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The CRISPR-Cas9 system has proven to be a powerful tool for genome editing allowing for the precise modification of specific DNA sequences within a cell. Many efforts are currently underway to use the CRISPR-Cas9 system for the therapeutic correction of human genetic diseases. CRISPR/Cas9 has revolutionized our ability to engineer genomes and conduct genome-wide screens in human cells.
CRISPR–Cas9 induces a p53-mediated DNA damage response and cell cycle arrest in immortalized human retinal pigment epithelial cells, leading to a selection against cells with a functional p53 pathway. Inhibition of p53 prevents the damage response and increases the rate of homologous recombination from a donor template. These results suggest that p53 inhibition may improve the efficiency of genome editing of untransformed cells and that p53 function should be monitored when developing cell-based therapies utilizing CRISPR–Cas9.
Whereas some cell types are amenable to genome engineering, genomes of human pluripotent stem cells (hPSCs) have been difficult to engineer, with reduced efficiencies relative to tumour cell lines or mouse embryonic stem cells. Using hPSC lines with stable integration of Cas9 or transient delivery of Cas9-ribonucleoproteins (RNPs), an average insertion or deletion (indel) efficiency greater than 80% was achieved. This high efficiency of insertion or deletion generation revealed that double-strand breaks (DSBs) induced by Cas9 are toxic and kill most hPSCs.
The toxic response to DSBs was P53/TP53-dependent, such that the efficiency of precise genome engineering in hPSCs with a wild-type P53 gene was severely reduced. These results indicate that Cas9 toxicity creates an obstacle to the high-throughput use of CRISPR/Cas9 for genome engineering and screening in hPSCs. As hPSCs can acquire P53 mutations, cell replacement therapies using CRISPR/Cas9-enginereed hPSCs should proceed with caution, and such engineered hPSCs should be monitored for P53 function.
CRISPR-based editing of T cells to treat cancer, as scientists at the University of Pennsylvania are studying in a clinical trial, should also not have a p53 problem. Nor should any therapy developed with CRISPR base editing, which does not make the double-stranded breaks that trigger p53. But, there are pre-existing humoral and cell-mediated adaptive immune responses to Cas9 in humans, a factor which must be taken into account as the CRISPR-Cas9 system moves forward into clinical trials.
Hepatitis B virus can cause serious, long-term health problems, such as liver disease and cancer, and can spread from mother-to-child during delivery. According to the latest estimates from the World Health Organization (WHO), approximately 257 million people in 2015 were living with the virus. Countries in Asia have a high burden of hepatitis B. There is no cure, and antiviral drugs used to treat the infection usually need to be taken for life.
To prevent infection, WHO recommends that all newborns receive their first dose of hepatitis B vaccine within 24 hours of delivery. Infants born to hepatitis B-infected mothers are also given protective antibodies called hepatitis B immune globulin (HBIG). However, mother-to-child transmission can still occur in women with high levels of virus in their blood, as well as those with mutated versions of the virus.
Tenofovir disoproxil fumarate (TDF), an antiviral drug commonly prescribed to treat hepatitis B infection, does not significantly reduce mother-to-child transmission of hepatitis B virus when taken during pregnancy and after delivery, according to a phase III clinical trial in Thailand funded by the National Institutes of Health. The study tested TDF therapy in addition to the standard preventative regimen — administration of hepatitis B vaccine and protective antibodies at birth — to explore the drug’s potential effects on mother-to-child transmission rates. The results appear in the New England Journal of Medicine.
The present study was conducted at 17 hospitals of the Ministry of Public Health in Thailand. It screened more than 2,500 women for eligibility and enrolled 331 pregnant women with hepatitis B. The women received placebo (163) or TDF (168) at intervals from 28 weeks of pregnancy to two months after delivery. All infants received standard hepatitis B preventatives given in Thailand, which include HBIG at birth and five doses of the hepatitis B vaccine by age 6 months (which differs from the three doses given in the United States). A total of 294 infants (147 in each group) were followed through age 6 months.
Three infants in the placebo group had hepatitis B infection at age 6 months, compared to zero infants in the TDF treatment group. Given the unexpectedly low transmission rate in the placebo group, the researchers concluded that the addition of TDF to current recommendations did not significantly reduce mother-to-child transmission of the virus.
According to the study, the clinical trial had enough participants to detect statistical differences if the transmission rate in the placebo group reached at least 12 percent, a rate observed in previous studies. Though the reasons are unknown, the researchers speculate that the lower transmission rate seen in the study may relate to the number of doses of hepatitis B vaccine given to infants in Thailand, lower rates of amniocentesis and Cesarean section deliveries in this study, or the lower prevalence of mutated viruses that result in higher vaccine efficacy in Thailand compared to other countries.
What does this mean for Immunotherapy? FDA put a temporary hold on Juno’s JCAR015, Three Death of Celebral Edema in CAR-T Clinical Trial and Kite Pharma announced Phase II portion of its CAR-T ZUMA-1 trial
Economic Potential of a Drug Invention (Prof. Zelig Eshhar, Weitzman Institute, registered the patent) versus a Cancer Drug in Clinical Trials: CAR-T as a Case in Point, developed by Kite Pharma, under Arie Belldegrun, CEO, acquired by Gilead for $11.9 billion, 8/2017.
Two research groups from Harvard Medical School based at Dana Faber Cancer Institute have discovered a genetic mechanism in a cancer cells that influence whether they respond or resist to immunotherapy drugs, otherwise called as checkpoint inhibitors. The results are published in Science as part of two articles. One article is focused on clinical trial patients with advanced kidney cancer treated with checkpoint inhibitors comes from Eliezer van Allen’s group at Dana Farber Cancer Institute and Toni Choueiri group at Lank Center for Genitourinary Oncology at Dana Farber. The second articles is focused on identifying the immunotherapy resistance mechanism in melanoma cells comes from Kai Wucherpfennig at Dana-Farber and Shirley Liu at Dana -Farber. The two groups joined on that the resistance to immune checkpoint blockade is critically controlled by changes in a group of proteins that regulate how DNA is packaged in cells. The assortment of proteins, called a chromatin remodeling complex, is known as SWI/SNF. Its components are encoded by different genes, among them ARID2, PBRM1 and BRD7. SWI/SNF’s job is to open up stretches of tightly wound DNA so that its blueprints can be read by the cell to activate certain genes to make proteins.
Scientists led by Van Allen and Choueiri wanted a clarification for why some patients with a form of metastatic kidney cancer, clear cell renal carcinoma (ccRCC) gain clinical benefit from treatment with immune checkpoint inhibitors that block the PD-1 checkpoint while others patients don’t. The researchers use whole exome DNA sequencing to analyze tumor samples from 35 patients treated in a clinical trial with Opdivo, a checkpoint blocker nivolumab to search for other characteristics of ccRCC tumors that influence immunotherapy response and/or resistance. The scientist discovered that patients from the trial benefited from the immunotherapy treatment with longer survival and progression free survival were those whose tumors lacked a functioning PRBM1 gene. Loss of PRBM1 gene function caused cancer cells to have increased expression of other genes including those in the gene pathway known as IL6/JAK-STAT3, which is involved in immune system stimulation.
When the PBRM1 gene was knocked out in experiments, the melanoma cells became more sensitive to interferon gamma produced by T cells and, in response, produced signaling molecules that recruited more tumor-fighting T cells into the tumor. The two other genes in the PBAF complex—ARID2 and BRD7—are also found mutated in some cancers, according to the researchers, and those cancers, like the melanoma lacking ARID2 function, may also respond better to checkpoint blockade. According to the researchers, finding ways to alter those target molecules “will be important to extend the benefit of immunotherapy to larger patient populations, including cancers that thus far are refractory to immunotherapy.”
Includes FDA Approved Drugs for Infections and Infectious Diseases: Bacterial Infection, Viral Infection, Fungal Infection, Allergy-related Infections and Other, 1995 – 2016
VOLUME 2: covers the frontier of research on Infectious Diseases and the Human Immune System. The Immune Response, Disease Specific Immune Response, Immunodiagnostics and Immunotherapy, Immunotherapy and Autoimmunity,
Bacterial Infections, Bacteria Types, Antibactirial Therapeutics, FDA Approved Drugs for Infections and Infectious Diseases: Bacterial Infection, 1995 – 2016. Viral Infection: Virus Types, Antiviral Therapeutics, and FDA Approved Drugs for Infections and Infectious Diseases: Viral Infection, Fungal Infections, Allergy-related Infections, Other Infections,1995 – 2016,
VOLUME 3: covers the state of Science on the Historical Perspective of Immunology, Development of the Immune System, Signaling and Immunology, Cellular Immunity, Immunology and Inflammatory Response. Antibody-based Immunity, Vaccines and Microbiome, Immuno-Pharmaceutics, Cancer Immunotherapy, Immunomodulation and Neuro-Immunology.
Volume 2: Summary
The material that has been covered is a considerable material on the basic types of infections – bacterial, viral, and fungal, and diseases related to immune mechanisms. There has been a substantial coverage of the drugs and the manufacturers. This material brings to the discussion an international problem of drug resistance that applies much to bacteria, and a considerable amount of material on advances in drug development that takes into consideration protein structure and protein-protein interactions. The coverage of virus diseases brings to the forefront vaccines. However, in such cases as the influenza virus, a rapid genetic change of the virus makes the use of vaccines an issue for continuing revision.
Volume 3: Summary
The second volume is only concerned with the pathobiology of the inflammatory response, including sepsis, and it does not leave out hematopoiesis, and it lays out the difference between the B-clles and the T-cells that are related to the Toll receptor. Here we have looked closely at two immune disorders, Inflammatory Bowel Disease (Crohn’s Disease) and Rheumatoid Arthritis. Here we have discussed immunomodulation and signaling of the pathways involved, and the programmed cell death response. We have also covered the relationship of the immune response to autoimmune disorders and to cancer. The treatment of cancer now heavily leans toward the blocking of destructive processes in the immunomodulatory pathways.
Epilogue – Volume 2
Volume 2 has covered the most common bacterial and viral diseases that we find widely, or sporadically. It detailed the development of sepsis, and the immune response factor. The immune response involves local cellular invasion of lymphocytes related to initiation of T-cells and macrophages, and also the proteomic generated B-cell antibodies. These reactions are both local and systemic, as bacterial invasion is local and usually related to the tissue of residence (large intestine, oral, lung, genital). In the case of virus, the site of entry is often respiratory or by food intake, but these agents may rapidly become systemic. The other matter of the immune response is autoimmune, a reaction against the self. It is not entirely clear how this is initiated, but it has been related to failure to develop immunity in the prenatal or postnatal period. The only other possibility that might be considered would be by the mechanism of cell remodeling by an apoptotic related mechanism. The other chapters deal with therapeutics.
Epilogue – Volume 3
These two volumes have traversed a large knowledge-base. The first was directed largely at the well known bacterial, virus, fungal diseases, as well as autoimmunity. It specified recent FDA approved recommendations of pharmaceutics for these conditions. It also gives some attention to the immune response in inflammatory and autoimmune diseases, but not cancer. The second volume gives a concise history of development of Leukemias, Lymphomas pathology.
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
8:30 – 9:45 Session V Moderator: Stefani Spranger | MIT, Koch Institute
K. Christopher Garcia – Stanford University Exploiting T Cell and Cytokine Receptor Structure and Mechanism to Develop New Immunotherapeutic Strategies
T Cell Receptor, peptide-MHC, 10 to the power of 10 is combinatorics – Library for selection to determine enrichment possibilities
Ligand identification for orphan TCRs
Industrializing process
use pMHC
IL-2 – Receptor Signaling Complex
Effector cells (NK, T)
Engineered T Cell – Tunable expansion, ligand-Receptor interface
Randomize IL-2RBeta interface: Orthogonal receptor vs wild type
In Vivo adoptive transfer model: to quantify orthogonality ratio
CD4, CD8, Treg,C57BL/6J
Ligand discovery
Orthogonal IL-2
Stefani Spranger – MIT, Koch Institute Batf3-DC as Mediators of the T Cell-Inflamed Tumor Microenvironment
Melanoma – solid cancer and other types, Immune inhibitory regulatory pathway patient with Immune response present
T cell-inflamed Tumor vs Non-T cell-inflamed Tumor
identify oncogenic pathways differentially activated between T cell-inflamed and non-Tcell-inflamed infiltration
If on Tumor:
Braf/PTEN
Braf/CAT
Braf/PTEN/CAT
The role of T cell priming – lack of initial
Beta-catenin-expressing tumors fail to prime 2C TCR-transgenic T cells
Deficiency in number of CD8+ and CD103+ dendritic cells
CD103+ DC are essential for T cell Priming and T cell-inflammation #StefaniSpranger
Adoptive transfer of effector 2C T cells fails to control Beta-catenin+ tumors
Vaccination induced anti-gen specific T cell memory fails to control Beta-catenin+ tumors
What cell type in tumor microenvironment effect monilization of T cell
CD103+ Dendritic cellsare source chymokine
Recruitment of effector T cells: Reconstitution od Beta-catenin-expressing SIY+
Are Batf3-DC within the tumor required for the recruitment of effector T cells?
Tumor-residing Batf3-drive CD103+ DC are required for the recruitment of effector T cells
Gene spore for correlation with recturment of effector cells
T cell Priming – CD103+ DC are essential for effector T cells
George Georgiou – University of Texas at Austin The Human Circulating Antibody Repertoire in Infection, Vaccination or Cancer
Serological Antibody Repertoire: in blood or in secretions
Antibody in serum – is difficult sequence identity
Serum IgG – 7-17 mg/ml if less immune deficient if more hyper globular
antibodies produced in long lived plasma cells in the bone marrow — experimentally inaccessible
Discovery of antibodies from the serological repertoire – not B cells
BM-PCs
Serum antibodies function via Fc effector mechanism – complement activation
Ig-SEQ – BCR-SEQ
Repertoire-wide computational modelling of antibody structures
En masse analysis & Mining of the Human Native Antibody Repertoire
hypervariable – High-Throughput Single B Cell VH:VL (or TCRalpha, beta) sequencing
HuNoV causes 800 death in the US per year of immune deficient
Influenza Trivalent Vaccine: Antibodies to hemaggiutinin: H1, H3, and B COmponenet
Abundant H1 +H3 Serum IgGs do not neutralize but confer Protection toInfluenza challenge with Live Virus #GeorgeGeorgiou
Non-Neutralizing Antibodies: The role of Complement in Protection
9:45 – 10:15 Break
10:15 – 11:30 Session VI Moderator: K. Dane Wittrup | MIT, Koch Institute
Harvey Lodish – Whitehead Institute and Koch Institute Engineered Erythrocytes Covalently Linked to Antigenic Peptides Can Protect Against Autoimmune Disease
Modified Red blood cells are microparticles for introducing therapeutics & diagnostics into the human body
Bool transfusion is widely used therapeutics
Covalently linking unique functional modalities to mouse or human red cells produced in cell culture:
PRODUCTION OF HUMAN RED BLOD CELLS EXPRESSING A FOREIN PROTEIN: CD34+ stem/progenitor cells that generates normal enucleated RBC.
PPAR-alpha and glucocorticoticoid receptor
Norman morphology: Sortase A is a bactrial transpeptidase that covalently links a “donor”
Engineering Normal Human RBC biotin-LPETG
Covelantely – Glycophorin A with camelid VHHs specific for Botulinum toxin A or B
HLA-DR4 library design and selection to enrich HLA-DM: Amino Acid vs Peptide position: Depleted vs Enriched – relative to expected for NNK codon
6852 _ predicted to bind vs 220 Non-binding peptides
HLA polymorphism: repertoire differences caused by
Antigen – T cell-driven antigen discovery: engaging Innate and Adaptive Immune response
Sorting TIL and select: FOcus of T cell-driven antigen discovery
T cell-driven antigen discovery: TCR
Jennifer R. Cochran – Stanford University Innate and Adaptive Integrin-targeted Combination Immunotherapy
alpa-TAA
TargetingIntegrin = universal targetinvolved in binding to several receptors: brest, lung, pancreatic, brain tumors arising by mutations – used as a handle for binding to agents
NOD201 Peptide-Fc Fusion: A Psudo Ab
Handle the therapeutics: NOD201 + alphaPD1
NOD201 effectively combines with alphaPD-L1, alphaCTLA-4, and alpha4-1BB/CD137
Corresponding monotherapies vs ComboTherapy invoking Innate and Adaptive Immune System
Microphages, CD8+ are critical vs CD4+ Neutrophils, NK cells, B cells #JenniferR. Cochran
Macrophages activation is critical – Day 4, 4 and 5
NOD201 + alphaPD1 combo increases M1 macrophages
Who are the best responders to PD1 – genes that are differentially expressed
NOD201 deives T cells reaponses through a “vaccinal” effect
CAncer Immune CYcle
Integrin – localization
Prelim NOD201 toxicity studies: no significant effects
Targeting multiple integrins vs antibodies RJ9 – minimal effect
NOD201 – manufacturability – NEW AGENT in Preclinical stage
2:15 – 2:45 Break
2:45 – 3:35 Session VIII Moderator: Jianzhu Chen | MIT, Koch Institute
Jennifer Wargo – MD Anderson Cancer Center Understanding Responses to Cancer Therapy: The Tissue is the Issue, but the Scoop is in the Poop
Optimize Targeted Treatment response
Translational research in patients on targeted therapy revealed molecular and immune mechanisms of response and resistance
Molecular mechanisms – T cell infiltrate after one week of therapy
Role of tumor stroma in mediating resistance to targeted therapy
Tumor microenvironment
Intra-tumoral bacteria identified in patients with Pancreatic Cancer
Translational research in patients on immune checkpoint blockade revealed molecualr and immune mechanism of response and resistance
Biomarkers not found
SYstemic Immunity and environment (temperature) on response to checkpoint blockade – what is the role?
Role of mIcrobiome in shaping response to checkpoint blockade in Melanoma
Microbime and GI Cancer
Diversity of the gut microbiome is associated with differential outcomes in the setting of stem cell transplant in AML
Oral and gut fecal microbiome in large cohort patient with metastatic melanoma undergoing systemic therapy
Repeat oral & gut AFTER chemo
WGSeq – Diversity of microbiome and response (responders vs non-responders to anti PD-1 – High diversity of microbiome have prolonged survival to PD-1 blockade
Anti tumor Immunity and composition of gut microbiome in patient on anti-PD-1 favorable AND higher survival #JenniferWargo
Enhance therapeutic responses in lang and renal carcinoma: If on antibiotic – poorer survival
sharing data important across institutions
Jianzhu Chen – MIT, Koch Institute Modulating Macrophages in Cancer Immunotherapy
Humanized mouth vs de novo human cancer
B cell hyperplasia
double hit lymphoma
AML
Overexpression of Bcl-2 & Myc in B cells leads to double-hit lymphoma
antiCD52 – CLL
Spleen, Bone marrow, Brain
Microphages are required to kill Ab-bound lymphoma cells in vivo #JianzhuChen
COmbinatorial chemo-Immunotherapy works for solid tumors: treating breast cancer in humanized mice
Infiltration of monocytic cells in the bone marrow
Cyclophosphophamide-antibody synergy extending to solid tumor and different antibodies #JianzhuChen
Polarization of macrophages it is dosage-dependent M1 and M2
Antibiotic induces expression of M1 polarizing supresses development and function of tumor-associated macrophages (TAM)
Antibiotic inhibits melanoma growth by activating macrophages in vivo #JianzhuChen
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
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
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
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
success limited to B cells cancers = blood vs solid tumors
adverse effects
OFF-TUMOR effects
Cell engineering for Cancer Therapy: User remote control (drug) – user control safety
Cell Engineering for TX
new sensors – decision making for
tumor recognition – safety,
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
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
decrease cytokine release
avoid neurological toxicity – homing
new targets address antigene escape variants – Resistance, CD19 is shaded, another target needed
B Cell Maturation Antigen (BCMA) Target
Bluebird Bio: Response duratio up to 54 weeks – Active dose cohort
natural ligand CAR based on April
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
Specific antigen targets
tumor heterogeneity
inhibitory microenvironment
CART in Glioblastoma
rationale for EGFRvIII as therapeutic target
Preclinical Studies & Phase 1: CAR t engraft, not as highly as CD19
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
Economic Potential of a Drug Invention (Prof. Zelig Eshhar, Weitzman Institute, registered the patent) versus a Cancer Drug in Clinical Trials: CAR-T as a Case in Point, developed by Kite Pharma, under Arie Belldegrun, CEO, acquired by Gilead for $11.9 billion, 8/2017.
Curator: Aviva Lev-Ari, PhD, RN
Article ID #245: Economic Potential of a Drug Invention (Prof. Zelig Eshhar, Weitzman Institute, registered the patent) versus a Cancer Drug in Clinical Trials: CAR-T as a Case in Point, developed by Kite Pharma, under Arie Belldegrun, CEO, acquired by Gilead for $11.9 billion, 8/2017. Published on 10/4/2017
WordCloud Image Produced by Adam Tubman
UPDATED on 2/21/2021
The Announcement of the 2021 Dan David Prize Laureates – YouTube – PRIZE $1MM per Winner for contributors to CAR-T MOA leading to development of immunotherapy anti cancer drugs
Prof. Zelig Eshhar – Weitzmann Institute his student Arie S. Belldegrun was CEO at Kate Pharmaceutics sold to Gilead for $12Bil
Prof. Carl June of UPenn
Steven Rosenberg, PhD, NIH
UPDATED on 10/15/2020
Hooked by the science, Arie Belldegrun joins a group of influentials who believe Dewpoint may have the key to the next big thing in biotech John Carroll Editor & Founder Amir Nashat knew he had years of preclinical work to do when he talked to me at the beginning of 2019 about Dewpoint Therapeutics and its rare focus on the role bimolecular condensates could play in crafting a wide-ranging pipeline of therapeutics.
The Cambridge, MA-based Dewpoint team, which will now double in size over the next year, doesn’t have a late-stage preclinical program it can shove into the clinic. The biotech is investing in neurodegeneration, cancer, cardiovascular and other areas for a platform that could, eventually, have extensive applications. But asked about a timeline to proof-of-concept data, Nashat frankly estimates that it will take 4-5 years to birth some hard human data. The money should get them through 3 years and a considerable de-risking approach to their preclinical efforts
The CSO is Mark Murcko, an experienced and well known startup player.
Mark Murcko “When I think about new companies a lot of it is about timing; is it too soon or too late?” Murcko notes enthusiastically in our interview. “Is there enough information available to make you think you can take that and use it toward new drugs? Five years ago it was too early, too nascent.”
Now, Murcko adds, seems like a great time to give this a go.
Gilead is writing off its anti-BCMA CAR-T for multiple myeloma, eliminating one of the many efforts focused on that target and driving a big part of the company’s $820 million impairment charge for R&D in the 4th quarter of last year. But this could just be a taste of what’s to come.
A $12 billion buyout of Kite Pharma in 2017 brought with it the CAR-T therapy Yescarta (axicabtagene ciloleucel) and a foothold in immuno-oncology. But last year’s results make clear that return on that investment will be slow to materialize.
Buried in among Gilead’s fourth-quarter results statement is a line revealing it has abandoned an anti-BCMA cell therapy for multiple myeloma, part of its $12 billion acquisition of Kite Pharma.
The failed KITE-585 program and other costs associated with the acquisition resulted in a whopping $820 million impairment charge in the quarter and add to analyst speculation that with sales of approved CAR-T Yescarta still disappointing, Gilead may have to write down the value of the Kite deal entirely, according to a Bloomberg report.
Gilead’s decision to drop the KITE-585 CAR-T program reflects the increasing competition in the anti-BCMA category and doesn’t come out of the blue. The company said at the J.P. Morgan conference (JPM) last month that it would only press ahead with development of KITE-585 if its profile was very compelling.
Robert W. Baird & Co. analyst Brian Skorney says Gilead may have to write down the deal, which the company values at $11.9 billion. That means lowering the projections on its balance sheet, if the multi billion-dollar sales Wall Street expects don’t materialize. The long-time bull cut his rating on the stock to neutral in July following the management exodus.
It’s also clear that public investors did quite well in these deals – unlike some outcomes, both private and public investors can only be happy with these deals. Kite’s IPO investors made over a whopping 10x, and Juno’s nearly a 3.6x (in 3 years, so still a very strong public market return). Even the follow-on financing participants made handsome returns: both Kite’s and Juno’s follow-on financings about 4-6 months prior to acquisition delivered a 2x return in a short period. What’s clear is that participating at any point only these price curves was a positive for investors. Obviously that doesn’t always happen, but great to see when it does.
A final takeaway is that there is “no one size fits all” for how to build business models that can work in biotech these days, even to get to similar product and patient outcomes. While Kite and Juno have remarkably similar products, similar platforms, and similar overall acquisition valuations, the stories were built quite differently when it comes to financing their growth.
Kite Pharma, under Arie Belldegrun, CEO, acquired by Gilead for $11.9 billion, 8/2017.
Kite’s Yescarta™ (Axicabtagene Ciloleucel) Becomes First CAR T Therapy Approved by the FDA for the Treatment of Adult Patients With Relapsed or Refractory Large B-Cell Lymphoma After Two or More Lines of Systemic Therapy
— Manufacturing Success Rate of 99 Percent in ZUMA-1 Pivotal Trial with a Median 17 Day Turnaround Time —
CAR T therapy is a breakthrough in hematologic cancer treatment in which a patient’s own T cells are engineered to seek and destroy cancer cells. CAR T therapy is manufactured specifically for each individual patient.
“The FDA approval of Yescarta is a landmark for patients with relapsed or refractory large B-cell lymphoma. This approval would not have been possible without the courageous commitment of patients and clinicians, as well as the ongoing dedication of Kite’s employees,” said Arie Belldegrun, MD, FACS, Founder of Kite. “We must also recognize the FDA for their ability to embrace and support transformational new technologies that treat life-threatening illnesses. We believe this is only the beginning for CAR T therapies.”
“Today is an important day for patients with relapsed or refractory large B-cell lymphoma who have run out of options and have been waiting for new treatments that may help them in their fight against cancer,” said John Milligan, PhD, President and Chief Executive Officer of Gilead Sciences. “With the combined innovation, talent and drive of the Kite and Gilead teams, we will rapidly advance cell therapy research and aim to bring new options to patients with many other types of cancer.”
The list price of Yescarta in the United States is $373,000.
Yescarta has been granted Priority Medicines (PRIME) regulatory support for DLBCL in the European Union. A Marketing Authorization Application (MAA) for axicabtagene ciloleucel is currently under review with the European Medicines Agency (EMA) and potential approval is expected in the first half of 2018.
The approval of Yescarta is supported by data from the ZUMA-1 pivotal trial. In this study, 72 percent of patients treated with a single infusion of Yescarta (n=101) responded to therapy (overall response rate) including 51 percent of patients who had no detectable cancer remaining (complete remission; 95% CI: 41, 62). At a median follow-up of 7.9 months, patients who had achieved a complete remission had not reached the estimated median duration of response (95% CI: 8.1 months, not estimable [NE]).
In the study, 13 percent of patients experienced grade 3 or higher cytokine release syndrome (CRS) and 31 percent experienced neurologic toxicities. The most common (≥ 10%) Grade 3 or higher reactions include febrile neutropenia, fever, CRS, encephalopathy, infections-pathogen unspecified, hypotension, hypoxia and lung infections. Serious adverse reactions occurred in 52% of patients and included CRS, neurologic toxicity, prolonged cytopenias (including neutropenia, thrombocytopenia and anemia), and serious infections. Fatal cases of CRS and neurologic toxicity occurred. FDA approved Yescarta with a Risk Evaluation and Mitigation Strategy.
Yescarta Indication
Yescarta is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.
Yescarta is not indicated for the treatment of patients with primary central nervous system lymphoma.
Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma (NHL), accounting for three out of every five cases. In the United States each year, there are approximately 7,500 patients with refractory DLBCL who are eligible for CAR T therapy. Historically, when treated with the current standard of care, patients with refractory large B-cell lymphoma had a median overall survival of approximately six months, with only seven percent attaining a complete response. Currently, patients with large B-cell lymphoma in second or later lines of therapy have poor outcomes and greater unmet need, since nearly half of them either do not respond or relapse shortly after transplant.
“With CAR T therapy, we are reengineering a patient’s own immune system to detect and kill cancer cells, and the results have been impressive,” said Frederick L. Locke, MD, ZUMA-1 Co-Lead Investigator and Vice Chair of the Department of Blood and Marrow Transplant and Cellular Immunotherapy at Moffitt Cancer Center in Tampa, Florida. “Many of the patients that received CAR T therapy had already relapsed several times with traditional treatments such as chemotherapy or hematopoietic stem cell transplant. Now, thanks to this new therapy many patients are in remission for months.”
“This therapy is a new option for patients with relapsed or refractory large B-cell lymphoma who have run out of treatment options and face a dire prognosis,” said Louis J. DeGennaro, PhD, President and Chief Executive Officer of The Leukemia & Lymphoma Society (LLS). “Early on, LLS recognized the potential of CAR T therapy and we are proud to be part of making this historic approval possible.”
“Engineered cell therapies like Yescarta represent the potential for a changing treatment paradigm for cancer patients,” said David Chang, MD, PhD, Worldwide Head of Research and Development and Chief Medical Officer at Kite. “Together, Gilead and Kite will accelerate studies of CAR T therapy in multiple blood cancers and advance other cell therapy approaches for solid tumors, with the goal of helping patients with diverse cancers benefit from this new era of personalized cancer therapy.”
ABOUT Drug Invention (Prof. Zelig Eshhar, Weitzman Institute, registered the patent)
ABOUT Gilead’s $12 billion buy of Kite Pharma
ABOUT the Drug Development process and the COMMERCIALIZATION GENIUS of Arie Belldegrun – Interviewed by Globes
ABOUT the Perspective of Drug Invention (Prof. Zelig Eshhar, Weitzman Institute, registered the patent) following the Gilead’s $12 billion buy of Kite Pharma – Interviewed by Globes
ABOUT the Economic significance of Kite Pharma Acquisition for the Venture Capital Investment in Biotech in Israel
I agree with Prof. Zelig Eshhar that this Case in Point is “one more invention, or parts of an invention, came from an Israeli laboratory (at the Weizmann Institute in this case) and fell into foreign hands. It is another enormous missed opportunity in the field of biomedicine and ethical drugs.”
I agree with Prof. Zelig Eshhar that this Case in Point should have been a TEVA commercialization effort. It is a regrettable reality that the development and the manufacturing will not benefit the State of Israel, home of the Weitzman Institute where the Patentable invention took place by Prof. Zelig Eshhar.
It is to be acknowledged that for CAR-T – the process of treatment using the drug – personalized genetic engineering of each patient’s cells – a grafting process with no precedent in the pharmaceutical industry (Juno has related process) – is bringing to the Oncology arena a NOVEL treatment for hematological malignancies cancer patients
I agree with Prof. Zelig Eshhar that the Barriers in the pharmaceutical industry are especially high. Developing ethical drugs is a process requiring huge amounts of time, patience, money, and failures. It is exactly, therefore, all need to acknowledge that the Drug Development process and the COMMERCIALIZATION GENIUS of Arie Belldegrun is inseparable from the breakthrough invention of Prof. Zelig Eshhar to develop the drug from the Lab bench to the FDA accelerated process of Drug approval.
The Biotech industry in Israel needs to develop more MDs, PhDs with the level of training of Arie Belldegrun and with his entrepreneur acumen, keenness and depth of perception, discernment, discrimination especially in practical aspects of Translation Medicine, Clinical Research, Clinical Trial Design and abilities to engage in innovating the FDA processes.
The Biotech industry in US needs to develop more MDs, PhDs with the level of training of Prof. Zelig Eshhar to carry the scientific gravitas and the creativity to become inventors of novel drugs.
ABOUT Drug Invention (Prof. Zelig Eshhar, Weitzman Institute, registered the patent)
Pioneers of Cancer Cell Therapy: Turbocharging the Immune System to Battle Cancer Cells — Success in Hematological Cancers vs. Solid Tumors
FDA has approved the world’s first CAR-T therapy, Novartis for Kymriah (tisagenlecleucel) and Gilead’s $12 billion buy of Kite Pharma, no approved drug and Canakinumab for Lung Cancer (may be?)
ABOUT the Perspective of Drug Invention (Prof. Zelig Eshhar, Weitzman Institute, registered the patent) following the Gilead’s $12 billion buy of Kite Pharma – Interviewed by Globes
Kite Pharma was a $12b missed opportunity for Israel – Interview with Professor Zelig Eshhar
Some Israeli media headlines depicted Kite as an Israeli exit. But it is a US company that does no business in Israel and has no employees here.
Professor Zelig Eshhar is the man who registered the patent on the cancer treatment drug developed by Kite Pharma, recently acquired by Gilead for $11.9 billion.
“Globes”: Do you believe that any party in Israel could have financed the product and brought it where it is today?
Eshhar: “On the one hand, yes. The level of investment in the product before it reached Nasdaq was something that an Israeli concern could certainly have financed. On the other hand, Kite Pharma founder Professor Arie Belldegrun, with his energy and connections, brought it to a completely different place (Eshhar previously tried to interest various concerns in Israel in financing the drug, but all of them told him that it was too early, or that the product was not effective enough, E.T.).
Was the development already in its final form in the 1980s?
“Almost. I went to the National Institutes of Health (NIH), where I met for the first time Professor Steven Rosenberg, who later became the first doctor to conduct clinical trials with the technology. Rosenberg heard about my technology, and offered me exceptional conditions. We set up a team there, and had the best of everything. I only wish I had it now.”
They say that Belldegrun didn’t want the product at first. Today, he’s devoting all his efforts to it.
“When Arie founded Cougar Biotechnology, which developed a drug for prostate cancer, and was eventually sold to Johnson & Johnson for $1 billion, I contacted him and offered him the technology, but he was busy with Cougar’s product, and maybe didn’t think that he had enough capital for such a production. Only after he sold Cougar did he get back to me with an offer to buy the rights to my patent. At that time (2009-2010), the technology was already arousing great interest, and there were negotiations with several large companies.” (from an April 2015 “Globes” interview with Eshhar, who was awarded the Israel Prize).
Israelis can be very provincial. In at least some of the media headlines, Kite Pharma was portrayed as a “huge Israeli exit,” and the impression was given that it was an Israeli company. The truth is very different. Kite Pharma is not an Israeli company; it is a 100% US company. It does no business in Israel; its nearly $12 billion exit has no significance whatsoever for the Israeli economy, and will contribute nothing to it: no jobs, and the tax contribution will be marginal, and certainly not on the scale of Mobileye, for example. Let me say it again: Kite Pharma does not have even one employee in Israel (and has no reason to employ anyone here), and certainly does not pay taxes in Israel. There are no Israelis on the company’s management team or board of directors. This is a US company for all intents and purposes. The word “Israel” appears exactly once in the company’s full documents – where registration of the company’s patents is concerned. The fact that every story about the company mentions the small holdings of several Israeli financial institutions in it is a bad joke. Everyone should remember that Israeli financial institutions are of course entitled to invest in any foreign share, such as Google, Amazon, Facebook, Apple Computers, and so forth. Kite Pharma is one of those foreign shares, and nothing more.
Of course, there is cause for pride in the fact that Eshhar, owner of the patent for Kite Pharma’s drug is “one of ours,” i.e. an Israeli researcher at the Weizmann Institute of Science. Another source of pride is Kite Pharma founder and CEO Arie Belldegrun, a graduate of the Hebrew University Medical School who did his post-doctorate at the Weizmann Institute, where he met Eshhar, and Kite Pharma later bought his patent for the cancer drug. Belldegrun was also a director at Teva Pharmaceutical Industries Ltd. (NYSE: TEVA; TASE: TEVA) until recently, resigning at the peak of that company’s crisis. Beyond this Israeli connection, however, the Kite Pharma exit has no great significance for Israel. All it means is that one more invention, or parts of an invention, came from an Israeli laboratory (at the Weizmann Institute in this case) and fell into foreign hands. It is another enormous missed opportunity in the field of biomedicine and ethical drugs.
It is necessary to realize that while Belldegrun is indeed a big biomedical brain with many achievements in the field, he is a brain that has left Israel, and we all have to ask ourselves why he left, why Kite Pharma is not an Israeli company, and why its (as yet non-existent) product was not developed in Israel and will not be manufactured there. The headline in Israel for the Kite Pharma exit should ask why Israel lost out on it, even though the patent came from Israeli laboratories, albeit with US cooperation.
Belldegrun is likely to keep his experiences on the Teva board of directors to himself. Of all the directors in the company, what he has to say is the most interesting, but he is unlikely to divulge what happened there with the inflated deal with Allergan, and exactly what he said at the board of directors meeting that approved the deal that led Teva into its current major crisis. The Kite Pharma exit and his other exits only highlight the lost opportunity. Kite Pharma, still without a product and without approval for a product, was sold for $11.9 billion in cash. Teva yesterday hit another low point, with a market cap of $16 billion. It is simply inconceivable: a company with an enormous potential, but no product, is worth three quarters of a huge veteran company with at least dozens of products, including products in the ethical drug sector. Kite Pharma is actually one of the indirect reasons for Teva’s decline – for the fact that Teva, which could have been a hothouse for developments like Copaxone, chose a huge inflated gamble on the generics market – a gamble that is now jeopardizing Teva’s future and very existence.
It is true that developing drugs is a very long process, requires huge amounts of capital, and involves many failures, but Teva decided to neglect it, and when a major company like Teva neglects Israeli developments, there are enough competitors in the pharma industry ready to turn Israeli research into gold. Kite Pharma is one example of this research.
The Weizmann Institute is a fruitful source of biomedical research. According to previous estimates published in “Globes,” the Weizmann Institute gets NIS 1 billion each year in royalties on medical and other developments, amounting to half of its budget. Directly and indirectly, the Weizmann Institute, together with other universities in Israel, is responsible for tens of billions of pharmaceutical sales. Only a few billions of this, however, results from drugs developed in Israel, like Copaxone, and far less than that is also made in Israel. The reports by Yeda R&D Company Ltd., the technology transfer arm of the Weizmann Institute of Science, are top secret, and there is a good reason for that. Exposing them will only highlight the scale of the missed opportunities. Instead of these inventions providing a base for a major pharmaceutical industry here, the commercialization companies are benefiting only the inventors and the Weizmann Institute itself (that is certainly natural and legitimate, and they are entitled to it), even though the research infrastructure from which they sprung is Israeli know-how, as in the case of Eshhar.
Barriers in the pharmaceutical industry are especially high. Developing ethical drugs is a process requiring huge amounts of time, patience, money, and failures. When it succeeds, however, the profit is enormous – for the industry, the employees, and the state (provided that some tax is paid). For example, Pfizer’s peak sales of Lipitor, a very popular drug for reducing cholesterol and fat in the bloodstream, reached $11 billion, and its profit on the drug was $9 billion, before competition from a generic version began. In addition to money, a great deal of experience and marketing power is required, and that is the reason why most developments wind up in the hands of major companies like Pfizer, Merck, and others at some stage. After all these qualifying statements, everyone who celebrated Kite Pharma’s exit should weep over it – it is another part of the sale of Israeli know-how overseas for a mess of pottage. Instead of consolidating a splendid pharma industry here, Israel is selling the brains with their know-how to foreigners. More than anything else, Teva’s decline and the Kite Pharma exit epitomize this sad and dangerous trend.
Published by Globes [online], Israel Business News – www.globes-online.com – on August 30, 2017
ABOUT the Economic significance of Kite Pharma Acquisition for the Venture Capital Investment in Biotech in Israel
Israeli investors profit from $11.9b Kite acquisition
Pontifax fund and Israeli institutional investors will profit from the US personalized cancer drug company’s huge sale. Part of the technology was developed at the Weizmann Institute
Pharmaceutical company Gilead Sciences Inc. has announced that it will acquire US company Kite Pharma Inc., developer of personalized cancer treatment drugs, at a company value of $11.9 billion. This is one of the biggest ever acquisitions of a company whose products have not yet been approved for marketing. The company value for the acquisition reflects a 29% premium on the market price.
Kite Pharma has developed a new method for genetically engineering immune system cells, so that they will make a focused attack on the malignant tumor. The company was founded in the US by Israeli-American Professor Arie Belldegrun, who already has two exits to his credit. He is also a former director at Teva Pharmaceutical Industries Ltd. (NYSE: TEVA; TASE: TEVA) (whose current value is not much more than the value at which Kite Pharma, a company with no products approved for marketing yet, is being acquired).
A significant part of the technology on which the product is based was developed by Professor Zelig Eshhar of the Weizmann Institute of Science.
Kite Pharma is waiting for marketing approval of its first product, following a successful trial on 100 patients on a very abbreviated track for innovative cancer products. The product was initially designed for treatment of blood cancer, but it is now hoped that its use can later be expanded to treatment of other types of cancer. Gilead is making a big gamble, first of all that the US Food and Drug Administration (FDA) will fulfill its commitment to approve the product, even though the development plan it devised, together with the company, was very short and limited. The second gamble involves the process of treatment using the drug – personalized genetic engineering of each patient’s cells – a grafting process with no precedent in the pharmaceutical industry.
Speaking about the talks to sell Kite, Prof. Arie Belldegrun told “Globes.” “We handled like in the IDF 669 unit. Nobody knew anything. Nobody heard anything. We held meetings in places where nobody would see us. And before we announced it only five employees knew about it.”
Published by Globes [online], Israel Business News – www.globes-online.com – on August 28, 2017
Cancer Therapies: Metabolic, Genomics, Interventional, Immunotherapy and Nanotechnology in Therapy Delivery (Series C Book 2) – on Amazon since 5/18/2017
Lectures by The 2017 Award Recipients of Warren Alpert Foundation Prize in Cancer Immunology, October 5, 2017, HMS, 77 Louis Paster, Boston
Reporter: Aviva Lev-Ari, PhD, RN
Article ID #242: LIVE: Lectures by The 2017 Award Recipients of Warren Alpert Foundation Prize in Cancer Immunology, October 5, 2017, HMS, 77 Louis Paster, Boston. Published on 9/8/2017
WordCloud Image Produced by Adam Tubman
Top, from left: James Allison and Lieping Chen. Bottom, from left: Gordon Freeman, Tasuku Honjo (NOT ATTENDED), Arlene Sharpe.
Leaders in Pharmaceutical Business Intelligence (LPBI) Group
The 2017 Warren Alpert Foundation Prize has been awarded to five scientists for transformative discoveries in the field of cancer immunology.
Collectively, their work has elucidated foundational mechanisms in cancer’s ability to evade immune recognition and, in doing so, has profoundly altered the understanding of disease development and treatment. Their discoveries have led to the development of effective immune therapies for several types of cancer.
The 2017 award recipients are:
James Allison, professor of immunology and chair of the Department of Immunology, The University of Texas MD Anderson Cancer Center – Immune checkpoint blockage in Cancer Therapy strictly Genomics based drug
2017 FDA approved a genomics based drug
and co-stimulatory signals
CTLA-4 blockade, CD28, AntiCTLA-4 induces regression of Transplantable Murine tumor
enhance tumor-specific immune response
Fully antibody human immune response in 10,000 patients – FDA approved 2011
Ipi/Nivo vs. Ipi – combination – 60% survival vs Ipi alone
Anti CTA4 vs Anti-PD-1
responsive T cell population – MC38 TILs
MC38 Infiltrating T cell populations: T-reg, CD4, Effector, CD8, NKT/gamma-delta
Checkpoint blockage modulates infiltrating T cell population frequencies
T reg correlated with Tumor growth
Combination therapy lead to CURE survival at 80% rate vs CTAL-4 40% positive outcome
Not Attended — Tasuku Honjo, professor of immunology and genomic medicine, Kyoto University – Immune regulation of Cancer Therapy by PD-1 Blockade
Lieping Chen, United Technologies Corporation Professor in Cancer Research and Professor of immunobiology, of dermatology and of medicine, Yale University – Adoptive Resistance: Molecular Pathway t Cancer Therapy – focus on solid tumors
Enhancement – Enhance normal immune system – Co-stimulation/Co-inhibition Treg, and Cytokines, adoptive cell therapy, Lymphoid organs stores
Normalization – to correct defective immune system – normalizing tumor immunity, diverse tumor escape mechanisms
Anti-PD therapy: regression of large solid tumors: normalizing tumor immunity targeting tumor microenvironment: Heterogeneity, functional modulation, cellular and molecular components – classification by LACK of inflamation, adaptive resistance, other inhibitory pathways, intrinsic induction
avoid autoimmune toxicity,
Resetting immune response (melanoma)
Understad Resistance: Target missing resistance or Adaptive resistance Type II= acquired immunity
Gordon Freeman, professor of medicine, Dana-Farber Cancer Institute, Harvard Medical School – PD-L1/PD-1 Cancer Immunotherapy
B7 antibody
block pathway – checkpoint blockage, Expand the T cells after recognition of the disease. T cell receptor signal, activation, co -stimulatory: B71 molecule, B72 – survival signals and cytokine production,.Increased T cell proliferation,
PDL-1 is a ligand of PD 1. How T cell die? genes – PD1 Gene was highly expressed,
PD-L! sisgnat inhibit T-cell activation: turn off Proliferation and cytokine production — Decreasing the immune response
T cell DNA Content: No S-phase devided cell
PD-L1 engagement of PD-1 results in activation : Pd-1 Pathway inhibits T Cell Actiivation – lyposite motility,
Pd-L2 is a second ligand for PD-1 and inhibits T cell activation
PDl-1 expression: BR CA, Ovarian, Colonol-rectal, tymus, endothelial
Blockage of the Pathway – Immune response enhanced
Dendritic cells express PD-L1, PD-L2 and combination of Two, Combination was best of all by increase of cytokine production, increasing the immune response.
PD-L1 blockade enhanced the immune response , increase killing and increased production of cytokines,
anti-tumor efficacy of anti-PD-1/Pd-L1
Pancreatic and colono-rector — PD-L, PDL1, PDL2 — does not owrkd.
In menaloma: PD-1 works better than CYLA-4
Comparison of Targeted Therapy: BRAF TKI vs Chemo high % but short term
Immunotherapy – applies several mechanism: pre-existing anti-therapy
Immune desert: PD=L does not work for them
COMBINATION THERAPY: BLOCK TUMOR INVASION THEN STIMULATE IMMUNE RESPONSE — IT WILL WORK
PD blockage + nutrients and probiotic
Tumor Genome Therapy
Tumore Immuno-evasion Score
Antigens for immune response – choose the ones
20PD-1 or PD-L1 drugs in development
WHO WILL THE DRUG WORK FOR?
Arlene Sharpe, the George Fabyan Professor of Comparative Pathology, Harvard Medical School; senior scientist, department of pathology, Brigham and Women’s Hospital – Multi-faceted Functionsof the PD-1 Pathway
function of the pathway: control T cell activation and function of maintain immune tolerance
protect tissues from damage by immune response
T cell dysfunction during cancer anf viral infection
protection from autoimmunity, inflammation,
Mechanism by which PD-1 pathway inhibits anti-tumor immunity
regulation of memoryT cell responce of PD-1
PD-1 signaling inhibit anti-tumor immunity
Compare: Mice lacking CD8-Cre- (0/5) cleared vs PD-1-/-5/5 – PD-1 DELETION: PARTIAL AND TIMED: DELETION OF PD-1 ON HALF OG TILS STARTING AT DAY 7 POSTTUMOR IMPLANTATION OF BOTH PD-1 AND PD-1 TILS: – Tamoxifen days 7-11
Transcription profile: analysis of CD8+ TILs reveal altered metabolism: Fatty Acid Metabolism vs Oxidative Phosphorylation
DOes metabolic shift: WIld type mouth vs PD-1-/_ P14: analyze Tumor cell killingPD-1-/- enhanced FAO increases CD8+ T cell tocicity
Summary: T cell memory development and PD-1: T effectors vs T cell memory: Primary vs Secondary infection: In the absent of PD-1, CD8+ T cels show increase expansion of T cells
INFLUENZA INFECTION: PRIMARY more virus in lung in PD-1 is lacking
Acute infection: PD-1 controls memory T cell differentiation vs PD-1 increase expansion during effector phase BUT impaired persistence during memory phase: impaired cytokine production post re-challenge
PD-1 immunotherapy work for patients with tumor: Recall Response and Primary response
TIL density Primary vs Long term survivor – 5 days post tumor implantation – rechallenged long term survival
Hot tumor vs Cold tumor – Deletion of PD-1 impairs T memory cell development
Opening Remarks: George Q. Daley, MD, PhD, DEAN, HMS
Scientific collaboration check point – avoid the body attacking itself, sabotaging the immune system
1987 – Vaccine for HepB
Eight of the awardees got the Nobel Prize
Moderated by Joan Brugge, PhD, HMS, Prof. of Cell Biology
Evolution of concepts of Immunotherapy: William Coley’s Toxin streptoccocus skin infection.
20th century: Immuno-surveilence, Immune response – field was dead in 1978 replaced by Immunotherapy
Rosenberg at NIH, high dose of costimulatory molecule prevented tumor reappearanceantbody induce tumor immunity–>> immune theraphy by check point receptor blockade – incidence of tumor in immune compromised mice – transfer T cell
T cell defficient, not completely defficient, self recognition of tumor,
suppress immmune – immune evasion
Michael Atkins, MD, Detupy Director, Georgetown-Lombardi, Comprehensive Cancer Center Clinical applications of Checkpoint inhibitors: Progress and Promise
Overwhelm the Immune system, hide, subvert, Shield, defend-deactivating tumor trgeting T cells that ATTACK the immune system
Immune system to TREAT the cancer
Monotherapy – anti PD1/PD-L1: Antagonist activity
Evading immune response: prostate, colcn
MMR deficiency
Nivolumab in relaped/Refractory HODGKIN LYMPHOMAS – over expression of PD-L1 and PDL2in Lymphomas
18 month survival better with Duv in Lung cancer stage 3 – anti PD-1- adjuvant therapy with broad effectiveness
Biomarkers for pD-L1 Blockage
ORR higher in PD-L1
Improve Biomarkers: Clonality of T cells in Tumors
T-effector Myeloid Inflammation Low – vs Hogh:
Biomarker Model: Neoantigen burden vs Gene expression vs CD8+
Tissue DIagnostic Labs: Tumor microenveironmenr
Microbiome
Combination: Nivo vs Nivo+Ipi is superior: DETERMINE WHEN TO STOP TREATMENT
15/16 stopped treatment – Treatment FREE SURVIVAL
Sequencing with Standard Therapies
Brain metastasis – Immune Oncology Therapy – crosses the BBB
Less Toxic regimen, better toxicity management,
Use Immuno therapy TFS
combination – survival must be justified
Goal: to make Cancer a curable disease vs cancer becoming a CHronic disease
Closing Remarks: George Q. Daley, MD, PhD, DEAN, HMS
The honorees will share a $500,000 prize and will be recognized at a day-long symposium on Oct. 5 at Harvard Medical School.
The Warren Alpert Foundation, in association with Harvard Medical School, honors trailblazing scientists whose work has led to the understanding, prevention, treatment or cure of human disease. The award recognizes seminal discoveries that hold the promise to change our understanding of disease or our ability to treat it.
“The discoveries honored by the Warren Alpert Foundation over the years are remarkable in their scope and potential,” said George Q. Daley, dean of Harvard Medical School. “The work of this year’s recipients is nothing short of breathtaking in its profound impact on medicine. These discoveries have reshaped our understanding of the body’s response to cancer and propelled our ability to treat several forms of this recalcitrant disease.”
The Warren Alpert Foundation Prize is given internationally. To date, the foundation has awarded nearly $4 million to 59 scientists. Since the award’s inception, eight honorees have also received a Nobel Prize.
“We commend these five scientists. Allison, Chen, Freeman, Honjoand Sharpe are indisputable standouts in the field of cancer immunology,” said Bevin Kaplan, director of the Warren Alpert Foundation. “Collectively, they are helping to turn the tide in the global fight against cancer. We couldn’t honor more worthy recipients for the Warren Alpert Foundation Prize.”
The 2017 award: Unraveling the mysterious interplay between cancer and immunity
Understanding how tumor cells sabotage the body’s immune defenses stems from the collective work of many scientists over many years and across multiple institutions.
Each of the five honorees identified key pieces of the puzzle.
The notion that cancer and immunity are closely connected and that a person’s immune defenses can be turned against cancer is at least a century old. However, the definitive proof and demonstration of the steps in this process were outlined through findings made by the five 2017 Warren Alpert prize recipients.
Under normal conditions, so-called checkpoint inhibitor molecules rein in the immune system to ensure that it does not attack the body’s own cells, tissues and organs. Building on each other’s work, the five award recipients demonstrated how this normal self-defense mechanism can be hijacked by tumors as a way to evade immune surveillance and dodge an attack. Subverting this mechanism allows cancer cells to survive and thrive.
A foundational discovery made in the 1980s elucidated the role of a molecule on the surface of T cells, the body’s elite assassins trained to seek, spot and destroy invaders.
A protein called CTLA-4 emerged as a key regulator of T cell behavior—one that signals to T cells the need to retreat from an attack. Experiments in mice lacking CTLA-4 and use of CTLA-4 antibodies demonstrated that absence of CTLA-4 or blocking its activity could lead to T cell activation and tumor destruction.
Subsequent work identified a different protein on the surface of T cells—PD-1—as another key regulator of T cell response. Mice lacking this protein developed an autoimmune disease as a result of aberrant T cell activity and over-inflammation.
Later on, scientists identified a molecule, B7-H1, subsequently renamed PD-L1, which binds to PD-1, clicking like a key in a lock. This was followed by the discovery of a second partner for PD-1—the molecule PD-L2—which also appeared to tame T-cell activity by binding to PD-1.
The identification of these molecules led to a set of studies showing that their presence on human and mouse tumors rendered the tumors resistant to immune eradication.
A series of experiments further elucidated just how tumors exploit the interaction between PD-1 and PD-L1 to survive. Specifically, some tumor cells appeared to express PD-L1, essentially “wrapping” themselves in it to avoid immune recognition and destruction.
Additional work demonstrated that using antibodies to block this interaction disarmed the tumors, rendering them vulnerable to immune destruction.
Collectively, the five scientists’ findings laid the foundation for antibody-based therapies that modulate the function of these molecules as a way to unleash the immune system against cancer cells.
Antibody therapy that targets CTLA-4 is currently approved by the FDA for the treatment of melanoma. PD-1/PD-L1 inhibitors have already shown efficacy in a broad range of cancers and have been approved by the FDA for the treatment of melanoma; kidney; lung; head and neck cancer; bladder cancer; some forms of colorectal cancer; Hodgkin lymphoma and Merkel cell carcinoma.
In their own words
“I am humbled to be included among the illustrious scientists who have been honored by the Warren Alpert Foundation for their contributions to the treatment and cure of human disease in its 30+ year history. It is also recognition of the many investigators who have labored for decades to realize the promise of the immune system in treating cancer.” -James Allison
“The award is a great honor and a wonderful recognition of our work.” –Lieping Chen
“I am thrilled to have made a difference in the lives of cancer patients and to be recognized by fellow scientists for my part in the discovery of the PD-1/PD-L1 and PD-L2 pathway and its role in tumor immune evasion. I am deeply honored to be a recipient of the Alpert Award and to be recognized for my part in the work that has led to effective cancer immunotherapy. The success of immunotherapy has unleashed the energies of a multitude of scientists to further advance this novel strategy.” -Gordon Freeman
“I am extremely honored to receive the Warren Alpert Foundation Prize. I am very happy that our discovery of PD-1 in 1992 and subsequent 10-year basic research on PD-1 led to its clinical application as a novel cancer immunotherapy. I hope this development will encourage many scientists working in the basic biomedical field.” -Tasuku Honjo
“I am truly honored to be a recipient of the Alpert Award. It is especially meaningful to be recognized by my colleagues for discoveries that helped define the biology of the CTLA-4 and PD-1 pathways. The clinical translation of our fundamental understanding of these pathways illustrates the value of basic science research, and I hope this inspires other scientists.” -Arlene Sharpe
Previous winners
Last year’s award went to five scientists who were instrumental in the discovery and development of the CRISPR bacterial defense mechanism as a tool for gene editing. They were RodolpheBarrangou of North Carolina State University, Philippe Horvath of DuPont in Dangé-Saint-Romain, France, Jennifer Doudna of the University of California, Berkeley, Emmanuelle Charpentier of the Max Planck Institute for Infection Biology in Berlin and Umeå University in Sweden, and Virginijus Siksnys of the Institute of Biotechnology at Vilnius University in Lithuania.
Other past recipients include:
Tu Youyou of the China Academy of Chinese Medical Science, who went on to receive the 2015 Nobel Prize in Physiology or Medicine with two others, and Ruth and Victor Nussenzweig, of NYU Langone Medical Center, for their pioneering discoveries in chemistry and parasitology of malaria and the translation of their work into the development of drug therapies and an anti-malarial vaccine.
Oleh Hornykiewicz of the Medical University of Vienna and the University of Toronto; Roger Nicoll of the University of California, San Francisco; and Solomon Snyder of the Johns Hopkins University School of Medicine for research into neurotransmission and neurodegeneration.
David Botstein of Princeton University and Ronald Davis and David Hogness of Stanford University School of Medicine for contributions to the concepts and methods of creating a human genetic map.
Alain Carpentier of Hôpital Européen Georges-Pompidou in Paris and Robert Langer of MIT for innovations in bioengineering.
Harald zur Hausen and Lutz Gissmann of the German Cancer Research Center in Heidelberg for work on the human papillomavirus (HPV) and cancer of the cervix. Zur Hausenand others were honored with the Nobel Prize in Physiology or Medicine in 2008.
The Warren Alpert Foundation
Each year the Warren Alpert Foundation receives between 30 and 50 nominations from scientific leaders worldwide. Prize recipients are selected by the foundation’s scientific advisory board, which is composed of distinguished biomedical scientists and chaired by the dean of Harvard Medical School.
Warren Alpert (1920-2007), a native of Chelsea, Mass., established the prize in 1987 after reading about the development of a vaccine for hepatitis B. Alpert decided on the spot that he would like to reward such breakthroughs, so he picked up the phone and told the vaccine’s creator, Kenneth Murray of the University of Edinburgh, that he had won a prize. Alpert then set about creating the foundation.
To award subsequent prizes, Alpert asked Daniel Tosteson (1925-2009), then dean of Harvard Medical School, to convene a panel of experts to identify scientists from around the world whose research has had a direct impact on the treatment of disease.
Koch Institute Immune Engineering Symposium on October 16 & 17, 2017, Kresge, MIT
Reporter: Aviva Lev-Ari, PhD, RN
Koch Institute Immune Engineering Symposium on October 16 & 17, 2017.
Summary: Biological, chemical, and materials engineers are engaged at the forefront of immunology research. At their disposal is an analytical toolkit honed to solve problems in the petrochemical and materials industries, which share the presence of complex reaction networks, and convective and diffusive molecular transport. Powerful synthetic capabilities have also been crafted: binding proteins can be engineered with effectively arbitrary specificity and affinity, and multifunctional nanoparticles and gels have been designed to interact in highly specific fashions with cells and tissues. Fearless pursuit of knowledge and solutions across disciplinary boundaries characterizes this nascent discipline of immune engineering, synergizing with immunologists and clinicians to put immunotherapy into practice.
SPEAKERS:
Michael Birnbaum – MIT, Koch Institute
Arup Chakraborty – MIT, Insititute for Medical Engineering & Sciences
Jianzhu Chen – MIT, Koch Institute
Jennifer R. Cochran – Stanford University
Jennifer Elisseeff – Johns Hopkins University
K. Christopher Garcia – Stanford University
George Georgiou – University of Texas at Austin
Darrell Irvine – MIT, Koch Institute
Tyler Jacks – MIT, Koch Institute
Doug Lauffenburger – MIT, Biological Engineering and Koch Institute
Wendell Lim – University of California, San Francisco
Harvey Lodish – Whitehead Institute and Koch Institute
Marcela Maus – Massachusetts General Hospital
Garry P. Nolan – Stanford University
Sai Reddy – ETH Zurich
Nicholas Restifo – National Cancer Institute
William Schief – The Scripps Research Institute
Stefani Spranger – MIT, Koch Institute
Susan Napier Thomas – Georgia Institute of Technology
“I am humbled to be included among the illustrious scientists who have been honored by the Warren Alpert Foundation for their contributions to the treatment and cure of human disease in its 30+ year history. It is also recognition of the many investigators who have labored for decades to realize the promise of the immune system in treating cancer.”
“The award is a great honor and a wonderful recognition of our work.”
“I am extremely honored to receive the Warren Alpert Foundation Prize. I am very happy that our discovery of PD-1 in 1992 and subsequent 10-year basic research on PD-1 led to its clinical application as a novel cancer immunotherapy. I hope this development will encourage many scientists working in the basic biomedical field.”
“I am truly honored to be a recipient of the Alpert Award. It is especially meaningful to be recognized by my colleagues for discoveries that helped define the biology of the CTLA-4 and PD-1 pathways. The clinical translation of our fundamental understanding of these pathways illustrates the value of basic science research, and I hope this inspires other scientists.”
2012pharmaceutical
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