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LIVE Day One – Koch Institute 2019 Immune Engineering Symposium, January 28, 2019, Kresge Auditorium, MIT

Reporter: Aviva Lev-Ari, PhD, RN

Real Time Press Coverage: Aviva Lev-Ari, PhD, RN

• Confirmation Number: PVNYDMS4FND

• Pamela Difraia pdifraia@mit.edu

#IESYMPOSIUM @pharma_BI @AVIVA1950

MISSION The mission of the Koch Institute (KI) is to apply the tools of science and technology to improve the way cancer is detected, monitored, treated and prevented.

APPROACH We bring together scientists and engineers – in collaboration with clinicians and industry partners – to solve the most intractable problems in cancer. Leveraging MIT’s strengths in technology, the life sciences and interdisciplinary research, the KI is pursuing scientific excellence while also directly promoting innovative ways to diagnose, monitor, and treat cancer through advanced technology.

HISTORY The Koch Institute facility was made possible through a $100 million gift from MIT alumnus David H. Koch. Our new building opened in March 2011, coinciding with MIT’s 150th anniversary. Our community has grown out of the MIT Center for Cancer Research (CCR), which was founded in 1974 by Nobel Laureate and MIT Professor Salvador Luria, and is one of seven National Cancer Institute-designated basic (non-clinical) research centers in the U.S.

https://ki.mit.edu/files/ki/cfile/news/presskit/KI_Fact_Sheet_-_February_2018.pdf

January 28-29, 2019
Kresge Auditorium, MIT

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.

The 2019 symposium will include two poster sessions and four abstract-selected talks. Abstracts should be uploaded on the registration page. Abstract submission deadline is November 15, 2018. Registration closes December 14.

Featuring on Day 1, 1/28, 2019:

Dane Wittrup,, Koch Institute, MIT

IMMUNE BIOLOGY,

7 — Stephanie Dougan (Dana-Farber Cancer Institute) HMS, Department of Virology

• Shared antigens may be the only option for many patients
• Pathogens, self-antigens, tumor neoantigens, shared coexpressed
• T cell affinity low or high TCRs – Augment priming
• Radiation plus anti-CD40 induces vigorous T cell priming
• TNF family co-stimulatory receptor signaling can be mimicked by IAP antagonists
• SMACK – c-IAP12 – IAPi enhances function of many immune cells: B Cells, Dendritic cells,
• Pancreatic cancer cell immunologic memory : Primary challenge, re-challenge
• IAPi outperforms checkpoint blockade in T cell cold tumors
• reduction of tumor burden gencitabine cross-presenting DCs and CD8 T cells – T cell low 6694c2
• IAPi is a T cell-dependent immunotherapy in pancreatic cancer: MHC class I and IFN gemma sensing by tumor cells are critical for endogenous anti-tumor immunity and response to checkpoint blockade
• T cells are catalytic, they can kill some tumors not all – Genes deleted in tumor cells
• Intratumoral phagocytes are critical for endogenous: IAP antagonism increases phagocytosis in vivo
• Model: T cells provide antigen specificity for sustained innate immune response
• Antigen and adjuvants

12 — Michael Dustin (University of Oxford)

Delivery of T cell Effector function through extracellular vesicles

• Laterally mobile ligands track receptor interaction
• ICAM-1
• Signaling of synapse – Sustain signaling by transient in microclusters TCR related to Invadipodia
• Synaptic ectosome biogenisis Model: T cells: DOpamine cascade in germinal cell delivered to synaptic cleft – Effector CD40 – Transfer is cooperative
• Synaptic ectosome composition
• ESCRT pathway associated with synaptic ectosomes
• Locatization, Microscopy (STORM, PALM, GSD)
• Updated Model T cells Exosome transport Cytotoxic T cell granules CTLs release extracellular vescicles similar to T Helper with perforin and granzyme – CTL vesicles kill targets

6 — Darrell Irvine (MIT, Koch Institute; HHMI)

Innate immune recognition of glycosylation in nano particle vaccines

• HIV Vaccines: Why is it such a challenge
• HIV vaccine – Immunogen design – CD4 binding site-targeting
• rational for nanoparticles forms of env immunogens
• eOD-60mer nanoparticles vs Ferritin-trimer 8-mer
• Nanoparticle delivery increases anti-Env titers substantially
• Nanoparticles delivery accelerate the lymphatic system drainage
• Immunogens drives to lymph nodes: nanoparticles changes environment in the lumph nodes
• kidney medula – lymphatic system drainage
• Liposome conjugate allows SOSIP – the germinal center:m training ground for immune response
• nanoparticle – mechanism of germinal center targeting
• GC targeting is dependent on complement component CIQ – activation: Mannose-binding lectins recognize eOD-60mer but not eOD monomer or trimers
• Engineering follicle delivery through synthetic glycans: eOD-60mer nanoparticles vs Ferritin-trimer 8-mer (density dependent)
• SUMMARY – HIV env nanopartices activate a bridge between innate and adaptive immunity
• Multiple formulations of nanoparticles shows rapid immune response, comparison with influenza vaccine

2 — Tyler Jacks (MIT, Koch Institute; HHMI) – Tumor Biology Lab

Exploring tumor-immune interactions with genetically engineered Cancer Models – A case of Lung Cancer

• Factors controlling tumor progression – genetically-engineered model of lung adenocarcinoma, metastasis causing death
• Infiltration of cells: SEQUENCE EXOME – NO TUMOR BURDEN,
• Exome sequencing reveals few mutations in KP model
• Programmed neoantogen expression in the KP model: Kras, p53 – both are well researched in Lung cancer – immune cell dependent – tumors escape immune response due to immunosuppression – regulatory T cells most important in this model system
• tissue specific responses to antigens
• Lung Cancer – late stage — Programmed neo-antigen expression
• Single cell mRNA sequencing of CD* T cell over time – sort cells, 8 weeks, 12 weeks, 20 weeks – progression of single cell similarity lymph cells vs lungs cells – cell identities  – transcription activation of dysfunction in cells
• SIIN+ CD8 T cells show markers of dysfunction over time – up regulated signs of exhaustion,
• T cells becomes exhausted, checkpoint inhibitors beyond a certain point – has no capacity  –
• Interrogating markers of T cell dysfunction – chance biology of cells by CRISPR Cas9 – EGR2 at 2 weeks dysfunctioning is reduced – presence of EDR2 mutant class plays a role in cell metabolism – cell becomes more functional by modification protocols
• Effects of CRISPR-mediated vs Combinatorial effects of CRISPR-mediated mutation of inhibitory models

8 — Max Krummel (University of California, San Francisco)

Dynamic Emergent behavior in Immune Systems

• T cells are captured on tumor margins (without desired cytotoxicity)
• Myeloid cells Underlie Intratumoral T cell capture
• Anti tumor (CD4 CD8) vs Pro-tumor (CD9)
• If many cells predicting Outcome more favorable – cellular abundance
• Alternative T Cell reactions in Tissue: T-Helper 1, T-Helper 2
• Gene expression association between two genes:
• NK and cDC1 numbers are tightly linked and correlated with response to checkpoint blockage
• A CD4-Enhaced Class of Melanoma Patients Also can be Checkpoint
• CD4 T cells in Cancer – control tumors on their on
• If high ICOS and CD4
• Stimulate CD4: pull out of lymph nodes cells mCD301B
• CD4 T cell proliferation but they don’t make PD1 ICOS CD4T
• CD4 – required: Regulatory T Cells control CS4-dependent Tumor control via Lymph Node depletion (dLN)
• If CD4 depleted, Lymph Node (LN) connected
• Regulatory of PD1 ICOS CD4T
• CD8 CD4 Tumor Affinity
• Melanoma – T-reg hi or low – Responders are T-reg hi they have CD8
• Existing Paired presence of T-reg, together with cDC2 number classifies Pt with better CD4
• In Head and Neck: DC needed to stimulate immune response by CD4
• Architypes of Immune systems in Tumors – Generally
• CLASS I, II, III, IV – phynotypic
• IMMUNE “ACCOMODATION” ARCHYTYPES: MYELOID TUNING OF ARCHITYPES
• Myeloid function and composition

11 — Mikael Pittet (Massachusetts General Hospital)

Myeloid Cells in Cancer

• complexity of Myeloid
• Myeloid cells for cancer therapy: Outcomes good and bad: Tumor suppressing vs Tumor Promoting
• Myeloid and immunotherapy
• aPD-1 mAbs do not bind IL-12+DCs (scRNAseq): DC Classical and PlasmaCytoid (Allon Klein)
• Indirect mechanism AFTER a-PD-1 Treatment
• IFN-gamma Sensing Fosters IL-12 & therapeutic Responses
• a PD-1-Mediated Activation of Tumor Immunity – Direct activation and the ‘Licensing’ Model

1 — Bob Schreiber (Wash University of St. Louis)

Neoantigens and the molecular basis of Cancer Immnutherapy

NeoAntigens (NEON Therapeutics, Co-Founder

• MHC- I, MCH-II, tumor specific vaccine, if BOTH present THEN Clinical therapeutic efficacy is enhanced
• Cancer Immunoediting to Personalized Cancer Vaccines
• neoedited Tumors,
• Tumor vaccines: Tumor Associated Antigens vs Tumor Specific Neoantigens
• MCH Class II Immune responses to Cancer
• CD4+
• Immune Checkpoint Blockade Therapy eliminates T3 Sarcomas via a CD4+ CD8+ T cell dependent Mechanism
• Control mAb vs (alphaPD-1 CTLA-4) vs (alphaPD-1 CTLA-4) + alpha CD8
• Mutant Class II Neoepitopes: mltgb1 is the best peptide found
• Cell Response CD4+ to T3
• T3 – Median Mutant Affinity Value vs Affinity + Abundance: Prediction N711Y Mutant
• MHC-II
• Oncogene-Driven (Kras – G12D-p53 -/- =KP
• KP Sarcomas  – do not Prime for their own rejection upon re-Challenge: Average Tumor Diameter
• KP Sarcomas lack Strong Class I Neoepitopes MCA Sarcoma vs KP Sarcomas: Mutant Affinity
• KP Sarcomas: Kras – G12D-p53
• MHC Class I and Class II: Promotes PRIMING of mLama4-Specific CD8+ T Cells when KP.mLama4 Tumors express the mltgb1
• mltgb1 enhances generation of mLama4-Specific CTL
• controls: (alpha-PD-1), (PD-1 + CD4+)
• Vaccine protects against T3 Outgrowth
• CONCLUSIONS: Optimal CD8+ T cells mediated immune responses to T3 sarcomas require CD4+ T cell help

9 — Stefani Spranger (MIT, Koch Institute)

The role of Tumor-resident Dendritic Cells for productive anti-tumor immune response

• CD8+ T cell T cell-inflamed Tumor vs Non-T cell inflamed Tumor
• Tumor cell intrinsic – Workflow to identify oncogenic pathways differentially activated between T cell-inflamed
• T cell infiltration (Braf PTEN CD3 T cells/total living cells
• Response to checkpoint blockade
• Non-T cell-inflamed – is LACK OF T CELL INFILTRATION – do not accumulate in Tumor,
• Tumor-intrinsic Beta-catenin signaling mediates lack of T cell infiltration
• Adoptive transfer of effector CT cells fails to control Beta – T cells remain motile and migrate in a directional fashion after tumor eradication
• CD103 dendritic cells – Tumor-residing Braf3-driven CD103
• Cross-presenting cDC1 are essential for effector T cells
• How can we raise the curve and increase the number of long-term survivors
• Understanding the role of tumor-resident DC
• Accumulation of CD103 DC independent of T cells
• Regression tumor mount T cell response independent of DC1 DC
• Induction of anti-tumor immunity is independent of the canonical
• Single cell RNA-Seq reveal new subset to regressiong tumors and stimulate T cells via non-conventional
• Working hypothesis: productive anti-tumor immunity depends on multiple tumor-resident DC subsets

5 — Melody Swartz (University of Chicago)

Lymphangiogenesis and immunomodulation

• Lymphangiogenesisfor in Inflammation
• Immunosuppression drives metastasis
• promotion of resolution in disease progression
• Tumors uses lymphatic system vessels
• Tumor VEGF-C enhances immune cell interactions with lymphatic system
• Lymphangiogenesis promore immune suppression in the tumor microenvironment
• Recruitment of immune cells system: Dendritic Cells,
• Lymphangiogenesis melanomas – highly responsive to immunotherapy : Vaccination
• Lymphangiogenesis promote antigen spreading
• Lymphangiogenesis potentiation: CCL21, CCR7
• Lymphangiogenesis attractive to Native T cells, in VEGF-C tumors
• T cell homing inhibitors vs block T cell egress inhibitors – Immunotherapy induces T cell killing
• Allergic airway inflammation is driven lung and lymph node Lymphangiogenesis
• Innate Immune cell infiltration reduced
• Memory recall responses reflect adaptive immunity
•  pathology exacerbated with VEGFR-3 blockade response of memory recall cell is enhanced
• VEGFR-3 signaling shifts T call balance, and CCL@1, from Lymph nodes to Lung
• Differential changes in T cell balance between lung vs adaptive immune response to allergic airway inflammation
• Lymphangiogenesis in the lung, competition with adaptive immune response to allergic airway inflammation in the lung

4 — Cathy Wu, Dana Farber Cancer Institute, HMS – CoFounder of NEON

Building better personal cancer vaccines

• Vaccine: up to 20 personalized neoantigens as SLPs with adjuvant (polyICLC)
• high risk melanoma – RESULTS: new immune responses – new responses mutiple immune responses CD4 & CD8: mutated vs Wild type  differences
• Enduring complete radiographic responses after Neovax + alpha-PD-1 treatment (anti-PD-1)
• NeoVax vs IVAC MutaNOME
• Ex vivo responses to assay peptide pools – immune response identified
• NeoVax: ‘warming’ a cold tumor
• immune cell infiltration – not studied in Glioblastoma which is a pooled tumor: TCR repertoire and MHC. Available materials: PBMC vs Fresh frozen and FFPE tumor material: Blood va FF brain tissue sequencing
• Pt 8 neoantigen-specific clonotypesID’s – reactive T cells track to the brain after vaccination
• Single cells from brain tissue vs single cells from neoantigen specific T cells – intratumoral neoantigen-specific T cells: mutARGAP35-specific T cell identified at site of disease – breakthrough for Brain Tumor #vaccine based neoantigen-specific T cell at intracranial site
• VAX steering the Immune system
• commission at Dana Farber – Prediction algorithms of denovo neoantigen targets: Newly profiled peptides to train a model vs peptide in the DB – Single vs Multi-allele HLA peptide sequencing by MassSpectroscopy
• Mono-allelic MS data reveals novel motifs and sub-motifs
• Endogenous signals contribution to predictive power
• NeuroNets Algoriths : Integrative models identify tumor-presented epitopes more accurately than models without training like NeuroNets
• 5778 class I peptides from 4 cancers class I allele
• CONCLUSIONS: proteosomal processing endogenous signals transcriptome

Poster Presenters

3 — Scott Wilson,  U of Chicago

Antigen-specific Tolerance: A Cure for Autoimmunity

• Activation of auto-reactive T cell
• Leveraging the Liver’s Tolerogenic Environment for the Induction of Antigen-specific Tolerance
• Design Criteria for HAPC- Targeting Platform – Target Antigens to HAPCs
• Minimal biomaterial footprint
• Deliver system Hepatic APC-targeting Glycosylations
• IV INJECTION: OVAALBUMIN OVA-P(GALINAC), P(GLCNAC), SUPRESS T CELL RESPONSE
• Glyco-conjucates Abate T cells response – Reduced cytokine production &  increased T-regs

1- — Noor Momin, MIT, Prof. K. Dane Wittrup Lab

The role of Collagen and Cytokines in Immunotherapy drug development

• Cytokine therapies have poor therapeutic windows
• Intratumoral Cytokine Delivery: Expectation vs Reality
• Anchor intratumorally adm cytokines to collagen and protein
• collagen abundent (toxicity) and long-lived (maximize efficacy)
• Lumican – homology model – mediate collagen-anchoring? How to mediate anchoring
• Lumican fusion to IL-2 improves treatment efficacy however toxic – Anti-TAA mAb – TA99 vs IL-2
• Best efficacy in Lumican-MSA-IL-2 vs MSA-IL2
• Lumican-cytokines improve control of distant lesions – Lumican-fusion potentiates systemic anti-tumor immunity
• Lumican-cytokines efficacious in Braf/Pten GEMM
• Lumican fusion cytokine IL-2 IL-12 Binds collagen