LIVE Day Two – Koch Institute 2019 Immune Engineering Symposium, January 29, 2019, Kresge Auditorium, MIT
Real Time Press Coverage: Aviva Lev-Ari, PhD, RN
#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 2, 1/29, 2019:
Session IV
Moderator: Michael Birnbaum, Koch Institute, MIT
Jamie Spangler (John Hopkins University)
“Reprogramming anti-cancer immunity through molecular engineering”
- Reprogramming anti-cancer immunity response through molecular engineering”
- Cytokines induce receptor dimerization
- Clinical Use of cytokines: Pleiotropy, expression and stability isssues
- poor pharmacological properties
- cytokine therapy: New de novo protein using computational methods
- IL-2 signals through a dimeric nad a trimeric receptor complex
- IL-2 pleiotropy hinders its therapeutic efficacy
- IL-2 activate immunosuppression
- potentiation of cytokine activity by anti-IL-2 antibody selectivity
- Cytokine binding – Antibodies compete with IL-2 receptor subunits
- IL-2Ralpha, IL-2 Rbeta: S4B6 mimickry of alpha allosterically enhances beta
- stimulates both Effectors and T-regs
- JES6-1 immunocomplex selectively stimulates IL-2Ralpha cells
- Engineering translational single-chain cytokine/antibody fusion
- Engineering an EFFECTOR cell-based immunocytokine (602)
- JES6-1 Immunocytokine – inhibiting melanoma
- Engineering a Treg cell-biased immunocytokine
- double mutant immunocytokine shows enhanced IL-2Ralpha exchange
- Affinity – molecular eng De Novo design of a hyper-stable, effector biased IL-2
- De novo IL-2 poteniator in therapeutic superior to the natural cytokine by molecular engineering
Bryan Bryson (MIT, Department of Biological Engineering)
“Exploiting the macrophage axis in Mycobacterium tuberculosis (Mtb) infection”
- TB – who develop Active and why?
- Immunological life cycle of Mtb
- Global disease Mtb infection outcome varies within individual host
- lesion are found by single bacteria
- What are the cellular players in immune success
- MACROPHAGES – molecular signals enhancing Mtb control of macrophages
- modeling the host- macrophages are plastic and polarize
- Building “libraries” – surface marker analysis of Microphages
- Polarized macrophages are functionally different
- quant and qual differences
- History of GM-CSF suppresses IL-10
- Loss of polarization potential: scRNAseq reveals transcriptional differences Thioredoxin facilitates immune response to Mtb is a marker of an inflammatory macrophage state
- functional spectrum of human microphages
Facundo Batista (Ragon Institute (HIV Research) @MGH, MIT and Harvard)
“Vaccine evaluation in rapidly produced custom humanized mouse models”
- Effective B cell activation requires 2 signals Antigen and binding to T cell
- VDJ UCA (Unmutated common Ancestor)
- B Cell Receptor (BCR) co-receptors and cytoskeleton
- 44% in Women age 24-44
- Prototype HIV broadly neutralizing Antibodies (bnAb) do not bind to Env protein – Immunogen design and validation
- Target Identification –>> Immunogen Design –>>> Immunogen Validation
- Human Ig Knock-ins [Light variable 5′ chain length vs 7′ length] decisive to inform immunogenicity – One-Step CRISPR approach does not require ES cell work
- Proof of principle with BG18 Germline Heavy Chain (BG18-gH) High-mannose patch – mice exhibit normal B cell development
- B cells from naive human germline BG18-gH bind to GT2 immunogen
- GT2-nanoparticle 9NP) induces robust BG18-gH-500 cells: CD45.2 GL7 IgD
- Interrogate immune response for HIV, Malaria, Zika, Flu
Session V
Moderator: Dane Wittrup, Koch Institute, MIT
Yvonne Chen (University of California, Los Angeles)
“Engineering smarter and stronger T cells for cancer immunotherapy”
- Adoptive T-Cell Therapy
- Tx for Leukemia – Tumor Antigen escape fro CAR T-cell therapy, CD19/CD20 OR-Gate CARs for prevention of antigen escape – 15 month of development
- reduce probability of antigen escape due to two antigen CD19/CD20: Probing limits of modularity in CAR design
- In vivo model: 75% wild type & 25% CD19 – relapse occur in the long term, early vs late vs no relapse: Tx with CAR t had no relapse
- OR-Gate cause no relapse – Probing limits of modularity in CAR Design
- Bispecific CARs are superior to DualCAR: One vs DualCAR (some remained single CAR)
- Bispecific CARs exhibit superior antigen-stimulation capacity – OR-Gate CAR Outperforms Single-Input CARs
- Lymphoma and Leukemia are 10% of all Cancers
- TGF-gamma Rewiring T Cell Response
- Activation of t Cell use CAR t
- Engineer CAR-T to respond to soluble form of antigens: CD19 CAR Responds to soluble CD19
- GFP MCAR responds to Dimeric GFP
- “Tumor microenvironment is a scary place”
Michael Birnbaum, MIT, Koch Institute
“A repertoire of protective tumor immunity”
- Decoding T and NK cell recognition – understanding immune recognition and signaling function for reprogramming the Immune system – Neoantigen vaccine pipeline
- Personal neoantigen vax improve immunotherapy
- CLASS I and CLASS II epitomes: MHC prediction performance – more accurate for CLASS I HLA polymorphisms
- Immune Epitope DB and Analysis Resources 448,630 Peptide Epitomes
- B cell assay: 413,000
- T cell assays: 313,000
- peptide sequence relationships – naturally occurring antigen predictions
- Cleavable pMHC yeast display to determine peptide loading
- HLA-DR4 libraries enrich a large collection of peptides: 96000 1/5 of entire peptide DB: Enriched motif, prediction algorithms
- Algorithmic false negatives vs peptide concentration(nM)
- HLA-DR4 effects outside of “peptide anchor” residues
- Class I MHC – HLA-E down regulate T and NK cells
- Receptor Binding: Positional preferences noted for NKG2A
- Training data vs Algorithmic approach
- Globally oriented –
- TCR sequencing – TCR pairings – Multicell-per-well sequencing
- MAD-HYPE algorithm
Glenn Dranoff, Novartis Institute for Biomedical Research
“Mechnism of protective tumor immunity”
- Immune checkpoint blockade elicit 10 years survival in melanoma
- PD-1 blockage esophageal carcinoma effective showing survival
- renal cells, bladder
- 20% benefit from Immuno therapy – CTLA-4 toxicity is high small % patient benefit
- PD-1/PD-L1 anti CLTA-4 mAbs
- solid tumors challenging
- Requirement for effective IO – Tumor receptivity to immune infiltration
- modulation
- Novartis IO in the clinic: multiple tumor immune escape – complexity
- Approach: focus trials aimed to learn immune response complementation groups manipulate into response
- work with Engineering for delivery nimble to generate new data
- Translational research in the clinic
- CAR T cells
- B cell malignancies are ideal targets for CAR T cells
- Relapsed/Refractory – pediatric ALL refractory advanced to no relapse – complete response 80% – 6 years response
- Antigen loss CD19 – targeting with combinatorial approach to avoid relapse
- Large B cell lymphoma
- Neurologic toxicities of CART t IL-6 activation
- AML – complete response – weekly dose of XmAb CD123X CD3 bispecific antibody – protein engineering – anti tumor effect in refractory Leukemia
- anaplastic thyroid carcinoma
- PD-L1 blockade elicits responses in some patients: soft part sarcoma
- LAG-3 combined with PD-1 – human peripheral blood tumor
- TIM-3 key regulator of T cell and Myeloid cell function: correlates in the TCGA DB with myeloid
- Adenosine level in blood or tissue very difficult to measure in blood even more than in tissue – NIR178 + PDR 001 Mono-therapy (NIR178) combine with PD receptor blockage (PDR) – shows benefit
- A alone vs A+B in Clinical trial
Session VI
Moderator: Stefani Spranger, Koch Institute, MIT
Tim Springer, Boston Children’s Hospital, HMS
The Milieu Model for TGF-Betta Activation”
- Protein Science – Genomics with Protein
- Antibody Initiative – new type of antibodies not a monoclonal antibody – a different type
- Pro TGF-beta
- TGF-beta – not a typical cytokine it is a prodamine for Mature growth factor — 33 genes mono and heterogeneous dimers
- Latent TGF-Beta1 crystal structure: prodomaine shields the Growth Factor
- Mechanism od activation of pro-TGF-beta – integrin alphaVBeta 6: pro-beta1:2
- Simulation in vivo: actin cytoskeleton cytoplasmic domain
- LIFE CYCLE OF PROTGF-BETA
- LRRC33 – GARP class relative
- microglia and macrophage – link TGF-beta phenotype knock outs
- TGF compartments of microglia separated myelination loss
- Inhibition of TGF-beta enhances immune checkpoint
- Loss of LRRC33-dependent TGF-beta signaling would counteract immune suppression in tumor and in slow tumor growth
- lung metastasis of B16 in melanoma
- immuno-histo-chemistry: LRRC33 tumor-associated myeloid cell lack cell surface proTGF-beta1
- blocking antibodies LRRC33 mitigate toxicity on PD-L1 treatment
Alex Shalek, MIT, Department of Chemistry, Koch Institute
“Identifying and rationally modulating cellular drivers of enhanced immunity”
- Balance in the Immune system
- Profiling Granulomas using Seq-Well 2.0
- lung tissue in South Africa of TB patients
- Granulomas, linking cell type abundance with burden
- Exploring T cells Phenotypes
- Cytotoxic & Effector ST@+ Regulatory
- Vaccine against TB – 19% effective, only 0 IV BCG vaccination can elicit sterilizing Immunity
- Profiling cellular response to vaccination
- T cell gene modules across vaccine routes
- T Cells, Clusters
- Expression of Peak and Memory
- Immunotherapy- Identifying Dendritic cells enhanced in HIV-1 Elite Controllers
- moving from Observing to Engineering
- Cellular signature: NK-kB Signaling
- Identifying and testing Cellular Correlates of TB Protection
- Beyond Biology: Translation research: Data sets: dosen
Session VII
Moderator: Stefani Spranger, Koch Institute, MIT
Diane Mathis, Harvard Medical School
“Tissue T-regs”
- T reg populations in Lymphoid Non–lymphoid Tissues
- 2009 – Treg tissue homeostasis status – sensitivity to insulin, 5-15% CD4+ T compartment
- transcriptome
- expanded repertoires TCRs
- viceral adipose tissue (VAT) – Insulin
- Dependencies: Taget IL-33 its I/1r/1 – encoded Receptor ST2
- VAT up-regulate I/1r/1:ST2 Signaling
- IL-33 – CD45 negative CD31 negative
- mSC Production of IL-33 is Important to Treg
- The mesenchyme develops into the tissues of the lymphatic and circulatory systems, as well as the musculoskeletal system. This latter system is characterized as connective tissues throughout the body, such as bone, muscle and cartilage. A malignant cancer of mesenchymal cells is a type of sarcoma.
- mesenchymal Stromal Cells – mSC – some not all, VAT mSCs express IL-33
- development of a mAb Panel for sorting the mSC Subtypes
- Deeper transcriptome for Phenotyping of VAT mSCs
- physiologic & pathologic perturbation
- Age-dependent Treg and mSC changes – Linear with increase in age
- Sex-dependent Treg and mSC changes – Female
- Treg loss in cases of Obesity leading to fibrosis
- Treg keep IL-33-Producing mSCs under rein
- Lean tissue vs Obese tissue
- Aged mice show poor skeletal muscle repair – it is reverses by IL-33 Injection
- Immuno-response: target tissues systemic T reg
- Treg and mSC
Aviv Regev, Broad Institute; Koch Institute
“Cell atlases as roadmaps to understand Cancer”
- Colon disease UC – genetic underlining risk, – A single cell atlas of healthy and UC colonic mucosa inflammed and non-inflammed: Epithelial, stromal, Immune – fibroblast not observed in UC colon IAFs; IL13RA2 + IL11
- Anti TNF responders – epithelial cells
- Anti TNF non-responders – inflammatory monocytes fibroblasts
- RESISTANCE to anti-cancer therapy: OSM (Inflammatory monocytes-OSMR (IAF)
- cell-cell interactions from variations across individuals
- Most UC-risk genes are cell type specific
- Variation within a cell type helps predict GWAS gene functions – epithelial cell signature – organize US GWAS into cell type specific – genes in associated regions: UC and IBD
- Melanoma
- malignant cells with resistance in cold niches in situ
- cells express the resistance program pre-treatment: resistance UP – cold
- Predict checkpoint immunotherapy outcomes
- CDK4/6 – computational search predict as program regulators: abemaciclib in cell lines
Poster Presenters
Preeti Sharma, University of Illinois
T cell receptor and CAR-T engineering – T cell therapy
- TCR Complex: Vbeta Cbeta P2A Valpha Calpha
- CAR-T Aga2 HA scTCR/scFv c-myc
- Directed elovution to isolate optimal TCR or CAR
- Eng TCR and CARt cell therapy
- Use of TCRs against pep/MHC allows targeting a n array of cancer antigens
- TCRs are isolated from T cell clones
- Conventional TCR identification method vs In Vitro TCR Eng directed evolution
- T1 and RD1 TCRs drive activity against MART-1 in CD4+ T cells
- CD8+
- TCR engineering for Targeting glycosylated cancer antigens
- Normal glycosylation vs Aberrant glycosylation
- Engineering 237-CARs libraries with conjugated (Tn-OTS8) against multiple human Tn-antigend
- In vitro engineering: broaden specificity to multiple peptide backbone
- CAR engineering collaborations with U Chicago, U Wash, UPenn, Copenhagen, Germany
Martin LaFleur, HMS
CRISPR- Cas9 Bone marrow stem cells for Cancer Immunotherapy
- CHIME: CHimeric IMmune Editing system
- sgRNA-Vex
- CHIME can be used to KO genes in multiple immune lineages
- identify T cell intrinsic effects in the LCMV model Spleen-depleted, Spleen enhanced
- Loss of Ptpn2 enhances CD8+ T cell responses to LCMV and Tumors
- Ptpn2 deletion in the immune system enhanced tumor immunity
- CHIME enables in vivo screening
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