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
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TUESDAY, AUGUST 29
7:00 am Registration
7:25 Breakout Discussion Groups with Continental Breakfast
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 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
Matthew 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 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
- GBM highly Immunosuppressive Cancer
- Impairment of MHC Class I presentation
- CG80, CD86 – down regulation of co-stimulatory molecule, Kb MHC I Db MHC I NKligand
- oHSV induces anti-tumor immunity
- armed with immune modulatory transgenes
- Immune checkpoint inhibitors can reduce immunosuppression in tumor and boost immune response
- 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 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
- DNA Demage: SIngle strand break, double strand break, bulky sdducts, base mismatch insertion/deletion, base alkalation
- PARP inhibition
- PARPi combination with anti-cancer – PARPi and oHSV increase apoptosis and DNA damage
- Genetic engineering of oHSV confers cancer PARPi-selectivity and PARPi-resistant GSCs
- Rad51
- oHSV inhibits HR
- oHSV-induces proteasomal degradation of Rad51 mediates – Rad51-silencing abrogates the synergy between PARPi and oHSV
- infiltration: Intracelebral vs Intra-tumor
- Induction of aptosis and DNA demage in brain tumors in vivo
- 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
Day 1 | Day 2 | Short Courses | Download Brochure
TUESDAY, AUGUST 29
12:00 pm Registration
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
2:50 The Generation of Lentiviral Vector-Modified CAR-T Cells Using an Automated Process
Boro 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.
- Very stealth – no genotoxicity
- efficient transduction
- HIV vector, AIDS
- Implementation of suspention Serum-Free Chemically-dependent
- USA cGMP
- Generic and novel CD19 CAR-T LV – demonstrated target-specisif lysis in vivo, eliminated Raji tumors in vivo in mice
- 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
- Fast track designation – Eligible: (AA) (PR)
- (FT)
- Breakthrough Therapy (BT) Multidisciplinary Meeting
- Accelerated Approval (AA) will include Post-Marketing Requirement (PMR) for a confirmatory study: Biomarkers
- Priority Review (PR)
- 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
- Adoptive T Cell Therapies – Gene modified T Cells
- Complex Manufacturing Process
- Typical CAR construct: Complex Vector Design: SIgnal 1 + SIgnal @2012pharmaceuticalCD19 IND Applications
- 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
- Efficacy, Safety, Relative Efficacy, Relative Value (Cost-Benefit Analysis), Budget Impact (# of candidates for a given budget)
- 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:
- ICER (Evidence Reports),
- OSCO Value Framework),
- NCCN (Evidence Blocks),
- 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:
- Triple Aim/ Institute for HC Improvement 2008
- HC Services
- Pharmaceuticals: Financial-based
- Value based in the US: Medicaid Best price, Medicare part B, 340B, anti-kickback statues
- Specific to Oncology:
- PFS, OS, HR, CR – not captured in medical claims data
- 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.
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The basic unit of life. The number of cells in a living organism ranges from one (e.g. yeast) to quadrillions (e.g. blue whale). A cell is composed of four key macromolecules that allow it to function (protein, lipids, carbohydrates, and nucleic acids). Among other things, cells can build and break down molecules, move, grow, divide, and die.
An infectious entity that can only persist by hijacking a host organism to replicate itself. Has its own genome, but is technically not considered a living organism. Viruses infect all organisms, from humans to plants to microbes. Multicellular organisms have sophisticated immune systems that combat viruses, while CRISPR systems evolved to stop viral infection in bacteria and archaea.
Abbreviation of deoxyribonucleic acid, a long molecule that encodes the information needed for a cell to function or a virus to replicate. Forms a double-helix shape that resembles a twisted ladder. Different chemicals called bases, abbreviated as A, C, T, and G, are found on each side of the ladder, or strand. The bases have an attraction for each other, making A stick to T while C sticks to G. These rungs of the ladder are called base pairs. The sequence of these letters is called the genetic code.
Pronounced “crisper.” An adaptive immune system found in bacteria and archaea, co-opted as a genome engineering tool. Acronym of “clustered regularly interspaced short palindromic repeats,” which refers to a section of the host genome containing alternating repetitive sequences and unique snippets of foreign DNA. CRISPR-associated surveillance proteins use these unique sequences as molecular mugshots as they seek out and destroy viral DNA to protect the cell.
A segment of DNA that encodes the information used to make a protein. Each gene is a set of instructions for making a particular molecular machine that helps a cell, organism, or virus function.
A type of disease caused by uncontrolled growth of cells. Cancerous cells may form clumps or masses known as tumors, and can spread to other parts of the body through a process known as metastasis.
The entire DNA sequence of an organism or virus. The genome is essentially a huge set of instructions for making individual parts of a cell and directing how everything should run.
The study of the genome, all the DNA from a given organism. Involves a genome’s DNA sequence, organization and control of genes, molecules that interact with DNA, and how these different components affect the growth and function of cells.
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