Advertisements
Feeds:
Posts
Comments

Archive for the ‘Human Naive B Cell Repertoire’ Category


Newly Found Functions of B Cell

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

The importance of B cells to human health is more than what is already known. Vaccines capable of eradicating disease activate B cells, cancer checkpoint blockade therapies are produced using B cells, and B cell deficiencies have devastating impacts. B cells have been a subject of fascination since at least the 1800s. The notion of a humoral branch to immunity emerged from the work of and contemporaries studying B cells in the early 1900s.

 

Efforts to understand how we could make antibodies from B cells against almost any foreign surface while usually avoiding making them against self, led to Burnet’s clonal selection theory. This was followed by the molecular definition of how a diversity of immunoglobulins can arise by gene rearrangement in developing B cells. Recombination activating gene (RAG)-dependent processes of V-(D)-J rearrangement of immunoglobulin (Ig) gene segments in developing B cells are now known to be able to generate an enormous amount of antibody diversity (theoretically at least 1016 possible variants).

 

With so much already known, B cell biology might be considered ‘‘done’’ with only incremental advances still to be made, but instead, there is great activity in the field today with numerous major challenges that remain. For example, efforts are underway to develop vaccines that induce broadly neutralizing antibody responses, to understand how autoantigen- and allergen-reactive antibodies arise, and to harness B cell-depletion therapies to correct non-autoantibody-mediated diseases, making it evident that there is still an enormous amount we do not know about B cells and much work to be done.

 

Multiple self-tolerance checkpoints exist to remove autoreactive specificities from the B cell repertoire or to limit the ability of such cells to secrete autoantigen-binding antibody. These include receptor editing and deletion in immature B cells, competitive elimination of chronically autoantigen binding B cells in the periphery, and a state of anergy that disfavors PC (plasma cell) differentiation. Autoantibody production can occur due to failures in these checkpoints or in T cell self-tolerance mechanisms. Variants in multiple genes are implicated in increasing the likelihood of checkpoint failure and of autoantibody production occurring.

 

Autoantibodies are pathogenic in a number of human diseases including SLE (Systemic lupus erythematosus), pemphigus vulgaris, Grave’s disease, and myasthenia gravis. B cell depletion therapy using anti-CD20 antibody has been protective in some of these diseases such as pemphigus vulgaris, but not others such as SLE and this appears to reflect the contribution of SLPC (Short lived plasma cells) versus LLPC (Long lived plasma cells) to autoantibody production and the inability of even prolonged anti-CD20 treatment to eliminate the later. These clinical findings have added to the importance of understanding what factors drive SLPC versus LLPC development and what the requirements are to support LLPCs.

 

B cell depletion therapy has also been efficacious in several other autoimmune diseases, including multiple sclerosis (MS), type 1 diabetes, and rheumatoid arthritis (RA). While the potential contributions of autoantibodies to the pathology of these diseases are still being explored, autoantigen presentation has been posited as another mechanism for B cell disease-promoting activity.

 

In addition to autoimmunity, B cells play an important role in allergic diseases. IgE antibodies specific for allergen components sensitize mast cells and basophils for rapid degranulation in response to allergen exposures at various sites, such as in the intestine (food allergy), nose (allergic rhinitis), and lung (allergic asthma). IgE production may thus be favored under conditions that induce weak B cell responses and minimal GC (Germinal center) activity, thereby enabling IgE+ B cells and/or PCs to avoid being outcompeted by IgG+ cells. Aside from IgE antibodies, B cells may also contribute to allergic inflammation through their interactions with T cells.

 

B cells have also emerged as an important source of the immunosuppressive cytokine IL-10. Mouse studies revealed that B cell-derived IL-10 can promote recovery from EAE (Experimental autoimmune encephalomyelitis) and can be protective in models of RA and type 1 diabetes. Moreover, IL-10 production from B cells restrains T cell responses during some viral and bacterial infections. These findings indicate that the influence of B cells on the cytokine milieu will be context dependent.

 

The presence of B cells in a variety of solid tumor types, including breast cancer, ovarian cancer, and melanoma, has been associated in some studies with a positive prognosis. The mechanism involved is unclear but could include antigen presentation to CD4 and CD8 T cells, antibody production and subsequent enhancement of presentation, or by promoting tertiary lymphoid tissue formation and local T cell accumulation. It is also noteworthy that B cells frequently make antibody responses to cancer antigens and this has led to efforts to use antibodies from cancer patients as biomarkers of disease and to identify immunotherapy targets.

 

Malignancies of B cells themselves are a common form of hematopoietic cancer. This predilection arises because the gene modifications that B cells undergo during development and in immune responses are not perfect in their fidelity, and antibody responses require extensive B cell proliferation. The study of B cell lymphomas and their associated genetic derangements continues to be illuminating about requirements for normal B cell differentiation and signaling while also leading to the development of targeted therapies.

 

Overall this study attempted to capture some of the advances in the understanding of B cell biology that have occurred since the turn of the century. These include important steps forward in understanding how B cells encounter antigens, the co-stimulatory and cytokine requirements for their proliferation and differentiation, and how properties of the B cell receptor, the antigen, and helper T cells influence B cell responses. Many advances continue to transform the field including the impact of deep sequencing technologies on understanding B cell repertoires, the IgA-inducing microbiome, and the genetic defects in humans that compromise or exaggerate B cell responses or give rise to B cell malignancies.

 

Other advances that are providing insight include:

  • single-cell approaches to define B cell heterogeneity,
  • glycomic approaches to study effector sugars on antibodies,
  • new methods to study human B cell responses including CRISPR-based manipulation, and
  • the use of systems biology to study changes at the whole organism level.

With the recognition that B cells and antibodies are involved in most types of immune response and the realization that inflammatory processes contribute to a wider range of diseases than previously believed, including, for example, metabolic syndrome and neurodegeneration, it is expected that further

  • basic research-driven discovery about B cell biology will lead to more and improved approaches to maintain health and fight disease in the future.

 

References:

 

https://www.cell.com/cell/fulltext/S0092-8674(19)30278-8

 

https://onlinelibrary.wiley.com/doi/full/10.1002/hon.2405

 

https://www.pnas.org/content/115/18/4743

 

https://onlinelibrary.wiley.com/doi/full/10.1111/all.12911

 

https://cshperspectives.cshlp.org/content/10/5/a028795

 

https://www.sciencedirect.com/science/article/abs/pii/S0049017218304955

 

Advertisements

Read Full Post »


TWEETS by @pharma_BI and @AVIVA1950 at #IESYMPOSIUM – @kochinstitute 2019 #Immune #Engineering #Symposium, 1/28/2019 – 1/29/2019

 

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

 

eProceedings for Day 1 and Day 2

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

https://pharmaceuticalintelligence.com/2019/01/28/live-day-one-koch-institute-2019-immune-engineering-symposium-january-28-2019-kresge-auditorium-mit/

 

LIVE Day Two – Koch Institute 2019 Immune Engineering Symposium, January 29, 2019, Kresge Auditorium, MIT

https://pharmaceuticalintelligence.com/2019/01/29/live-day-two-koch-institute-2019-immune-engineering-symposium-january-29-2019-kresge-auditorium-mit/

 

 

  1. AMAZING Conference I covered in Real Time

  2. Aviv Regev 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 abemaciclib in cell lines

  3. Aviv Regev, a cell-cell interactions from variations across individuals Most UC-risk genes are cell type specificVariation – epithelial cell signature – organize US GWAS into cell type spec

  4. Diane Mathis 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/Obese tissue

  5. Martin LaFleur 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

  6. Alex Shalek Identifying and rationally modulating cellular drivers of enhanced immunity T Cells, Clusters Expression of Peak and Memory Immunotherapy- Identifying Dendritic cells enhanced in HIV-1 Elite Controllers

  7.   Retweeted

    Onward: our own Michael Birnbaum, who assures us that if you feel like you’re an immunoengineer, then you ARE one!

  8. Glenn Dranoff Adenosine level in blood or tissue very difficult to measure in blood even more than in tissue – NIR178 + PDR 001 Monotherapy (NIR178) combine with PD receptor blockage (PDR) show benefit A alone vs A+B in Clinical trial

  9. Glenn Dranoff 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 myeloid

  10. Glenn Dranoff Institute for Biomedical Research of Neurologic toxicities of CART t IL-6 activation AML – complete response – weekly dose of XmAb CD123X CD3 bispecific antibody anti tumor effect

  11. of protective 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

  12. Yvonne Chen 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”

  13. Yvonne Chen Do we need a ligand to be a dimers? Co-expressed second-generation TGF-beta signaling

  14. Yvonne Chen “Engineering smarter and stronger T cells for cancer immunotherapy” 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)

  15.   Retweeted

    Ending the 1st session is Cathy Wu of detailing some amazing work on vaccination strategies for melanoma and glioblastoma patients. They use long peptides engineered from tumor sequencing data.

  16.   Retweeted

    Some fancy imaging: Duggan gives a nice demo of how dSTORM imaging works using a micropatterend image of Kennedy Institute for Rheumatology! yay!

  17.   Retweeted

    Lots of interesting talks in the second session of the – effects of lymphoangiogenesis on anti-tumor immune responses, nanoparticle based strategies to improve bNAbs titers/affinity for HIV therapy, and IAPi cancer immunotherapy

  18.   Retweeted

    Looking forward to another day of the . One more highlight from yesterday – from our own lab showcased her work developing cytokine fusions that bind to collagen, boosting efficacy while drastically reducing toxicities

  19.   Retweeted

    Members of our cell therapy team were down the street today at neighboring for the presented by .

  20.   Retweeted

    He could have fooled me that he is, in fact, an immunologist!

  21.  
  22.   Retweeted

    Come and say Hi! ACIR will be back tomorrow at the Immune Engineering Symposium at MIT. Learn more at . . And stay tuned to read our summary of the talks on Feb 6.

  23. Facundo Batista @MGH # in 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

  24. Preeti Sharma, U Illinois T cell receptor and CAR-T engineering TCR engineering for Targeting glycosylated cancer antigens Nornal glycosylation vs Aberrant Engineering 237-CARs libraries with conjugated (Tn-OTS8) against Tn-antigend In vitro

  25. Bryan Bryson 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

  26. Bryan Bryson macrophage axis in Mycobacterium tuberculosis Building “libraries” – surface marker analysis of Microphages Polarized macrophages are functionally different quant and qual differences History of GM-CSF suppresses IL-10

  27. Jamie Spangler John Hopkins University “Reprogramming anti-cancer immunity RESPONSE through molecular engineering” De novo IL-2 potetiator in therapeutic superior to the natural cytokine by molecular engineering mimicking other cytokines

  28. Jamie Spangler JES6-1 Immunocytokine – inhibiting melanoma Engineering a Treg cell-biased immunocytokine double mutant immunocytokine shows enhanced IL-2Ralpha exchange Affinity De Novo design of a hyper-stable, effector biased IL-2

  29. , Volume Five: in of Cardiovascular Diseases. On com since 12/23/2018

  30. Michael Dustin ESCRT pathway associated with synaptic ectosomes Locatization, Microscopy Cytotoxic T cell granules CTLs release extracellular vescicles similar to T Helper with perforin and granzyme – CTL vesicles kill targets

  31. Michael Dustin Delivery of T cell Effector function through extracellular vesicles Synaptic ectosome biogenisis Model: T cells: DOpamine cascade in germinal cell delivered to synaptic cleft – Effector CD40 – Transfer is cooperative

  32. Michael Dustin 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 Invadipodia

  33. Mikael Pittet @MGH Myeloid Cells in Cancer Indirect mechanism AFTER a-PD-1 Treatment IFN-gamma Sensing Fosters IL-12 & therapeutic Responses aPD-1-Mediated Activation of Tumor Immunity – Direct activation and the ‘Licensing’ Model

  34. Stefani Spranger KI Response to checkpoint blockade Non-T cell-inflamed – is LACK OF T CELL INFILTRATION Tumor CD103 dendritic cells – Tumor-residing Batf3-drivenCD103 Tumor-intrinsic Beta-catenin mediates lack of T cell infiltration

  35. Max Krummel Gene expression association between two genes: and numbers are tightly linked to response to checkpoint blockage IMMUNE “ACCOMODATION” ARCHYTYPES: MYELOID TUNING OF ARCHITYPES Myeloid function and composition

  36. Noor Momin, MIT Lumican-cytokines improve control of distant lesions – Lumican-fusion potentiates systemic anti-tumor immunity

    Translate Tweet

  37. Noor Momin, MIT Lumican fusion to IL-2 improves treatment efficacy reduce toxicity – Anti-TAA mAb – TA99 vs IL-2 Best efficacy and least toxicity in Lumican-MSA-IL-2 vs MSA-IL2 Lumican synergy with CAR-T

  38.   Retweeted

    excited to attend the immune engineering symposium this week! find me there to chat about and whether your paper could be a good fit for us! 🦠🧬🔬🧫📖

  39.   Retweeted

    Bob Schreiber and Tyler Jacks kicked off the with 2 great talks on the role of Class I and Class II neo-Ag in tumor immunogenicity and how the tumor microenvironment alters T cell responsiveness to tumors in vivo

  40.   Retweeted

    Scott Wilson from gave a fantastic talk on glycopolymer conjugation to antigens to improve trafficking to HAPCs and enhanced tolerization in autoimmunity models. Excited to learn more about his work at his faculty talk!

  41. AMAZING Symposinm

  42.   Retweeted

    Immune Engineering Symposium at MIT is underway!

  43.   Retweeted

    ACIR is excited to be covering the Immune Engineering Symposium at MIT on January 28-29. Learn more at .

  44. Tyler Jacks talk was outstanding, Needs be delivered A@TED TALKs, needs become contents in the curriculum of Cell Biology graduate seminar as an Online class. BRAVO

  45.   Retweeted

    Here we go!! Today and tomorrow the tippity top immunologists converge at

  46.   Retweeted

    Exciting start to this year’s Immune Engineering Symposium put on by at . A few highlights from the first section…

  47. Stephanie Dougan (Dana-Farber Cancer Institute) Dept. Virology 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

  48. Darrell Irvine (MIT, Koch Institute; HHMI) Engineering follicle delivery through synthetic glycans: eOD-60mer nanoparticles vs Ferritin-trimer 8-mer (density dependent)

  49. Darrell Irvine (MIT, Koch Institute; HHMI) GC targeting is dependent on complement component CIQ – activation: Mannose-binding lectins recognize eOD-60mer but not eOD monomer or trimers

  50. Melody Swartz (University of Chicago) 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

  51. Cathy Wu @MGH breakthrough for Brain Tumor based neoantigen-specific T cell at intracranial site Single cells brain tissue vs single cells from neoantigen specific T cells – intratumoral neoantigen-specific T cells: mutARGAP35-spacific

  52. Cathy Wu (Massachusetts General Hospital) – CoFounder of NEON Enduring complete radiographic responses after + alpha-PD-1 treatment (anti-PD-1) NeoVax vs IVAC Mutanome for melanoma and Glioblastoma clinical trials

  53. , U of Chicago IV INJECTION: OVAALBUMIN OVA-P(GALINAC), P(GLCNAC), SUPRESS T CELL RESPONSE Abate T cells response – Reduced cytokine production & increased -regs

  54. Interrogating markers of T cell dysfunction – chance biology of cells by CRISPR – EGR2 at 2 weeks dysfuntioning is reduced presence of EDR2 mutant class plays role in cell metabolism cell becomes functional regulator CD8 T cell

  55. Bob Schreiber (Wash University of St. Louis) Optimal CD8+ T cells mediated to T3 require CD4+ T help

Read Full Post »


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
  1. Age-dependent Treg and mSC changes – Linear with increase in age
  2. 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

 

 

Read Full Post »


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

 

 

 

 

Read Full Post »


Image Source:Koch Institute

 

LIVE – OCTOBER 16 – DAY 1- Koch Institute Immune Engineering Symposium 2017, MIT, Kresge Auditorium

Koch Institute Immune Engineering Symposium 2017

http://kochinstituteevents.cvent.com/events/koch-institute-immune-engineering-symposium-2017/agenda-64e5d3f55b964ff2a0643bd320b8e60d.aspx

 

#IESYMPOSIUM

 

Image Source: Leaders in Pharmaceutical Business Intelligence (LPBI) Group

Aviva Lev-Ari, PhD, RN will be in attendance covering the event in REAL TIME

@pharma_BI

@AVIVA1950

#IESYMPOSIUM

@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:
  1. Immune Response (IR),
  2. 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
  1. success limited to B cells cancers = blood vs solid tumors
  2. adverse effects
  3. OFF-TUMOR effects
  • Cell engineering for Cancer Therapy: User remote control (drug) – user control safety
  • Cell Engineering for TX
  1. new sensors – decision making for
  2. tumor recognition – safety,
  3. 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

  1. resistence of T cell based IT due to loss of function mutations
  2. 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:
  1. subunits of the MHC Class I complex
  2. 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
  1. Immune response to bioscafolds
  2. 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
  1. decrease cytokine release
  2. avoid neurological toxicity – homing
  3. new targets address antigene escape variants – Resistance, CD19 is shaded, another target needed
  4. B Cell Maturation Antigen (BCMA) Target
  5. Bluebird Bio: Response duratio up to 54 weeks – Active dose cohort
  6. natural ligand CAR based on April
  7. 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
  1. Specific antigen targets
  2. tumor heterogeneity
  3. inhibitory microenvironment
  • CART in Glioblastoma
  1. rationale for EGFRvIII as therapeutic target
  2. Preclinical Studies & Phase 1: CAR t engraft, not as highly as CD19
  3. 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

Read Full Post »