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Archive for the ‘Cancer Vaccines: Targeting Cancer Genes for Immunotherapy’ Category


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

 

A mutated gene called RAS gives rise to a signalling protein Ral which is involved in tumour growth in the bladder. Many researchers tried and failed to target and stop this wayward gene. Signalling proteins such as Ral usually shift between active and inactive states.

 

So, researchers next tried to stop Ral to get into active state. In inacvtive state Ral exposes a pocket which gets closed when active. After five years, the researchers found a small molecule dubbed BQU57 that can wedge itself into the pocket to prevent Ral from closing and becoming active. Now, BQU57 has been licensed for further development.

 

Researchers have a growing genetic data on bladder cancer, some of which threaten to overturn the supposed causes of bladder cancer. Genetics has also allowed bladder cancer to be reclassified from two categories into five distinct subtypes, each with different characteristics and weak spots. All these advances bode well for drug development and for improved diagnosis and prognosis.

 

Among the groups studying the genetics of bladder cancer are two large international teams: Uromol (named for urology and molecular biology), which is based at Aarhus University Hospital in Denmark, and The Cancer Genome Atlas (TCGA), based at institutions in Texas and Boston. Each team tackled a different type of cancer, based on the traditional classification of whether or not a tumour has grown into the muscle wall of the bladder. Uromol worked on the more common, earlier form, non-muscle-invasive bladder cancer, whereas TCGA is looking at muscle-invasive bladder cancer, which has a lower survival rate.

 

The Uromol team sought to identify people whose non-invasive tumours might return after treatment, becoming invasive or even metastatic. Bladder cancer has a high risk of recurrence, so people whose non-invasive cancer has been treated need to be monitored for many years, undergoing cystoscopy every few months. They looked for predictive genetic footprints in the transcriptome of the cancer, which contains all of a cell’s RNA and can tell researchers which genes are turned on or off.

 

They found three subgroups with distinct basal and luminal features, as proposed by other groups, each with different clinical outcomes in early-stage bladder cancer. These features sort bladder cancer into genetic categories that can help predict whether the cancer will return. The researchers also identified mutations that are linked to tumour progression. Mutations in the so-called APOBEC genes, which code for enzymes that modify RNA or DNA molecules. This effect could lead to cancer and cause it to be aggressive.

 

The second major research group, TCGA, led by the National Cancer Institute and the National Human Genome Research Institute, that involves thousands of researchers across USA. The project has already mapped genomic changes in 33 cancer types, including breast, skin and lung cancers. The TCGA researchers, who study muscle-invasive bladder cancer, have looked at tumours that were already identified as fast-growing and invasive.

 

The work by Uromol, TCGA and other labs has provided a clearer view of the genetic landscape of early- and late-stage bladder cancer. There are five subtypes for the muscle-invasive form: luminal, luminal–papillary, luminal–infiltrated, basal–squamous, and neuronal, each of which is genetically distinct and might require different therapeutic approaches.

 

Bladder cancer has the third-highest mutation rate of any cancer, behind only lung cancer and melanoma. The TCGA team has confirmed Uromol research showing that most bladder-cancer mutations occur in the APOBEC genes. It is not yet clear why APOBEC mutations are so common in bladder cancer, but studies of the mutations have yielded one startling implication. The APOBEC enzyme causes mutations early during the development of bladder cancer, and independent of cigarette smoke or other known exposures.

 

The TCGA researchers found a subset of bladder-cancer patients, those with the greatest number of APOBEC mutations, had an extremely high five-year survival rate of about 75%. Other patients with fewer APOBEC mutations fared less well which is pretty surprising.

 

This detailed knowledge of bladder-cancer genetics may help to pinpoint the specific vulnerabilities of cancer cells in different people. Over the past decade, Broad Institute researchers have identified more than 760 genes that cancer needs to grow and survive. Their genetic map might take another ten years to finish, but it will list every genetic vulnerability that can be exploited. The goal of cancer precision medicine is to take the patient’s tumour and decode the genetics, so the clinician can make a decision based on that information.

 

References:

 

https://www.ncbi.nlm.nih.gov/pubmed/29117162

 

https://www.ncbi.nlm.nih.gov/pubmed/27321955

 

https://www.ncbi.nlm.nih.gov/pubmed/28583312

 

https://www.ncbi.nlm.nih.gov/pubmed/24476821

 

https://www.ncbi.nlm.nih.gov/pubmed/28988769

 

https://www.ncbi.nlm.nih.gov/pubmed/28753430

 

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Image Source:Koch Institute

 

LIVE – OCTOBER 16 – DAY 1- Koch Institute Immune Engineering Symposium 2017, MIT, Kresge Auditorium

Koch Institute Immune Engineering Symposium 2017

http://kochinstituteevents.cvent.com/events/koch-institute-immune-engineering-symposium-2017/agenda-64e5d3f55b964ff2a0643bd320b8e60d.aspx

 

#IESYMPOSIUM

 

Image Source: Leaders in Pharmaceutical Business Intelligence (LPBI) Group

Aviva Lev-Ari, PhD, RN will be in attendance covering the event in REAL TIME

@pharma_BI

@AVIVA1950

#IESYMPOSIUM

@KOCHINSTITUTE

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

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

SYMPOSIUM SCHEDULE

OCTOBER 16 – DAY 1

7:00 – 8:15 Registration

8:15 – 8:30Introductory Remarks
Darrell Irvine | MIT, Koch Institute; HHMI

  • Stimulating the Immune system not only sustaining it for therapies

K. Dane Wittrup | MIT, Koch Institute

8:30 – 9:45Session I
Moderator: Douglas Lauffenburger | MIT, Biological Engineering and Koch Institute

Garry P. Nolan – Stanford University School of Medicine
Pathology from the Molecular Scale on Up

  • Intracellular molecules,
  • how molecules are organized to create tissue
  • Meaning from data Heterogeneity is an illusion: Order in Data ?? Cancer is heterogeneous, Cells in suspension – number of molecules
  • System-wide changes during Immune Response (IR)
  • Untreated, Ineffective therapy, effective therapy
  • Days 3-8 Tumor, Lymph node…
  • Variation is a Feature – not a bug: Effective therapy vs Ineffective – intercellular modules – virtual neighborhoods
  • ordered by connectivity: very high – CD4 T-cells, CD8 T-cels, moderate, not connected
  • Landmark nodes, Increase in responders
  • CODEX: Multiples epitome detection
  • Adaptable to proteins & mRNA
  • Rendering antibody staining via removal to neighborhood mapping
  • Human tonsil – 42 parameters: CD7, CD45, CD86,
  • Automated Annotations of tissues: F, P, V,
  • Normal BALBs
  • Marker expression defined by the niche: B220 vs CD79
  • Marker expression defines the niche
  • Learn neighborhoods and Trees
  • Improving Tissue Classification and staining – Ce3D – Tissue and Immune Cells in 3D
  • Molecular level cancer imaging
  • Proteomic Profiles: multi slice combine
  • Theory is formed to explain 3D nuclear images of cells – Composite Ion Image, DNA replication
  • Replication loci visualization on DNA backbone – nascent transcriptome – bar code of isotopes – 3D  600 slices
  • use CRISPR Cas9 for Epigenetics

Susan Napier Thomas – Georgia Institute of Technology
Transport Barriers in the Tumor Microenvironment: Drug Carrier Design for Therapeutic Delivery to Sentinel Lymph Nodes

  • Lymph Nodes important therapeutics target tissue
  • Lymphatic flow support passive and active antigen transport to lymph nodes
  • clearance of biomolecules and drug formulations: Interstitial transport barriers influence clearance: Arteriole to Venule –
  • Molecular tracers to analyze in vivo clearance mechanisms and vascular transport function
  • quantifying molecular clearance and biodistribution
  • Lymphatic transport increases tracer concentrations within dLN by orders of magnitude
  • Melanoma growth results in remodeled tumor vasculature
  • passive transport via lymphatic to dLN sustained in advanced tumors despite abrogated cell trafficking
  • Engineered biomaterial drug carriers to enhance sentinel lymph node-drug delivery: facilitated by exploiting lymphatic transport
  • TLR9 ligand therapeutic tumor in situ vaccination – Lymphatic-draining CpG-NP enhanced
  • Sturcutral and Cellular barriers: transport of particles is restriced by
  • Current drug delivery technology: lymph-node are undrugable
  • Multistage delivery platform to overcome barriers to lymphatic uptake and LN targeting
  • nano particles – OND – Oxanorbornade OND Time sensitive Linker synthesized large cargo – NP improve payload
  • OND release rate from nanoparticles changes retention in lymph nodes – Axilliary-Brachial delivery
  • Two-stage OND-NP delivery and release system dramatically – OND acumulate in lymphocyte
  •  delivers payload to previously undraggable lymphe tissue
  • improved drug bioactivity  – OND-NP eliminate LN LYMPHOMAS
  • Engineered Biomaterials

Douglas Lauffenburger – MIT, Biological Engineering and Koch Institute
Integrative Multi-Omic Analysis of Tissue Microenvironment in Inflammatory Pathophysiology

  • How to intervene, in predictive manner, in immunesystem-associated complex diseases
  • Understand cell communication beteen immune cells and other cells, i.e., tumor cells
  • Multi-Variate in Vivo – System Approach: Integrative Experiment & COmputational Analysis
  • Cell COmmunication & Signaling in CHronic inflammation – T-cell transfer model for colitis
  • COmparison of diffrential Regulation (Tcell transfer-elicited vs control) anong data types – relying solely on mRNA can be misleading
  • Diparities in differential responses to T cell transfer across data types yield insights concerning broader multi-organ interactions
  • T cell transfer can be ascertained and validated by successful experimental test
  • Cell COmmunication in Tumor MIcro-Environment — integration of single-cell transcriptomic data and protein interaction
  • Standard Cluster Elucidation – Classification of cell population on Full gene expression Profiles using Training sets: Decision Tree for Cell Classification
  • Wuantification of Pairwise Cell-Cell Receptor/Ligand Interactions: Cell type Pairs vs Receptor/Ligand Interaction
  • Pairwise Cell-Cell Receptor/Ligand Interactions
  • Calculate strength of interaction and its statistical significance
  • How the interaction is related to Phenotypic Behaviors – tumor growth rate, MDSC levels,
  • Correlated the Interactions translated to Phynotypic behavior for Therapeutic interventions (AXL via macrophage and fibroblasts)
  • Mouth model translation to Humans – New machine learning approach
  • Pathways, false negative, tumor negative expression
  • Molecular vs Phynotypical expression
  • Categories of inter-species translation
  • Semi-supervised Learning ALgorithms on Transcriptomic Data can ascertain Key Pathways/Processes in Human IBD from mapping mouse IBD

9:45 – 10:15 Break

10:15 – 11:30Session II
Moderator: Tyler Jacks | MIT, Koch Institute; HHMI

Tyler Jacks – MIT, Koch Institute; HHMI
Using Genetically Engineered Mouse Models to Probe Cancer-Immune Interactions

  • Utility of genetically-engineered mouse models of Cancer:
  1. Immune Response (IR),
  2. Tumor0immune microenvironment
  • Lung adenocarcinoma – KRAS mutation: Genetically-engineered model, applications: CRISPR, genetic interactions
  • Minimal Immune response to KP lung tumors: H&E, T cells (CD3), Bcells (B220) for Lenti-x 8 weeks
  • Exosome sequencing : Modeling loss-and gain-of-function mutations in Lung Cancer by CRISPR-Cas9 – germline – tolerance in mice, In vivo CRISPR-induced knockout of Msh2
  • Signatures of MMR deficient
  • Mutation burden and response to Immunotherapy (IT)
  • Programmed neoantigen expression – robust infiltration of T cells (evidence of IR)
  • Immunosuppression – T cell rendered ineffective
  • Lymphoid infiltration: Acute Treg depletion results in T cell infiltration — this depletion causes autoimmune response
  • Lung Treg from KP tumor-bearing mice have a distinct transcriptional heterogeneity through single cell mRNA sequencing
  • KP, FOXP3+, CD4
  • Treg from no existent to existance, Treg cells increase 20 fold =>>>  Treg activation and effectiveness
  • Single cells cluster by tissue and cell type: Treg, CD4+, CD8+, Tetramer-CD4+
  • ILrl1/II-33r unregulated in Treg at late time point
  • Treg-specific deletion of IL-33r results in fewer effector Tregs in Tumor-bearing lungs
  • CD8+ T cell infiltration
  • Tetramer-positive T cells cluster according to time point: All Lung CD8+ T cells
  • IR is not uniform functional differences – Clones show distinct transcriptional profiles
  • Different phynotypes Exhaustive signature
  • CRISPR-mediated modulation of CD8 T cell regulatory genes
  • Genetic dissection of the tumor-immune microenvironment
  • Single cell analysis, CRISPR – CRISPRa,i, – Drug development

Wendell Lim – University of California, San Francisco

Synthetic Immunology: Hacking Immune Cells

  • Precision Cell therapies – engineered by synthetic biology
  • Anti CD19 – drug approved
  • CAR-T cells still face major problems
  1. success limited to B cells cancers = blood vs solid tumors
  2. adverse effects
  3. OFF-TUMOR effects
  • Cell engineering for Cancer Therapy: User remote control (drug) – user control safety
  • Cell Engineering for TX
  1. new sensors – decision making for
  2. tumor recognition – safety,
  3. Cancer is a recognition issue
  • How do we avoid cross-reaction with bystader tissue (OFF TISSUE effect)
  • Tumor recognition: More receptors & integration
  • User Control
  • synthetic NOTCH receptors (different flavors of synNotch) – New Universal platform for cell-to -cell recognition: Target molecule: Extracellular antigen –>> transciptional instruction to cell
  • nextgen T cell: Engineer T cell recognition circuit that integrates multiple inputs: Two receptors – two antigen priming circuit
  • UNARMED: If antigen A THEN receptor A activates CAR
  • “Bystander” cell single antigen vs “tumor” drug antigen
  • Selective clearance of combinatorial tumor – Boulian formulation, canonical response
  • Cell response: Priming –>> Killing: Spatial & Temporal choreographed cell
  • CAR expression while removed from primed cells deminished
  • Solid Tumor: suppress cell microenvironment: Selected response vs non-natural response
  • Immune stimulator IR IL2, IL12, flagellin in the payload — Ourcome: Immune enhancement “vaccination”
  • Immune suppression –  block
  • Envision ideal situation: Unarmed cells
  • FUTURE: identify disease signatures and vulnerabilities – Precision Medicine using Synthetic Biology

Darrell Irvine – MIT, Koch Institute; HHMI
Engineering Enhanced Cancer Vaccines to Drive Combination Immunotherapies

  • Vaccine to drive IT
  • Intervening in the cancer-immunity cycle – Peptide Vaccines
  • poor physiology  of solute transport to tissue
  • endogenous albumin affinity – Lymphe Node dying
  • Designing Albumin-hitchhiking vaccines
  • Amphiphile-vaccine enhance uptake in lymph nodes in small and large animal models
  • soluble vaccine vs Amphiphile-vaccine
  • DIRECTING Vaccines to the Lymph nodes
  • amph-peptide antigen: Prime, booster, tetramer
  • albimin-mediated LN-targeting of both antigen and adjuvant maximizes IR
  • Immuno-supressed microenvironment will not be overcome by vaccines
  • Replacing adoptive T cell transfer with potent vaccine
  • exploiting albumin biology for mucosal vaccine delivery by amph-vaccines
  • Amph-peptides and -adjuvants show enhanced uptake/retention in lung tissue
  •  Enhancing adoptive T cell therapy: loss of T cell functionality, expand in vivo
  • boost in vivo enhanced adoptive T cell therapy
  • CAR-T cells: Enable T cells to target any cell surface protein
  • “Adaptor”-targeting CAR-T cells to deal with tumor cell heterogeneity
  • Lymph node-targeting Amph as CAR T booster vaccine: prining, production of cytokines
  • Boosting CAR T with amph-caccines: anti FITC CAR-T by DSPE=PEG-FITC coated
  • Targeting FITC to lymph node antigen presenting cells
  • Modulatory Macrophages
  • Amph-FITC expands FITC-CAR T cells in vivo – Adjuvant is needed
  • Hijacking albumin’s natural trafficking pathway

11:30 – 1:00  Lunch Break

1:00 – 2:15Session III
Moderator: Darrell Irvine | MIT, Koch Institute; HHMI

Nicholas P. Restifo – National Cancer Institute
Extracellular Potassium Regulates Epigenetics and Efficacy of Anti-Tumor T Cells

Why T cell do not kill Cancer cells?

  • co-inhibition
  • hostile tumor microenvironment

CAR T – does not treat solid tumors

Somatic mutation

  1. resistence of T cell based IT due to loss of function mutations
  2. Can other genes be lost?

CRISPR Cas9 – used to identify agents – GeCKOv2 Human library

Two cell-type (2CT) CRISPR assay system for genome-wide mutagenesis

  • work flow for genome-scale SRISPR mutagenesis profiling of genes essential for T cell mediate cytosis
  • sgRNA enrichment at the individual gene level by multiple methods:
  1. subunits of the MHC Class I complex
  2. CRISPR mutagenesis cut germline
  • Measutring the generalizability of resistance mechanism and mice in vivo validation
  • Validation of top gene candidates using libraries: MART-1
  • Checkpoint blockade: cells LOF causes tumor growth and immune escape
  • Weird genesL Large Ribisomal Subunit Proteins are nor all essential for cell survival
  • Bias in enrichment of 60S vs 40S
  • Novel elements of MHC class I antigen processing and presentation
  • Association of top CRISPR hits with response rates to IT – antiCTLA-4
  • CRISPR help identify novel regulators of T cells
  • Analyzed sgRNA – second rarest sgRNA for gene BIRC2 – encoded the Baculoviral Inhibitor
  • Drugs that inhibit BIRC2
  • How T cells can kill tumor cells more efficiently
  • p38kiaseas target for adoptive immunotherapy
  • FACS-based – Mapk14
  • Potent targets p38 – Blockade PD-1 or p38 ??
  • p38 signaling: Inhibition augments expansion and memory-marked human PBMC and TIL cells, N. P. Restifo
  • Tumor killing capacity of human CD19-specific, gene engineered T cells

Jennifer Elisseeff – Johns Hopkins University
The Adaptive Immune Response to Biomaterials and Tissue Repair

  • design scafolds, tissue-specific microenvironment
  • clinical translation of biosynthetic implants for soft tissue reconstruction
  • Local environment affects biomaterials: Epidermis, dermis
  • CD4+ T cells
  • Immune system – first reponders to materials: Natural or Synthetic
  • Biological (ECM) scaffolds to repair muscle injury
  • Which immune cells enter the WOUND?
  • ECM alters Macrophages: CD86, CD206
  • Adaptive system impact on Macrophages: CD86
  • mTOR signaling pathway M2 depend on Th2 Cells in regeneration of cell healing of surgical wounds
  • Systemic Immunological changes
  • Is the response antigen specific? – IL-4 expression in ILN,
  • Tissue reconstruction Clinical Trial: FDA ask to look at what cells infiltrate the scaffold
  • Trauma/biomaterial response – Injury induction of Senescence, anti apoptosis
  • Injury to skin or muscle
  • Is pro-regenerative environment (Th2/M2) pro-tumorigenic?
  • SYNTHETIC Materials for scafolds
  • Biomaterials and Immunology
  1. Immune response to bioscafolds
  2. environment modulate the immune system
  • Regenerative Immunetherapy

Marcela Maus – Massachusetts General Hospital

Engineering Better T Cells

  • Comparing CD19 CARs for Leukemia – anti-CD19- directed CAR T cells with r/r B-cell ALL – age 3-25 – FDA approved Novartis tisagenlecleucel – for pediatric r/r/ ALL
  • Phase II in diffuse large B cell lymphoma. Using T cells – increases prospects for cure
  • Vector retroviral – 30 day expression
  • measuring cytokines release syndrome: Common toxicity with CAR 19
  • neurological toxicity, B-cell aplagia
  • CART issues with heme malignancies
  1. decrease cytokine release
  2. avoid neurological toxicity – homing
  3. new targets address antigene escape variants – Resistance, CD19 is shaded, another target needed
  4. B Cell Maturation Antigen (BCMA) Target
  5. Bluebird Bio: Response duratio up to 54 weeks – Active dose cohort
  6. natural ligand CAR based on April
  7. activated in response to TACI+ target cells – APRIL-based CARs but not BCMA-CAR is able to kill TACI+ target cells
  • Hurdles for Solid Tumors
  1. Specific antigen targets
  2. tumor heterogeneity
  3. inhibitory microenvironment
  • CART in Glioblastoma
  1. rationale for EGFRvIII as therapeutic target
  2. Preclinical Studies & Phase 1: CAR t engraft, not as highly as CD19
  3. Upregulation of immunosuppression and Treg infiltrate in CART EGFRvIII as therapeutic target, Marcela Maus
  • What to do differently?

 

2:15 – 2:45 Break

2:45 – 4:00 Session IV
Moderator: Arup K. Chakraborty | MIT, IMES

Laura Walker – Adimab, LLC
Molecular Dissection of the Human Antibody Response to Respiratory Syncytial Virus

  • prophylactic antibody is available
  • Barriers for development of Vaccine
  • Prefusion and Postfusion RSV structures
  • Six major antigenic sites on RSV F
  • Blood samples Infants less 6 month of age and over 6 month: High abundance RSV F -specific memory B Cells are group  less 6 month

Arup K. Chakraborty – MIT, Institute for Medical Engineering & Science
How to Hit HIV Where it Hurts

  • antibody  – Model IN SILICO
  • Check affinity of each Ab for the Seaman panel of strain
  • Breadth of coverage
  • immmunize with cocktail of variant antigens
  • Mutations on Affinity Maturation: Molecular dynamics
  • bnAb eveolution: Hypothesis – mutations evolution make the antigen binding region more flexible,
  • Tested hypothesisi: carrying out affinity maturation – LOW GERMLINE AFFINITY TO CONSERVE RESIDUES IN 10,000 trials, acquire the mutation (generation 300)

William Schief – The Scripps Research Institute
HIV Vaccine Design Targeting the Human Naive B Cell Repertoire

  • HIV Envelope Trimer Glycan): the Target of neutralizing Antibodies (bnAbs)
  • Proof of principle for germline-targeting: VRC)!-class bnAbs
  • design of a nanoparticle
  • can germline -targeting innumogens prime low frequency precursors?
  • Day 14 day 42 vaccinate
  • Precursor frequency and affinity are limiting for germline center (GC) entry at day 8
  • Germline-targeting immunogens can elicit robust, high quality SHM under physiological conditions of precursor frequency and affinity at day 8, 16, 36
  • Germline-targeting immunogens can lead to production of memory B cells

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

Reporter: David Orchard-Webb, PhD

 

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

 

Biomarkers

 

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

 

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

 

Targeting the tumour stroma with adenoviral vectors

 

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

 

Adenovirus tumor-specific immunogene (T-SIGn) Therapy

 

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

 

Vaccinia virus – overcoming the immunosuppressive cancer microenvironment

 

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

 

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

 

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

 

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

 

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

 

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

 

HSV-1 an update on immune checkpoint combinations

 

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

 

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

 

Reovirus – an update

 

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

 

Maraba virus – privileged antigen presentation in splenic B cell follicles

 

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

 

Oncolytic virus manufacturing

 

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

 

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

 

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

 

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

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

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

https://pharmaceuticalintelligence.com/2016/09/01/real-time-coverage-and-eproceedings-of-presentations-on-august-29-and-august-30-2016-chis-4th-immuno-oncology-summit-oncolytic-virus-immunotherapy-track/

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

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

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cancerandoncologyseriesccover

Series C: e-Books on Cancer & Oncology

Series C Content Consultant: Larry H. Bernstein, MD, FCAP

 

VOLUME ONE 

Cancer Biology and Genomics

for

Disease Diagnosis

2015

http://www.amazon.com/dp/B013RVYR2K

Stephen J. Williams, PhD, Senior Editor

sjwilliamspa@comcast.net

Tilda Barliya, PhD, Editor

tildabarliya@gmail.com

Ritu Saxena, PhD, Editor

ritu.uab@gmail.com

Leaders in Pharmaceutical Business Intelligence 

Part I

Historical Perspective of Cancer Demographics, Etiology, and Progress in Research

Chapter 1:  The Occurrence of Cancer in World Populations

1.1   Understanding Cancer

Prabodh Kandala, PhD

1.2  Cancer Metastasis

Tilda Barliya, PhD

1.3      2013 Perspective on “War on Cancer” on December 23, 1971

Aviva Lev-Ari, PhD, RN

1.4   Global Burden of Cancer Treatment & Women Health: Market Access & Cost Concerns

Aviva Lev-Ari, PhD, RN

1.5    The Importance of Cancer Prevention Programs: New Perspectives for Fighting Cancer

Ziv Raviv, PhD

1.6      The “Cancer establishments” examined by James Watson, co-discoverer of DNA w/Crick, 4/1953,  

Larry H Bernstein, MD, FCAP

1.7      New Ecosystem of Cancer Research: Cross Institutional Team Science

Aviva Lev-Ari, PhD, RN

1.8       Cancer Innovations from across the Web

Larry H Bernstein, MD, FCAP

1.9         Exploring the role of vitamin C in Cancer therapy

Ritu Saxena PhD

1.10        Relation of Diet and Cancer

Sudipta Saha, PhD

1.11      Association between Non-melanoma Skin Cancer and subsequent Primary Cancers in White Population 

Aviva Lev-Ari, PhD, RN

1.12       Men With Prostate Cancer More Likely to Die from Other Causes

Prabodh Kandala, PhD

1.13      Battle of Steve Jobs and Ralph Steinman with Pancreatic Cancer: How we Lost

Ritu Saxena, PhD

Chapter 2.  Rapid Scientific Advances Changes Our View on How Cancer Forms

2.1     All Cancer Cells Are Not Created Equal: Some Cell Types Control Continued Tumor Growth, Others Prepare the Way for Metastasis 

Prabodh Kandala, PhD

2.2      Hold on. Mutations in Cancer do Good

Prabodh Kandala, PhD

2.3       Is the Warburg Effect the Cause or the Effect of Cancer: A 21st Century View?

Larry H Bernstein, MD, FCAP

2.4          Naked Mole Rats Cancer-Free

Larry H Bernstein, MD, FCAP

2.5           Zebrafish—Susceptible to Cancer

Larry H Bernstein, MD, FCAP

2.6         Demythologizing Sharks, Cancer, and Shark Fins,

Larry H Bernstein, MD, FCAP

2.7       Tumor Cells’ Inner Workings Predict Cancer Progression

Prabodh Kandala, PhD

2.8      In Focus: Identity of Cancer Stem Cells

Ritu Saxena, PhD

2.9      In Focus: Circulating Tumor Cells

Ritu Saxena, PhD

2.10     Rewriting the Mathematics of Tumor Growth; Teams Use Math Models to Sort Drivers from Passengers 

Stephen J. Williams, PhD

2.11     Role of Primary Cilia in Ovarian Cancer

Aashir Awan, PhD

Chapter 3:  A Genetic Basis and Genetic Complexity of Cancer Emerges

3.1       The Binding of Oligonucleotides in DNA and 3-D Lattice Structures

Larry H Bernstein, MD, FCAP

3.2      How Mobile Elements in “Junk” DNA Promote Cancer. Part 1: Transposon-mediated Tumorigenesis. 

Stephen J. Williams, PhD

3.3      DNA: One Man’s Trash is another Man’s Treasure, but there is no JUNK after all

Demet Sag, PhD

3.4 Issues of Tumor Heterogeneity

3.4.1    Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing

Stephen J. Williams, PhD

3.4.2       Issues in Personalized Medicine: Discussions of Intratumor Heterogeneity from the Oncology Pharma forum on LinkedIn

Stephen J. Williams, PhD

3.5        arrayMap: Genomic Feature Mining of Cancer Entities of Copy Number Abnormalities (CNAs) Data

Aviva Lev-Ari, PhD, RN

3.6        HBV and HCV-associated Liver Cancer: Important Insights from the Genome

Ritu Saxena, PhD

3.7      Salivary Gland Cancer – Adenoid Cystic Carcinoma: Mutation Patterns: Exome- and Genome-Sequencing @ Memorial Sloan-Kettering Cancer Center

Aviva Lev-Ari, PhD, RN

3.8         Gastric Cancer: Whole-genome Reconstruction and Mutational Signatures

Aviva Lev-Ari, PhD, RN

3.9        Missing Gene may Drive more than a quarter of Breast Cancers

Aviva Lev-Ari, PhD, RN

3.10     Critical Gene in Calcium Reabsorption: Variants in the KCNJ and SLC12A1 genes – Calcium Intake and Cancer Protection

Aviva Lev-Ari,PhD, RN

Chapter 4: How Epigenetic and Metabolic Factors Affect Tumor Growth

4.1    Epigenetics

4.1.1     The Magic of the Pandora’s Box : Epigenetics and Stemness with Long non-coding RNAs (lincRNA)

Demet Sag, PhD, CRA, GCP

4.1.2     Stomach Cancer Subtypes Methylation-based identified by Singapore-Led Team

Aviva Lev-Ari, PhD, RN

4.1.3     The Underappreciated EpiGenome

Demet Sag, Ph.D., CRA, GCP

4.1.4     Differentiation Therapy – Epigenetics Tackles Solid Tumors

Stephen J. Williams, PhD

4.1.5      “The SILENCE of the Lambs” Introducing The Power of Uncoded RNA

Demet Sag, Ph.D., CRA, GCP

4.1.6      DNA Methyltransferases – Implications to Epigenetic Regulation and Cancer Therapy Targeting: James Shen, PhD

Aviva Lev-Ari, PhD, RN

4.2   Metabolism

4.2.1      Mitochondria and Cancer: An overview of mechanisms

Ritu Saxena, PhD

4.2.2     Bioenergetic Mechanism: The Inverse Association of Cancer and Alzheimer’s

Aviva Lev-Ari, PhD, RN

4.2.3      Crucial role of Nitric Oxide in Cancer

Ritu Saxena, PhD

4.2.4      Nitric Oxide Mitigates Sensitivity of Melanoma Cells to Cisplatin

Stephen J. Williams, PhD

4.2.5      Increased risks of obesity and cancer, Decreased risk of type 2 diabetes: The role of Tumor-suppressor phosphatase and tensin homologue (PTEN)

Aviva Lev-Ari, PhD, RN

4.2.6      Lipid Profile, Saturated Fats, Raman Spectrosopy, Cancer Cytology

Larry H Bernstein, MD, FCAP

4.3     Other Factors Affecting Tumor Growth

4.3.1      Squeezing Ovarian Cancer Cells to Predict Metastatic Potential: Cell Stiffness as Possible Biomarker

Prabodh Kandala, PhD

4.3.2      Prostate Cancer: Androgen-driven “Pathomechanism” in Early-onset Forms of the Disease

Aviva Lev-Ari, PhD, RN

Chapter 5: Advances in Breast and Gastrointestinal Cancer Research Supports Hope for Cure

5.1 Breast Cancer

5.1.1      Cell Movement Provides Clues to Aggressive Breast Cancer

Prabodh Kandala, PhD

5.1.2    Identifying Aggressive Breast Cancers by Interpreting the Mathematical Patterns in the Cancer Genome

Prabodh Kandala, PhD

5.1.3  Mechanism involved in Breast Cancer Cell Growth: Function in Early Detection & Treatment

Aviva Lev-Ari, PhD, RN

5.1.4       BRCA1 a tumour suppressor in breast and ovarian cancer – functions in transcription, ubiquitination and DNA repair

Sudipta Saha, PhD

5.1.5      Breast Cancer and Mitochondrial Mutations

Larry H Bernstein, MD, FCAP

5.1.6      MIT Scientists Identified Gene that Controls Aggressiveness in Breast Cancer Cells

Aviva Lev-Ari PhD RN

5.1.7       “The Molecular pathology of Breast Cancer Progression”

Tilda Barliya, PhD

5.1.8       In focus: Triple Negative Breast Cancer

Ritu Saxena, PhD

5.1.9       Automated Breast Ultrasound System (‘ABUS’) for full breast scanning: The beginning of structuring a solution for an acute need!

Dror Nir, PhD

5.1.10       State of the art in oncologic imaging of breast.

Dror Nir, PhD

 

5.2 Gastrointestinal Cancer

5.2.1         Colon Cancer

Tilda Barliya, PhD

5.2.2      PIK3CA mutation in Colorectal Cancer may serve as a Predictive Molecular Biomarker for adjuvant Aspirin therapy

Aviva Lev-Ari, PhD, RN

5.2.3     State of the art in oncologic imaging of colorectal cancers.

Dror Nir, PhD

5.2.4     Pancreatic Cancer: Genetics, Genomics and Immunotherapy

Tilda Barliya, PhD

5.2.5     Pancreatic cancer genomes: Axon guidance pathway genes – aberrations revealed

Aviva Lev-Ari, PhD, RN

Part II

Advent of Translational Medicine, “omics”, and Personalized Medicine Ushers in New Paradigms in Cancer Treatment and Advances in Drug Development

Chapter 6:  Treatment Strategies

6.1 Marketed and Novel Drugs

Breast Cancer                                   

6.1.1     Treatment for Metastatic HER2 Breast Cancer

Larry H Bernstein MD, FCAP

6.1.2          Aspirin a Day Tied to Lower Cancer Mortality

Aviva Lev-Ari, PhD, RN

6.1.3       New Anti-Cancer Drug Developed

Prabodh Kandala, Ph.D.

6.1.4         Pfizer’s Kidney Cancer Drug Sutent Effectively caused REMISSION to Adult Acute Lymphoblastic Leukemia (ALL)

Aviva Lev-Ari ,PhD, RN

6.1.5     “To Die or Not To Die” – Time and Order of Combination drugs for Triple Negative Breast Cancer cells: A Systems Level Analysis

Anamika Sarkar, PhD. and Ritu Saxena, PhD

Melanoma

6.1.6    “Thymosin alpha1 and melanoma”

Tilda Barliya, PhD

Leukemia

6.1.7    Acute Lymphoblastic Leukemia and Bone Marrow Transplantation

Tilda Barliya PhD

6.2 Natural agents

Prostate Cancer                 

6.2.1      Scientists use natural agents for prostate cancer bone metastasis treatment

Ritu Saxena, PhD

Breast Cancer

6.2.2        Marijuana Compound Shows Promise In Fighting Breast Cancer

Prabodh Kandala, PhD

Ovarian Cancer                  

6.2.3        Dimming ovarian cancer growth

Prabodh Kandala, PhD

6.3 Potential Therapeutic Agents

Gastric Cancer                 

6.3.1       β Integrin emerges as an important player in mitochondrial dysfunction associated Gastric Cancer

Ritu Saxena, PhD

6.3.2      Arthritis, Cancer: New Screening Technique Yields Elusive Compounds to Block Immune-Regulating Enzyme

Prabodh Kandala, PhD

Pancreatic Cancer                                   

6.3.3    Usp9x: Promising therapeutic target for pancreatic cancer

Ritu Saxena, PhD

Breast Cancer                 

6.3.4       Breast Cancer, drug resistance, and biopharmaceutical targets

Larry H Bernstein, MD, FCAP

Prostate Cancer

6.3.5        Prostate Cancer Cells: Histone Deacetylase Inhibitors Induce Epithelial-to-Mesenchymal Transition

Stephen J. Williams, PhD

Glioblastoma

6.3.6      Gamma Linolenic Acid (GLA) as a Therapeutic tool in the Management of Glioblastoma

Raphael Nir, PhD, MSM, MSc

6.3.7   Akt inhibition for cancer treatment, where do we stand today?

Ziv Raviv, PhD

Chapter 7:  Personalized Medicine and Targeted Therapy

7.1.1        Harnessing Personalized Medicine for Cancer Management, Prospects of Prevention and Cure: Opinions of Cancer Scientific Leaders

Aviva Lev-Ari, PhD, RN

7.1.2      Personalized medicine-based cure for cancer might not be far away

Ritu Saxena, PhD

7.1.3      Personalized medicine gearing up to tackle cancer

Ritu Saxena, PhD

7.1.4       Cancer Screening at Sourasky Medical Center Cancer Prevention Center in Tel-Aviv

Ziv Raviv, PhD

7.1.5       Inspiration From Dr. Maureen Cronin’s Achievements in Applying Genomic Sequencing to Cancer Diagnostics

Aviva Lev-Ari, PhD, RN

7.1.6       Personalized Medicine: Cancer Cell Biology and Minimally Invasive Surgery (MIS)

Aviva Lev-Ari, PhD, RN

7.2 Personalized Medicine and Genomics

7.2.1       Cancer Genomics – Leading the Way by Cancer Genomics Program at UC Santa Cruz

Aviva Lev-Ari, PhD, RN

7.2.2       Whole exome somatic mutations analysis of malignant melanoma contributes to the development of personalized cancer therapy for this disease

Ziv Raviv, PhD

7.2.3       Genotype-based Analysis for Cancer Therapy using Large-scale Data Modeling: Nayoung Kim, PhD(c)

Aviva Lev-Ari, PhD, RN

7.2.4         Cancer Genomic Precision Therapy: Digitized Tumor’s Genome (WGSA) Compared with Genome-native Germ Line: Flash-frozen specimen and Formalin-fixed paraffin-embedded Specimen Needed

Aviva Lev-Ari, PhD, RN

7.2.5         LEADERS in Genome Sequencing of Genetic Mutations for Therapeutic Drug Selection in Cancer Personalized Treatment: Part 2

Aviva Lev-Ari, PhD, RN

7.2.6       Ethical Concerns in Personalized Medicine: BRCA1/2 Testing in Minors and Communication of Breast Cancer Risk

Stephen J. Williams, PhD

7.3  Personalized Medicine and Targeted Therapy

7.3.1     The Development of siRNA-Based Therapies for Cancer

Ziv Raviv, PhD

7.3.2       mRNA interference with cancer expression

Larry H Bernstein, MD, FCAP

7.3.3       CD47: Target Therapy for Cancer

Tilda Barliya, PhD

7.3.4      Targeting Mitochondrial-bound Hexokinase for Cancer Therapy

Ziv Raviv, PhD

7.3.5       GSK for Personalized Medicine using Cancer Drugs needs Alacris systems biology model to determine the in silico effect of the inhibitor in its “virtual clinical trial”

Aviva Lev-Ari, PhD, RN

7.3.6         Personalized Pancreatic Cancer Treatment Option

Aviva Lev-Ari, PhD, RN

7.3.7        New scheme to routinely test patients for inherited cancer genes

Stephen J. Williams, PhD

7.3.8        Targeting Untargetable Proto-Oncogenes

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

7.3.9        The Future of Translational Medicine with Smart Diagnostics and Therapies: PharmacoGenomics 

Demet Sag, PhD

7.4 Personalized Medicine in Specific Cancers

7.4.1      Personalized medicine and Colon cancer

Tilda Barliya, PhD

7.4.2      Comprehensive Genomic Characterization of Squamous Cell Lung Cancers

Aviva Lev-Ari, PhD, RN

7.4.3        Targeted Tumor-Penetrating siRNA Nanocomplexes for Credentialing the Ovarian Cancer Oncogene ID4

Sudipta Saha, PhD

7.4.4        Cancer and Bone: low magnitude vibrations help mitigate bone loss

Ritu Saxena, PhD

7.4.5         New Prostate Cancer Screening Guidelines Face a Tough Sell, Study Suggests

Prabodh Kandala, PhD

Part III

Translational Medicine, Genomics, and New Technologies Converge to Improve Early Detection

Diagnosis, Detection And Biomarkers

Chapter 8:  Diagnosis Diagnosis: Prostate Cancer

8.1        Prostate Cancer Molecular Diagnostic Market – the Players are: SRI Int’l, Genomic Health w/Cleveland Clinic, Myriad Genetics w/UCSF, GenomeDx and BioTheranostics

Aviva Lev-Ari PhD RN

8.2         Today’s fundamental challenge in Prostate cancer screening

Dror Nir, PhD

Diagnosis & Guidance: Prostate Cancer

8.3      Prostate Cancers Plunged After USPSTF Guidance, Will It Happen Again?

Aviva Lev-Ari, PhD, RN

Diagnosis, Guidance and Market Aspects: Prostate Cancer

8.4       New Prostate Cancer Screening Guidelines Face a Tough Sell, Study Suggests

Prabodh Kandala, PhD

Diagnossis: Lung Cancer

8.5      Diagnosing lung cancer in exhaled breath using gold nanoparticles

Tilda Barliya PhD

Chapter 9:  Detection

Detection: Prostate Cancer

9.1     Early Detection of Prostate Cancer: American Urological Association (AUA) Guideline

Dror Nir, PhD

Detection: Breast & Ovarian Cancer

9.2       Testing for Multiple Genetic Mutations via NGS for Patients: Very Strong Family History of Breast & Ovarian Cancer, Diagnosed at Young Ages, & Negative on BRCA Test

Aviva Lev-Ari, PhD, RN

Detection: Aggressive Prostate Cancer

9.3     A Blood Test to Identify Aggressive Prostate Cancer: a Discovery @ SRI International, Menlo Park, CA

Aviva Lev-Ari, PhD, RN

Diagnostic Markers & Screening as Diagnosis Method

9.4      Combining Nanotube Technology and Genetically Engineered Antibodies to Detect Prostate Cancer Biomarkers

Stephen J. Williams, PhD

Detection: Ovarian Cancer

9.5      Warning signs may lead to better early detection of ovarian cancer

Prabodh Kandala, PhD

9.6       Knowing the tumor’s size and location, could we target treatment to THE ROI by applying imaging-guided intervention?

Dror Nir, PhD

Chapter 10:  Biomarkers

                                                Biomarkers: Pancreatic Cancer

10.1        Mesothelin: An early detection biomarker for cancer (By Jack Andraka)

Tilda Barliya, PhD

Biomarkers: All Types of Cancer, Genomics and Histology

10.2                  Stanniocalcin: A Cancer Biomarker

Aashir Awan, PhD

10.3         Breast Cancer: Genomic Profiling to Predict Survival: Combination of Histopathology and Gene Expression Analysis

Aviva Lev-Ari, PhD, RN

Biomarkers: Pancreatic Cancer

10.4         Biomarker tool development for Early Diagnosis of Pancreatic Cancer: Van Andel Institute and Emory University

Aviva Lev-Ari, PhD, RN

10.5     Early Biomarker for Pancreatic Cancer Identified

Prabodh Kandala, PhD

Biomarkers: Head and Neck Cancer

10.6        Head and Neck Cancer Studies Suggest Alternative Markers More Prognostically Useful than HPV DNA Testing

Aviva Lev-Ari, PhD, RN

10.7      Opens Exome Service for Rare Diseases & Advanced Cancer @Mayo Clinic’s OncoSpire

Aviva Lev-Ari, PhD, RN

Diagnostic Markers and Screening as Diagnosis Methods

10.8         In Search of Clarity on Prostate Cancer Screening, Post-Surgical Followup, and Prediction of Long Term Remission

Larry H Bernstein, MD, FCAP

Chapter 11  Imaging In Cancer

11.1  Introduction by Dror Nir, PhD

11.2  Ultrasound

11.2.1        2013 – YEAR OF THE ULTRASOUND

Dror Nir, PhD

11.2.2      Imaging: seeing or imagining? (Part 1)

Dror Nir, PhD

11.2.3        Early Detection of Prostate Cancer: American Urological Association (AUA) Guideline

Dror Nir, PhD

11.2.4        Today’s fundamental challenge in Prostate cancer screening

Dror Nir, PhD

11.2.5       State of the art in oncologic imaging of Prostate

Dror Nir, PhD

11.2.6        From AUA 2013: “HistoScanning”- aided template biopsies for patients with previous negative TRUS biopsies

Dror Nir, PhD

11.2.7     On the road to improve prostate biopsy

Dror Nir, PhD

11.2.8       Ultrasound imaging as an instrument for measuring tissue elasticity: “Shear-wave Elastography” VS. “Strain-Imaging”

Dror Nir, PhD

11.2.9       What could transform an underdog into a winner?

Dror Nir, PhD

11.2.10        Ultrasound-based Screening for Ovarian Cancer

Dror Nir, PhD

11.2.11        Imaging Guided Cancer-Therapy – a Discipline in Need of Guidance

Dror Nir, PhD

11.3   MRI & PET/MRI

11.3.1     Introducing smart-imaging into radiologists’ daily practice

Dror Nir, PhD

11.3.2     Imaging: seeing or imagining? (Part 2)

[Part 1 is included in the ultrasound section above]

Dror Nir, PhD

11.3.3    Imaging-guided biopsies: Is there a preferred strategy to choose?

Dror Nir, PhD

11.3.4     New clinical results support Imaging-guidance for targeted prostate biopsy

Dror Nir, PhD

11.3.5      Whole-body imaging as cancer screening tool; answering an unmet clinical need?

Dror Nir, PhD

11.3.6        State of the art in oncologic imaging of Lymphoma

Dror Nir, PhD

11.3.7      A corner in the medical imaging’s ECO system

Dror Nir, PhD

11.4  CT, Mammography & PET/CT 

11.4.1      Causes and imaging features of false positives and false negatives on 18F-PET/CT in oncologic imaging

Dror Nir, PhD

11.4.2     Minimally invasive image-guided therapy for inoperable hepatocellular carcinoma

Dror Nir, PhD

11.4.3        Improving Mammography-based imaging for better treatment planning

Dror Nir, PhD

11.4.4       Closing the Mammography gap

Dror Nir, PhD

11.4.5       State of the art in oncologic imaging of lungs

Dror Nir, PhD

11.4.6       Ovarian Cancer and fluorescence-guided surgery: A report

Tilda Barliya, PhD

11.5  Optical Coherent Tomography (OCT)

11.5.1       Optical Coherent Tomography – emerging technology in cancer patient management

Dror Nir, PhD

11.5.2     New Imaging device bears a promise for better quality control of breast-cancer lumpectomies – considering the cost impact

Dror Nir, PhD

11.5.3        Virtual Biopsy – is it possible?

Dror Nir, PhD

11.5.4      New development in measuring mechanical properties of tissue

Dror Nir, PhD

Chapter 12. Nanotechnology Imparts New Advances in Cancer Treatment,  Detection, and Imaging  

12.1     DNA Nanotechnology

Tilda Barliya, PhD

12.2     Nanotechnology, personalized medicine and DNA sequencing

Tilda Barliya, PhD       

12.3     Nanotech Therapy for Breast Cancer

Tilda Barliya, PhD

12.4     Prostate Cancer and Nanotecnology

Tilda Barliya, PhD

12.5     Nanotechnology: Detecting and Treating metastatic cancer in the lymph node

Tilda Barliya, PhD

12.6     Nanotechnology Tackles Brain Cancer

Tilda Barliya, PhD

12.7     Lung Cancer (NSCLC), drug administration and nanotechnology

Tilda Barliya, PhD

Volume Epilogue by Larry H. Bernstein, MD, FACP

Epilogue: Envisioning New Insights in Cancer Translational Biology

Larry H. Berstein, MD, FACP

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New York Times Articles on Cancer Immunotherapy and Cancer Treatment Options

Curators: Aviva Lev-Ari, PhD, RN, Stephen J Williams, PhD and Tilda Barliya, PhD

The following articles, 

Here are some ways cancer can thwart the new immunotherapy drugs

Laurie McGinley July 13, 2016

https://www.washingtonpost.com/news/to-your-health/wp/2016/07/13/here-are-some-ways-cancer-can-thwart-the-new-immunotherapy-drugs/

and

The list of cancers that can be treated by immunotherapy keeps growing

By Laurie McGinley April 19

https://www.washingtonpost.com/news/to-your-health/wp/2016/04/19/breakthrough-cancer-therapy-shows-growing-promise/?tid=a_inl

were brought to my attention by Tilda Barliya, PhD, on our R&D Team, DrugDiscovery @LPBI Group, it stimulated the following curation in several Parts:

This article has three parts:

  • Part One: LPBI Group: A Key Opinion Leader (KOL) in Cancer and Genomics
  • Part Two: History of Cancer Immunotherapy
  • Part Three: New York Times Articles on Cancer Immunotherapy and Cancer Treatment Options

 

Part One:

LPBI Group: A Key Opinion Leader (KOL) in Cancer and Genomics

 

Immune System Stimulants: Articles of Note @pharmaceuticalintelligence.com

Immune-Oncology Molecules In Development & Articles on Topic in @pharmaceuticalintelligence.com

Curators: Stephen J Williams, PhD and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/01/11/articles-on-immune-oncology-molecules-in-development-pharmaceuticalintelligence-com/

Cancer Biology & Genomics for Disease Diagnosis, on Amazon since 8/11/2015

http://www.amazon.com/dp/B013RVYR2K

Genomics Orientations for Personalized Medicine, on Amazon since 11/23/2015

http://www.amazon.com/dp/B018DHBUO6

Genomics Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS & BioInformatics, Simulations and the Genome Ontology

https://pharmaceuticalintelligence.com/biomed-e-books/genomics-orientations-for-personalized-medicine/volume-two-genomics-methodologies-ngs-bioinformatics-simulations-and-the-genome-ontology/

Cancer Volume Two: Cancer Therapies: Metabolic, Genomics, Interventional, Immunotherapy and Nanotechnology in Therapy Delivery

https://pharmaceuticalintelligence.com/biomed-e-books/series-c-e-books-on-cancer-oncology/volume-2-immunotherapy-in-oncology/

Part Two:

History of Cancer Immunotherapy

Pioneers of Cancer Cell Therapy:  Turbocharging the Immune System to Battle Cancer Cells — Success in Hematological Cancers vs. Solid Tumors

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/08/19/pioneers-of-cancer-cell-therapy-turbocharging-the-immune-system-to-battle-cancer-cells-success-in-hematological-cancers-vs-solid-tumors/

In 1987, researchers identified cytotoxic T-lymphocyte antigen 4, or CTLA-4. Allison found that CTLA-4 prevents T cells from attacking tumor cells. He wondered whether blocking CTLA-4 would allow the immune system to make those attacks. In 1996, Allison showed that antibodies against CTLA-4 allowed the immune system to destroy tumors in mice.[2] In 1999, biotech firm Medarex acquired rights to the antibody. In 2010, Medarex acquirer Bristol-Myers Squibb reported that patients with metastatic melanoma lived an average of 10 months on the antibody, versus 6 months without it. It was the first time any treatment had extended life in advanced melanoma in a randomized trial.[2]

In the early 1990s, a biologist discovered a molecule expressed in dying T cells, which he called programmed death 1, or PD-1 and which he recognized as another disabler of T cells. An antibody that targeted PD-1 was developed and by 2008 produced remission in multiple subjects across multiple cancer types. In 2013, clinicians reported that across 300 patients tumors shrunk by about half or more in 31% of those with melanoma, 29% with kidney cancer and 17% with lung cancer.[2]

In 1997 rituximab, the first antibody treatment for cancer, was approved by the FDA for treatment of follicular lymphoma. Since this approval, 11 other antibodies have been approved for cancer; alemtuzumab (2001), ofatumumab (2009) and ipilimumab (2011).

In 2003 cytokines such as interleukin were administered.[3] The adverse effects of intravenously administered cytokines[4] led to the extraction, in vitro expansion against a tumour antigen and reinjection of the cells[5] with appropriate stimulatory cytokines.

However, with both anti–CTLA-4 and anti–PD-1, some tumors continued to grow before vanishing months later. Some patients kept responding after the antibody had been discontinued. Some patients, developed side effects including inflammation of the colon or of the pituitary gland.[2]

The first cell-based immunotherapy cancer vaccine, sipuleucel-T, was approved in 2010 for the treatment of prostate cancer.[6][7]

After success harvesting T cells from tumors, expanding them in the lab and reinfusing them into patients reduced tumors, in 2010, Steven Rosenberg announced chimeric antigen receptor therapy, or CAR therapy. This technique is a personalized treatment that involves genetically modifying each patient’s T cells to target tumor cells. It produced complete remission in a majority of leukemia patients, although some later relapsed.[2]

By mid 2016 the FDA had approved one PD-L1 inhibitor (atezolizumab) and two PD-1 inhibitors (nivolumab and pembrolizumab).

SOURCE

https://en.wikipedia.org/wiki/Cancer_immunotherapy

Part Three:

New York Times Articles on Cancer Immunotherapy and Cancer Treatment Options

 

  1. What Is Immunotherapy? The Basics on These Cancer Treatments

    Some of the most promising advances in cancer research in recent years involve treatments known as immunotherapy. These advances are spurring billions of dollars in investment by drug companies, and are leading to hundreds of

  2. Immunotherapy Offers Hope to a Cancer Patient, but No Certainty

    declared him in remission. It was a result that put him at the vanguard of a new generation of cancer treatment called immunotherapy that casts into sharp relief the harshness of how we have long treated cancer and the less grueling

  3. Have You Received Immunotherapy Treatment for Cancer?

    The New York Times would like to hear from doctors and patients who have experience giving or receiving immunotherapy treatment for cancer.

  4. Immunotherapy Drug Fails Lung Cancer Trial

    The hot new field of immunotherapy got a shock on Friday when a best-selling new drug failed as an initial treatment for lung cancer in a clinical trial. Bristol-Myers Squibb said Friday that the drug, Opdivo, had not slowed the

  5. F.D.A. Approves Immunotherapy Drug for Treatment of Bladder Cancer

    The Food and Drug Administration on Wednesday approved a newimmunotherapy drug from Roche to treat bladder cancer, a form of cancer for which there have been no significant new medicines in years. The drug, called Tecentriq, is the

  6. Sean Parker, a Facebook and Napster Pioneer, to Start CancerImmunotherapy Effort

    media as the early president of Facebook. Now he wants to pioneer in a field that is already jumping with activity: cancer immunotherapy. Mr. Parker is announcing Wednesday that he is donating $250 million to a new effort that will

  7. Harnessing the Immune System to Fight Cancer

    Sloan Kettering Cancer Center in New York, recommended an experimental treatment: immunotherapy. Rather than attacking the cancer directly, as chemo does, immunotherapy tries to rally the patient’s own immune

  8. Cancer-Drug Ads vs. Cancer-Drug Reality

    She also took part in a clinical trial at Johns Hopkins for Opdivo, an immunotherapy drug made by the pharmaceutical company Bristol-Myers Squibb. Briefly stated, immunotherapy is a recently developed, highly

  9. Sean Parker on Cancer Research

    Sean Parker discusses his support of immunotherapy research.

  10. Paid Notice: Deaths SPRAYREGEN, NICHOLAS (NICK)

    family and many friends. Contributions in his memory may be made to Memorial Sloan Kettering Cancer Center, Melanoma and Immunotherapy Research under Dr. Jedd Wolchok. 1/3

    11. Paid Notice: Deaths SPRAYREGEN, NICHOLAS (NICK)

    St. and Amsterdam Ave. Contributions in his memory may be made to Memorial Sloan Kettering Cancer Center, Melanoma and Immunotherapy Research under Dr. Jedd Wolchok. 1/3

    12. Setting the Body’s ‘Serial Killers’ Loose on Cancer

    Sloan Kettering Cancer Center. This radical, science-fictionlike therapy differs sharply from the more established type of immunotherapy, developed by other researchers. Those off-the-shelf drugs, known as checkpoint inhibitors,

SOURCE

http://query.nytimes.com/search/sitesearch/?action=click&contentCollection&region=TopBar&WT.nav=searchWidget&module=SearchSubmit&pgtype=Homepage#/immunotherapy/since1851/allresults/2/

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Paul Allen announces $100 million gift to expand “frontiers of bioscience”

Life sciences a priority for Sean Parker’s new $600 million foundation

Cornell study finds some people may be genetically programmed to be vegetarians

Mom’s and — surprise! — dad’s pre-pregnancy caffeine intake may affect miscarriage risk, NIH study warns

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AGENDA for Oncolytic Virus Immunotherapy Unlocking Oncolytic Virotherapies: From Science to Commercialization CHI’S 4TH ANNUAL IMMUNO-ONCOLOGY SUMMIT – AUGUST 29-30, 2016 | Marriott Long Wharf Hotel – Boston, MA

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

 

Oncolytic Virus Immunotherapy Unlocking Oncolytic Virotherapies: From Science to Commercialization

MONDAY, AUGUST 29 & 30

MONDAY, AUGUST 29

7:30 am Registration & Morning Coffee

REALIZING THE POTENTIAL OF ONCOLYTIC VIRUS IMMUNOTHERAPY

8:25 Chairperson’s Opening Remarks

Brian Champion, Ph.D., Senior Vice President, R&D, PsiOxus Therapeutics Ltd

8:30 T-Vec: From Market Approval to Future Plans

Jennifer Gansert, Ph.D., Executive Director, Global Development Lead, Amgen, Inc.

9:00 Oncolytic Virotherapies as a Single Shot Cure?

Stephen J. Russell, M.D, Ph.D., Professor, Mayo Clinic

Oncolytic virotherapy is increasingly used as a cancer immunotherapy. However, certain oncolytic viruses can also mediate wholesale tumor destruction independently of an antitumor immune response. This is the oncolytic paradigm, where a cytolytic virus with preferential tumor tropism spreads extensively at sites of tumor growth and directly kills the majority of the tumor cells in the body leaving only a few uninfected tumor cells to be controlled by the concomitant antitumor immune response.

9:30 Coffee Break

UNDERSTANDING MECHANISMS OF ACTION

9:55 Chairperson’s Remarks Fares Nigim, M.D., Massachusetts General Hospital and Harvard Medical School

10:00 Designing Clinical Trials to Elucidate Oncolytic Virus Mechanisms-of-Action

Caroline 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.

10:30 Seprehvir, an Icp34.5 Deleted OHSV with Both Direct and Covert Modes of Action

Joe Conner, Ph.D., CSO, Virttu Biologics

Seprehvir, an oncolytic HSV, is a complex biologic with multi-mechanistic modes of action. Lytic cytotoxicity, induction of Th1 cytokines/chemokine responses, recruitment of innate and adaptive immune cells and changes in the tumor microenvironment can enhance therapeutic efficacy in combination with other anti-cancer agents. How these modes of action intersect with PD-1 checkpoint inhibitors, CAR T cells and small molecule targeted therapies will be discussed.

11:00 The Mechanism of Action of Oncos-102, Oncolytic Adenovirus-Based Immune Activator

Antti Vuolanto, Ph.D., Executive Vice President, Targovax

ONCOS-102 is an engineered human serotype 5 adenovirus expressing GMCSF. A total of 12 cancer patients were treated with repeated intratumoral injections of ONCOS-102 in a Phase I study. Eleven

out of twelve patients showed a post-treatment increase in tumor-infiltrating immune cells including CD8+ T cells and two patients showed systemic induction of tumor specific CD8+ T cells.

11:30 Moving Toward MultiFunctionality in PoxvirusBased Oncolytic Virotherapy

Eric Quemeneur, Ph.D., Pharm.D., Executive VP and CSO, Transgene

Poxviruses are powerful immunotherapeutics and tumor-targeting platforms. We recently expanded Transgene’s portfolio of armed oncolytic Vaccinia Viruses (oVV) by engineering a vector that targets anti-PD1 IgG expression into the tumor. Local concentration of virus-encoded antibody was ~10-50 times higher than the reference mAb, leading to significant improvement of survival in a sarcoma preclinical model. Such results announce the next-generation oVVs, combining immunogenic oncolysis with the capacity to deliver complex therapeutic modalities in the tumor micro-environment.

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

12:30 Session Break

BIOMARKERS AND IMPROVING VIRUS ACTIVITY

1:25 Chairperson’s Remarks

David Kirn, M.D., CEO & Co-Founder, 4D Molecular Therapeutics & Adjunct Professor of Bioengineering, UC Berkeley

1:30 New Biomarkers that Predict Response to Oncolytic Virus Immunotherapy

Howard L. Kaufman, M.D., FACS, Associate Director, Clinical Sciences, Rutgers Cancer Institute of New Jersey; Professor and Chief, Division of Surgical Oncology, Rutgers Robert Wood Johnson Medical School

T-VEC is the first oncolytic virus approved for the treatment of melanoma, and will soon enter clinical trials for treatment of other cancers. Further studies using T-VEC in combination with T cell checkpoint inhibitors are underway and showing promising early results. The identification of predictive biomarkers of response would be helpful for improving patient selection and optimizing therapeutic outcomes. We have recently focused on HSV-1 entry receptors and oncogenic signaling pathways within cancer cells as potential biomarkers of T-VEC response.

2:00 Therapeutic Viral Vector Evolution: A Robust Platform for the Discovery of Optimized Vectors

David Kirn, M.D., CEO & Co-Founder, 4D Molecular Therapeutics; Adjunct Professor, Bioengineering, University of California, Berkeley

Therapeutic virus vectors hold great promise for cancer gene and immunotherapy. However, novel vectors with improved efficacy are needed. Therapeutic Vector Evolution is a discovery platform from which optimized and proprietary viral vectors can be identified with beneficial characteristics of interest.

2:30 Enhancing Oncolytic Virus Activity by Engineering of Artificial MicroRNAs

John Bell, Ph.D., Senior Scientist, Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Professor, Departments of Medicine and Biochemistry, Microbiology & Immunology, University of Ottawa

We have devised a novel strategy to enhance the ability of oncolytic viruses to infect malignant cells by expressing artificial microRNAs (amiRNAs) from the oncolytic virus genome. We have screened a variety of amiRNAs and identified a number that enhance virus replication within tumour but not normal cells. The characterization of these miRNAs and their targets will be discussed.

3:00 Refreshment Break

3:30 KEYNOTE PRESENTATION: ONCOLYTIC IMMUNOTHERAPY IN THE ERA OF CHECKPOINT BLOCKADE

Robert Coffin, Ph.D., CEO, Replimmune

Oncolytic immunotherapy treats cancer by virus-mediated tumor cell lysis and generation of a patient specific cancer vaccine, including to neo-antigens, in situ directly in the patient. Both are likely important for the clinical efficacy seen with single agent use, and also for the clinical synergy observed with immune checkpoint blockade. Background and data supporting single agent and combination use will be discussed, and future directions described.

4:00 Arming the Oncolytic Virus Enadenotucirev to Develop Tumor-Localized Combination Immunotherapeutics

Brian Champion, Ph.D., Senior Vice President, R&D, PsiOxus Therapeutics Ltd.

We have developed a systemically deliverable, oncolytic adenoviral platform for directing efficient and selective local production of a combination of biotherapeutic agents selectively within the tumor. This has

the potential for enhanced efficacy while reducing side effects by limiting systemic exposure. Up to three separate biomolecules can be encoded in the same virus without affecting oncolytic properties of the virus.

4:30 Immuno-Oncolytic Viruses as Cancer Therapies

Stephen Thorne, Ph.D., Professor and Scientific Advisor, Inventor, Western Oncolytics

Oncolytic viruses primarily act as immunotherapies, yet most vectors still rely on the virus’ inherent immune activation, often coupled to single cytokine transgene expression. However, for optimal activity they will need to overcome the tumor¹s immunosuppressive microenvironment, to raise anti-tumor CTL and allow repeated systemic delivery. Approaches to achieve all of these activities in a single vector are being developed.

5:00 End of Day

 

TUESDAY, AUGUST 30

8:00 am Morning Coffee

TRANSLATIONAL AND CLINICAL UPDATES

8:25 Chairperson’s Opening Remarks

8:30 Phase I of Intravenous Vcn-01 in Patients with Advanced Cancer: Update on Clinical & Biologic Data

Manel Cascallo, Ph.D., Co-Founder, President and CEO, VCN Biosciences

A first-in-human Phase I dose escalation study of intravenous administration of VCN-01 (an oncolytic adenovirus with RB tumour-targeting properties and expressing hyaluronidase) with or without gemcitabine and Abraxane is ongoing for patients with advanced solid tumours including pancreatic cancer. Dose dependent tolerability data and VCN-01 levels in different biological samples (including blood and tumour biopsies) are available.

 

8:50 T-Stealth Technology Mitigates Antagonism between Oncolytic Viruses and the Immune System through Viral Evasion of Anti-Viral T-Cells

Matthew Mulvey, Ph.D., CEO, BeneVir

Simultaneous combination of OV and immune checkpoint inhibitors (ICI) are antagonistic because ICI enhance anti-viral T-cell effector activity and speed OV clearance. BeneVir’s T-StealthTM armed OV mitigate antagonism between OV and ICI because they evade anti-viral T-cells. This allows OV and ICI to be administered simultaneously over several treatment cycles to maximize the likelihood of a synergistic clinical response

9:10 Reolsyin: A Clinical Update of a Directed Cytotoxic Agent and Immune Modulator

Brad Thompson, Ph.D., CEO, Oncolytics Biotech

REOLYSIN was initially investigated for its potential as a selective cytotoxin. However, recent research shows that it also functions as an immune modulator. This dual mechanism of action for a single viral agent suggests that the potential of viral therapies may be broader than previously anticipated.

9:30 Retroviral Replicating Vectors for Cancer-Selective Immuno/Gene Therapy: Translational and Clinical Update

Noriyuki Kasahara, M.D., Ph.D., Professor, Departments of Cell Biology and Pathology, CoLeader, Viral Oncology Program, University of Miami

Pro-drug activator gene therapy with retroviral replicating vectors is tumor-selective, and can lead to development of anti-tumor immunity. Ascending dose Phase I trials by Tocagen Inc. in recurrent high-grade glioma demonstrated favorable safety and tolerability, intratumoral virus spread, radiographic responses, and survival surpassing historical benchmarks. Based on these results, a randomized controlled Phase II/III trial is now underway.

10:00 Sponsored Presentations (Opportunities Available)

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

11:15 Virus Manufacturing Comes of Age: Turning Bugs into Features Anthony Davies, Ph.D., COO, 4D Molecular Therapeutics

Viruses destroy the host in which you’re trying to produce them and then must be separated from all components of those cells. Many solutions to these challenges have been invented since the earliest production of viral vaccines in primary cells obtained directly form animals. But few have proven amenable to cost-effective, compliant and scaleable operation.

11:45 Manufacturing Large Enveloped Oncolytic Viruses for Human Clinical Trials

Mark J. Federspiel, Ph.D., Professor and Director, Viral Vector Production Laboratory, Mayo Clinic

The large-scale production and purification of larger enveloped oncolytic viruses are particularly challenging. We have developed enveloped virus GMP production processes using suspension cells in combination with gentle but effective purification using hollow fiber tangential flow filtration that result in greater than 99.5% removal of contaminants and greater than 100-fold increases in final infectious virus titers.

12:15 pm Close of Oncolytic Virus Immunotherapy

 

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AGENDA for Adoptive T Cell Therapy Delivering CAR, TCR, and TIL from Research to Reality, CHI’S 4TH ANNUAL IMMUNO-ONCOLOGY SUMMIT – SEPTEMBER 1-2, 2016 | Marriott Long Wharf Hotel – Boston, MA

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

 

THURSDAY, SEPTEMBER 1

 

7:45 am Registration & Morning Coffee

PRINCIPALS OF ENGINEERED RECEPTOR DESIGN

8:25 Chairperson’s Opening Remarks

Adrian Bot, M.D., Ph.D., Vice President, Translational Sciences, R&D, Kite Pharma Inc.

8:30 KEYNOTE PRESENTATION: CLINICAL DEVELOPMENT OF TUMOR-INFILTRATING LYMPHOCYTE THERAPY FOR SOLID TUMORS: THE MYTHS AND THE REALITY

Laszlo Radvanyi, Ph.D., Senior Vice President and Head, ImmunoOncology Translational Innovation Platform (TIP), EMDSerono

Many of the patients treated with TILs have progressed after multiple therapies, including checkpoint blockade with anti-CTLA-4 and anti-PD-1/PD-L1, making TIL also an ultimate salvage therapy option. In this presentation, we will discuss common misconceptions about TIL therapy and current efforts that can realistically bring TIL therapy into the mainstream as an approved product for melanoma care as well as its promise as a cellular therapy for other solid cancers.

 

9:00 Engineering Better T Cells

Daniel Williams, Head, UK Research Operations, Adaptimmune

Adaptimmune is a clinical-stage biopharmaceutical company developing engineered TCRs for adoptive T cell therapy. Engineering TCRs specific for tumor antigens which are self-antigens, requires balancing the need for increasing affinity to the target peptide to allow recognition of immune-selected tumors, with the risk of cross-reactivity, which increases at higher affinities. Target identification and validation, together with a broad and robust preclinical safety testing strategy are critical in the development of safe and efficacious affinity-enhanced TCRs.

 

9:30 Development of an Anti-BCMA Specific CAR with Potent Anti-Multiple Myeloma Activity

Richard A. Morgan, Vice President, Immunotherapy, bluebird bio

B cell maturation antigen (BCMA) is expressed on most multiple myeloma (MM) cells, yet normal tissue expression is limited to plasma and some B cells. Here we demonstrate that a potent, antigen-dependent, memory-like BCMA CAR T cells can be produced with a scalable manufacturing process that mediated robust tumor regressions in animal models. A Phase I clinical trial to test this approach in patients with relapse refractor MM is underway.

10:00 Coffee Break with Exhibit and Poster Viewing

TARGETS FOR T CELL INTERVENTIONS

10:45 CD19 as a Prototypic B Cell Lineage Target for CAR T Cells Adrian Bot, M.D., Ph.D., Vice President, Translational Sciences, R&D, Kite Pharma Inc. Anti-CD19 CAR T cells could be the first marketed products in this space. Prolonged B cell deficiency may not be desirable since B cells are required to combat major pathogens. Product candidates capable to mediate rapid and profound tumor debulking, can yield durable clinical responses without persisting B cell deficiency. Novel evidence will be presented, linking product characteristics, conditioning, and biomarkers, to the clinical outcome afforded by CAR T cells.

11:15 CAR-T Cells for Hematological Malignancies: Exploring Alternative Targets

Gianpietro Dotti, M.D., Professor, Microbiology and Immunology, University of North Carolina

Adoptive transfer of CD19-specific CAR-T cells showed remarkable anti-tumor activity in patients with B-cell derived acute lymphoblastic leukemia and lymphomas. Alternative targets have been explored in Phase I studies in hematological malignancies. Specifically, in the effort to reduce the B cell aplasia associated with effective and long-term persisting CD19-specific CAR T cells, we implemented at Baylor College of Medicine a Phase I study with CAR-T cells targeting the k-light chain of human immunoglobulin to selectively eliminate k+ tumors whilst sparing normal l+ B lymphocytes. To target Hodgkin’s Lymphoma and other CD30+ lymphomas, we also implemented a Phase I study with CAR-T cells targeting the CD30 antigen. Outcome of these studies and future directions will be reported.

11:45 PANEL: CAR T Cell Therapy: Target Antigen Discovery and Clinical Translation

Panelists: Adrian Bot, M.D., Ph.D., Vice President, Translational Sciences, R&D, Kite Pharma Inc. Gianpietro Dotti, M.D., Professor, Microbiology and Immunology, University of North Carolina Richard A. Morgan, Vice President, Immunotherapy, bluebird bio

  • Market potential of anti-CD19 CAR T Cells
  • The latest clinical results
  • Scalability and manufacturing challenges
  • Future directions for CAR therapies

12:15 pm Sponsored Presentations (Opportunities Available)

12:45 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

1:15 Session Break

2:00 Chairperson’s Remarks

Adrian Bot, M.D., Ph.D., Vice President, Translational Sciences, R&D, Kite Pharma Inc.

Adoptive T Cell Therapy Delivering CAR, TCR, and TIL from Research to Reality Cover Conference at-a-Glance Faculty Keynotes

2:05 Human Papillomavirus (HPV)-Targeted T Cells for HPV-Associated Cancers

Christian S. Hinrichs, M.D., Investigator, Experimental Transplantation and Immunology Branch, Lasker Clinical Research Scholar, NIH

Human papillomavirus (HPV) causes cancers of the uterine cervix, oropharynx, anus, vulva, vagina and penis. These cancers express the HPV E6 and E7 oncoproteins, which are attractive immunotherapeutic targets. Recent work has sought to target these antigens using tumor-infiltrating lymphocytes and genetically engineered T cells.

2:35 XPRESIDENT®-Guided Target Identification and Profiling of On-and Off Target Toxicity for Safer Adoptive Cell Therapy

Steffen Walter, Ph.D., CSO, Immatics Biotechnologies GmbH

A major constraint for the broad and safe application of Adoptive Cellular Therapy is the limited number of validated tumor targets and TCRs. We used a proprietary target discovery engine (XPRESIDENT®) combining highly sensitive quantitative mass spectrometry, transcriptomics, immunology and bioinformatics to characterize the immunopeptidome directly on human normal and tumor tissues. We show how this approach can be used to predict on- and off-target toxicities in TCR-based immunotherapies.

3:05 Sponsored Presentations (Opportunities Available)

3:35 Refreshment Break

4:05 Engineering Designer T Cells for Immunotherapy

Wolfgang Uckert, Associate Professor, Department of Cell Biology and Gene Therapy, Humboldt University Berlin

Successful immunotherapy using T cell receptor (TCR) gene-modified T cells to treat cancer, viral infections or autoimmune diseases is depending on the careful selection of: (i) the target antigen, (ii) a TCR with optimal affinity, (iii) an efficient gene delivery system, and (iv) a safety switch to interrupt therapy in case of severe adverse side effects. Examples of these different areas to generate designer T cells for successful TCR gene therapy are given and discussed.

4:35 KEYNOTE PRESENTATION: A COMPARISON OF TCRS AND CARS: SENSITIVITIES AND SPECIFICITIES

David M. Kranz, Phillip A. Sharp Professor, Biochemistry, University of Illinois, Urbana-Champaign

T cells, via their T-cell receptors (TCRs), evolved to target intracellular peptides as low-density, cell-surface complexes with MHC products. Synthetic constructs known as chimeric antigen receptors (CARs) contain an anti-tumor antigen scFv and recognize higher density antigens. We have designed high-affinity human TCRs in conventional heterodimer format and in CAR-like formats to directly compare features of both systems. These features include T cell surface levels, antigen sensitivities and other properties.

5:05 PANEL: Designing T Cells for Immunotherapies Panelists: Christian S. Hinrichs, M.D., Investigator, Experimental Transplantation and Immunology Branch, Lasker Clinical Research Scholar, NIH Steffen Walter, Ph.D., CSO, Immatics Biotechnologies GmbH Wolfgang Uckert, Ph.D., Associate Professor, Cell Biology and Gene Therapy, Humboldt University Berlin David M. Kranz, Phillip A. Sharp Professor, Biochemistry, Biochemistry, University of Illinois

  • Strategies for antigen selection and targeting
  • Increasing sensitivity and specificities
  • Utilizing efficient gene delivery systems
  • Dealing with toxicities

5:35 End of Day

FRIDAY, SEPTEMBER 2

 

8:00 am Morning Coffee

TARGETING SOLID TUMORS

8:25 Chairperson’s Opening Remarks

Armon Sharei, Ph.D., CEO, SQZ Biotechnologies

8:30 Vector-Free Engineering of Immune Cells for Enhanced Antigen Presentation

Armon Sharei, Ph.D., CEO,

SQZ Biotechnologies Robust engineering of immune cell function is critical to realizing the therapeutic potential of cell therapies in cancer. Our vector-free CellSqueeze technology has demonstrated novel capabilities in diverse areas including engineering antigen presentation to drive powerful and significant T-cell responses. We will present recent developments in our cell-based immunotherapy programs aimed at using patient-derived antigens to target a variety of cancer indications, including solid tumors.

9:00 Design of a Highly Efficacious CAR Targeting Mesothelin in Solid Tumors Boris Engels, Ph.D., Investigator, Exploratory ImmunoOncology, Novartis Institutes for Biomedical Research

The treatment of solid tumors with CAR T cells remains challenging. We describe the design of a human CAR targeting mesothelin, a tumor associated antigen overexpressed in many cancers. A pooled screen identified scFvs, which show enhanced efficacy, superior to the CARs currently used in the clinic. We performed in-depth characterization of the scFvs and CARs to gain insight into structure-activity relationships, which may influence CAR efficacy and future design.

9:30 Overcoming CAR T Cell Checkpoint Blockade in Solid Tumors Prasad S. Adusumilli, M.D., FACS, FCCP, Deputy Chief, Translational and Clinical Research, Thoracic Surgery; Associate Attending, Thoracic Surgery; Member, Center for Cell Engineering, Memorial Sloan-Kettering

Cancer Center CAR T-cell therapy for solid tumors is prone to the checkpoint blockade inhibition similar to innate tumor-infiltrating lymphocytes. Strategies to overcome this ‘Adaptive Resistance’ of infused CAR

Immuno-Oncology Summit.com T cells can promote their anti-tumor efficacy and functional persistence. Understanding solid tumor type-specific immune microenvironment can guide both cell-intrinsic and extrinsic strategies that can modulate the solid tumor microenvironment in addition to promoting CAR T-cell efficiency.

10:00 Coffee Break MANUFACTURE AND SCALE-UP

10:30 Challenges and Opportunities for Scale-up of CAR T Cells Máire Quigley, Ph.D., Research Investigator I, Cell and Gene Therapies Unit, Novartis

The response rates of autologous CAR T cell therapies in early clinical trials give hope that these treatments can be developed and widely distributed to patients with unmet need. To successfully evolve from small scale production to commercial manufacturing, multiple challenges must be overcome. Lessons learned from the process scale up of CD19 CAR T cell production will be discussed.

11:00 Cell Therapy: Quality and Good Manufacturing Practices

Yeong “Christopher” Choi, Ph.D., Director, TCPF and Assistant Professor, Oncology, Center for Immunotherapy, Roswell Park Cancer Institute

To bring ground breaking new cell therapies into the clinic, a massive amount of infrastructure is needed. One of the key components is a drug manufacturing facility, which is compliant with US FDA GMP regulations. One of the major challenges of operating a cell therapy cGMP facility, is maintaining a robust Quality Management System. Fortunately, there are a number of voluntary accrediting organizations to promote excellence in the laboratory.

11:30 Manufacturing of Cellectis’ Allogeneic UCART Product Candidates Arjan Roozen, Vice President, GMP Solutions & Manufacturing, Cellectis

This talk will provide an introduction of the concept of Cellectis’ allogeneic UCART product candidates and our technological platform. It will describe and explain the challenges during the process of bringing allogeneic UCART product candidates from R&D development phase to the GMP manufacturing phase, in order to have CTM (clinical trial material) available for clinical studies, and afterwards to plan commercial manufacturing of Cellectis’ allogeneic UCART GMP cellular gene therapy products.

12:00 pm Close of Adoptive T Cell Therapy

 

 

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