example, we found that the drug treatment reverses EMT — the process that tumor cells go through to slip out of the primary tumor and enter another organ. It is a crucially important step in the metastatic process. We also looked at indices related to the immune system and were able to improve immune competence and reduce inflammation with the drugs.”

The research team has conducted a similar study, which has not yet been published, on colorectal cancer patients and has found similar results.

The researchers are currently considering a larger-scale clinical trial to establish the clinical long-term beneficial effects of this treatment. “Positive outcomes should validate this treatment and lead to its becoming available for most cancer patients,” Prof. Ben-Eliyahu concluded.

 

Abstract

Purpose: Translational studies suggest that excess perioperative release of catecholamines and prostaglandins may facilitate metastasis and reduce disease-free survival. This trial tested the combined perioperative blockade of these pathways in breast cancer patients.

Experimental Design: In a randomized placebo-controlled biomarker trial, 38 early-stage breast cancer patients received 11 days of perioperative treatment with a β-adrenergic antagonist (propranolol) and a COX-2 inhibitor (etodolac), beginning 5 days before surgery. Excised tumors and sequential blood samples were assessed for prometastatic biomarkers.

Results: Drugs were well tolerated with adverse event rates comparable with placebo. Transcriptome profiling of the primary tumor tested a priori hypotheses and indicated that drug treatment significantly

(i) decreased epithelial-to-mesenchymal transition,

(ii) reduced activity of prometastatic/proinflammatory transcription factors (GATA-1, GATA-2, early-growth-response-3/EGR3, signal transducer and activator of transcription-3/STAT-3), and

(iii) decreased tumor-infiltrating monocytes while increasing tumor-infiltrating B cells.

Drug treatment also significantly

  • abrogated presurgical increases in serum IL6 and
  • C-reactive protein levels,
  • abrogated perioperative declines in stimulated IL12 and IFNγ production,
  • abrogated postoperative mobilization of CD16 “classical” monocytes, and
  • enhanced expression of CD11a on circulating natural killer cells.

Conclusions: Perioperative inhibition of COX-2 and β-adrenergic signaling provides a safe and effective strategy for inhibiting multiple cellular and molecular pathways related to metastasis and disease recurrence in early-stage breast cancer. Clin Cancer Res; 1–11. ©2017 AACR.

 

SOURCES

“Anti-Inflammatory and Anti-Stress Drugs Taken Before Surgery May Reduce Metastatic Recurrence.” NeuroscienceNews. NeuroscienceNews, 7 August 2017.

Original Research: Abstract for

“Perioperative COX-2 and β-Adrenergic Blockade Improves Metastatic Biomarkers in Breast Cancer Patients in a Phase-II Randomized Trial”

by Lee Shaashua, Maytal Shabat-Simon, Rita Haldar, Pini Matzner, Oded Zmora, Moshe Shabtai, Eran Sharon, Tanir Allweis, Iris Barshack, Lucile Hayman, Jesusa Arevalo, Jeffrey Ma, Maya Horowitz, Steven Cole and Shamgar Ben-Eliyahu in Clinical Cancer Research. Published online August 2017 doi:10.1158/1078-0432.CCR-17-0152

Post-zygotic Mutations, spontaneously arising in an embryonic cell after sperm meets egg, are important players in Autism Spectrum Disorder, a HMS & BCH large study suggests

Reporter: Aviva Lev-Ari, PhD, RN

 

Based on their findings, they classified 7.5 percent of ASD subjects’ de novo mutations as PZMs. Of these, 83 percent had not been picked up in the original analysis of their genome sequence.

Some PZMs affected genes already known to be linked to autism or other neurodevelopmental disorders (such as SCN2AHNRNPU and SMARCA4), but sometimes affected these genes in different ways. Many other PZMs were in genes known to be active in brain development (such as KLF16 and MSANTD2) but not previously associated with ASD.

Comparing these with the genomic sequencing data (based mostly on blood DNA samples) allowed the researchers estimate the timing of the PZMs and the brain regions they affected. In the image at right, representing the prenatal brain, the region with the most “hits” was the amygdala (AMY, in red), with minor hits in the striatum (STR) and cerebellar cortex (CBC) that did not reach statistical significance.

Image Credit: Mohammed Uddin

 

SOURCES

Late-breaking mutations may play an important role in autism

https://vector.childrenshospital.org/2017/07/post-zygotic-somatic-mutations-autism/

Late in the Game, Post-conception mutations may play an important role in autism

https://hms.harvard.edu/news/late-game?utm_source=Silverpop&utm_medium=email&utm_term=s3&utm_content=8.7.17.HMS

Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder

Nature Neuroscience (2017) doi:10.1038/nn.4598
Published online: 17 July 2017

Agios Pharmaceuticals target the metabolism of cancer cells for making drugs that essentially try to repair cancer cells

Reporter: Aviva Lev-Ari, PhD, RN

A small biotech behind a groundbreaking approach to tackling cancer just got its first drug approved

http://www.businessinsider.com/fda-approves-agios-pharmaceuticals-drug-targeting-cancer-cell-metabolism-2017-8

See

Cancer Metabolism

http://www.agios.com/research/cancer-metabolism/

Metabolic Immuno-Oncology

http://www.agios.com/research/metabolic-immuno-oncology/

 

 

The VOICE of Larry H. Bernstein, MD, FCAP

Cancer cells didn’t need as much oxygen to metabolize sugar as normal cells. 

Not correct. Cancer cells metabolize glucose by aerobic glycolysis (4 ATP) with an impaired mitochondrial oxygen utilization (36 ATP). 

There is a reverse Warburg effect in which the underlying stromal cell carries out crosstalk with the epithelial cell. 

There is also a 3rd dimension. Cells undergo a series of adaptive changes tied to proteostasis. This involves the sulfur amino acid cysteine and disulfide bonds, which is involved with protein oligomerization in the ER, and also signaling in the mitochondria with mDNA and the nucleus.