LIVE – OCTOBER 17 – DAY 2- 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
Image Source: Leaders in Pharmaceutical Business Intelligence (LPBI) Group
Aviva Lev-Ari, PhD, RN will be in attendance covering the event in REAL TIME
#IESYMPOSIUM
- 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 17 – DAY 2
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
- EBOV Vaccinee Peak ASCs (day 8) mining: Neutralization
- Features of the Serum Antibody Repertoire to Vaccine ANtigens:The Serum IgG Repertoire is Highly Polarized
- Each bar represents a distinct antibody lineage
- Serum IgG Repertoire becomes increasingly polarized with AGE >50 – may be predictive of tumor development process
- Human Norovirus – explosive Diarreha, chromically infected – HuNoV BNAb Discovery – Takeda 214 bivalent Vaccine – Binding antibodies binding to avccine antigen VLP
- 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
- Generation of immuno tolerance: SOruggable Mature RBCs: CRISPR mice expressing Kell-LPETG
- Ovalbumin as Model Antigens:
- OBI B,
- OTI CD8 T cells
- OTII CD4 T cells
- OT-1
- OT-2
- RBC induced peptides challenged and experiences apoptosis
- Type I Diabetes in NOD mice
- RBCs bearing InsB9-23 – prevented development of diabetes
Multiple sclerosis
- MOG – Myelin Oligodend
Sai Reddy – ETH Zurich
Molecular Convergence Patterns in Antibody Responses Predict Antigen Exposure
- Clonal diversity – estimating the size of antibody repertoire: 10 to power of 18 or 10 to 13
- Clonal selection in antibody repertoire
- Convergent selection in antibody repertoire
- Convergent selection in TCR repertoire complex have restriction with MCH interactions
- How molecular abundance of convergence predicts antigen exposure identify antigen-associated clusters #SaiReddy
- molecular convergence 0 gene expression analysis, immunization scheme molecular bar coding to correct errors
- Recoding antibody repertoire sequence space: Cross correlation reveals different clusters
- Building a classifier model based on cluster frequency: Clones from immunized mice
- epitope specificity is driving antibody repertoire response
- deep learning,
K. Dane Wittrup – MIT, Koch Institute
Temporal Programming of Synergistic Innate and Adaptive Immunotherapy
- Innate effector functions of anti-tumor antibodies
- Innate & adaptive Immunotherapy
- Innate mAb –>> tumor cell; adaptive CD8+ T cells
- Chemokines Antigens
- Cytokines Chemokines – back and forth innate Adaptive –> <— neutrophils impact
- AIPV vaccine:
- How anti-TAA mAbs helping T cell Immune response
- Anti-TAA mAbs drive vaccinal T cell responses: NK cells
- antibody drives T cells responses: alpha-TAA mAbs potentiate T cell therapies: ACT +MSA-IL-2 vs alphaPD-1 + vaccine
- CD8+ T cells required for alpha TAA mAb efficacy- In absence of T cells Treatment does not work
- Anti-TAA mAb +Fc/IL-2 induces intramural cytokine storm #KDaneWittrup
- How to simplify and improve AIPV? Hypothesis: ALign dose schedule
- Immune response to infection follwos a temporal progression: Innate … Adaptive
- Antigenic material kill cells: Chemo, cell death Antigen presentation, T cell priming, T cell recirculation, Lymphocyte tumor infiltrate, TCR
- IFN alpha 2 dys after mAb +Il-2: Curative: days post tumor injection
- Necessary components: CD8+ T cells & DC, Macrophages,
- Optimal IFNalpha coincides with max innate response vs Mature DCs after antigen loading #KDaneWittrup
- Optimal timing od agent administration effect on Therapy Outcome: IL-2, IFNalpha, TAAmAb
- Cytkine timing can be better than protein engineering #KDaneWittrup
11:30 – 1:00 Lunch Break
1:00 – 2:15 Session VII
Moderator: Michael Birnbaum | MIT, Koch Institute
Kai Wucherpfennig – Dana-Farber Cancer Institute
Discovery of Novel Targets for Cancer Immunotherapy
- POSITIVE STRESS SIGNAL during malignant Transformation
- NKG2G=D Receptor: MICA/B Results in Immune escape – Proteolytic cleavage shedding of MICA/B present in serum, indication of tumor progression
- Shed MICA vs Surface MICA/B – restore NK cell cytotoxicity and IFNgamma Production
- Human NK cells express NKG2D and Fc Receptors
- Synergistic NKG2D and CD16 signaling enhances NK cell cytootxicity: Control IgG vs Anti NKG2D
- MICA Antibody induces Immunity Against Lung Metastases
- NK cells are required to inhibit Growth of metastases: Anti-CD8beta,
- Contribution to Therapeutic Efficacy: NKG2D and CD16 Receptors #KaiWucherpfennig
- Strategy to analyze Pulmonary NK cells: Activation and expression
- Single cell RNA-seq of lung NK cells Revealed higher infiltration of activated NK cells: Isotype vs 7C6-migG2a
- Cytokines and Chemokines produce NK cells
- MICA/B increaces NK
- Induction of Tumor cell Apoptosis
- Xenotransplant Model with Human Melanoma Cel Line A2058
- Lung metastasis, liver metastasis
- Inhibition of human melanoma Metastases in NSG Mice Reconstitute with Human NK
- Liver metastases are controlled by Myeloid Cells that include Kupffer cells
Michael Birnbaum – MIT, Koch Institute
An Unbiased Determination of pMHC Repertoires for Better Antigen Prediction
- Vaccines TCR gene therapy adoptive T cel therapy
- Tumor genone – Tumor pMHC repertoire = Tumor TCR repertoire T cell repertoire
- Neoantigen vaccines as a personalized anti-cancer therapy
- Tumor procurement – Target selection – personal vaccine production – vaccine administration
- Prediction of neoantigen-MHC Binding due to polimorphism affecting recognition, rare in MHC Allells #Michael Birnbaum
- Antigenicity – Chaperones HLA-DM sculp the peptide binding repertoire of MHC
- Identification of loaded peptide ligands: pMHC mass spectroscopy of tissue
- TCR recognition, pMHC yeast display: Cleave peptide-MHC linker, catalyze peptide exchange
- 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
- Targeting Integrin = universal target involved 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
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