LIVE – OCTOBER 16 – DAY 1- Koch Institute Immune Engineering Symposium 2017, MIT, Kresge Auditorium
Reporter: Aviva Lev-Ari, PhD, RN
Image Source:Koch Institute
Koch Institute
Immune Engineering Symposium 2017
http://kochinstituteevents.cvent.com/events/koch-institute-immune-engineering-symposium-2017/agenda-64e5d3f55b964ff2a0643bd320b8e60d.aspx
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Image Source: Leaders in Pharmaceutical Business Intelligence (LPBI) Group
Aviva Lev-Ari, PhD, RN will be in attendance covering the event in REAL TIME
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@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:
- Immune Response (IR),
- 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
- 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
- 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
- resistence of T cell based IT due to loss of function mutations
- 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:
- subunits of the MHC Class I complex
- 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
- Immune response to bioscafolds
- 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
- 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
- Specific antigen targets
- tumor heterogeneity
- inhibitory microenvironment
- 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
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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