Funding, Deals & Partnerships: BIOLOGICS & MEDICAL DEVICES; BioMed e-Series; Medicine and Life Sciences Scientific Journal – http://PharmaceuticalIntelligence.com
Actemra, immunosuppressive which was designed to treat rheumatoid arthritis but also approved in 2017 to treat cytokine storms in cancer patients SAVED the sickest of all COVID-19 patients
Reporter: Aviva Lev-Ari, PhD, RN
Emergency room doctor, near death with coronavirus, saved with experimental treatment
Soon after being admitted to his own hospital with a fever, cough and difficulty breathing, he was placed on a ventilator. Five days after that, his lungs and kidneys were failing, his heart was in trouble, and doctors figured he had a day or so to live.
He owes his survival to an elite team of doctors who tried an experimental treatment pioneered in China and used on the sickest of all COVID-19 patients.
Lessons from his dramatic recovery could help doctors worldwide treat other extremely ill COVID-19 patients.
Based on the astronomical level of inflammation in his body and reports written by Chinese and Italian physicians who had treated the sickest COVID-19 patients, the doctors came to believe that it was not the disease itself killing him but his own immune system.
It had gone haywire and began to attack itself — a syndrome known as a “cytokine storm.”
The immune system normally uses proteins called cytokines as weapons in fighting a disease. For unknown reasons in some COVID-19 patients, the immune system first fails to respond quickly enough and then floods the body with cytokines, destroying blood vessels and filling the lungs with fluid.
Dr. Matt Hartman, a cardiologist, said that after four days on the immunosuppressive drug, supplemented by high-dose vitamin C and other therapies, the level of oxygen in Padgett’s blood improved dramatically. On March 23, doctors were able to take him off life support.
Four days later, they removed his breathing tube. He slowly came out of his sedated coma, at first imagining that he was in the top floor of the Space Needle converted to a COVID ward.
Effective humoral immune responses to infection and immunization are defined by high-affinity antibodies generated as a result of B cell differentiation and selection that occurs within germinal centers (GC). Within the GC, B cells undergo affinity maturation, an iterative and competitive process wherein B cells mutate their immunoglobulin genes (somatic hypermutation) and undergo clonal selection by competing for T cell help. Balancing the decision to remain within the GC and continue participating in affinity maturation or to exit the GC as a plasma cell (PC) or memory B cell (MBC) is critical for achieving optimal antibody avidity, antibody quantity, and establishing immunological memory in response to immunization or infection. Humoral immune responses during chronic infections are often dysregulated and characterized by hypergammaglobulinemia, decreased affinity maturation, and delayed development of neutralizing antibodies. Previous studies have suggested that poor antibody quality is in part due to deletion of B cells prior to establishment of the GC response.
In fact the impact of chronic infections on B cell fate decisions in the GC remains poorly understood. To address this question, researchers used single-cell transcriptional profiling of virus-specific GC B cells to test the hypothesis that chronic viral infection disrupted GC B cell fate decisions leading to suboptimal humoral immunity. These studies revealed a critical GC differentiation checkpoint that is disrupted by chronic infection, specifically at the point of dark zone re-entry. During chronic viral infection, virus-specific GC B cells were shunted towards terminal plasma cell (PC) or memory B cell (MBC) fates at the expense of continued participation in the GC. Early GC exit was associated with decreased B cell mutational burden and antibody quality. Persisting antigen and inflammation independently drove facets of dysregulation, with a key role for inflammation in directing premature terminal GC B cell differentiation and GC exit. Thus, the present research defines GC defects during chronic viral infection and identify a critical GC checkpoint that is short-circuited, preventing optimal maturation of humoral immunity.
Together, these studies identify a key GC B cell differentiation checkpoint that is dysregulated during chronic infection. Further, it was found that the chronic inflammatory environment, rather than persistent antigen, is sufficient to drive altered GC B cell differentiation during chronic infection even against unrelated antigens. However, the data also indicate that inflammatory circuits are likely linked to perception of antigen stimulation. Nevertheless, this study reveals a B cell-intrinsic program of transcriptional skewing in chronic viral infection that results in shunting out of the cyclic GC B cell process and early GC exit with consequences for antibody quality and hypergammaglobulinemia. These findings have implications for vaccination in individuals with pre-existing chronic infections where antibody responses are often ineffective and suggest that modulation of inflammatory pathways may be therapeutically useful to overcome impaired humoral immunity and foster affinity maturation during chronic viral infections.
4.1.8 Newly Found Functions of B Cell, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 4: Single Cell Genomics
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.
CytoReason is re-defining the Context of the Immune System for Drug Discovery
Reporter: Aviva Lev-Ari, PhD, RN
CytoReason is re-defining the context of the immune system at a cellular level in order to better understand disease and support more effective drug discovery and development.
Our leading-edge machine-learning driven approach identifies “cause and effect” of the gene/cell/cytokine relationships that lie at the heart of treating disease.
Faster and more accurately than ever before.
CytoReason’s mission is to simulate the cells that can stimulate discovery of:
New targets for treating disease
New insights to mechanism of actions (both of disease and drugs)
Differences in responses to both disease and treatment
Which diseases a drug can impact
We have developed a unique machine-learning driven approach to “seeing” the cells that can make the difference in patients seeing a better life.
The insights our approach generates, enable pharmaceutical and biotech companies to make the right decisions, at the right time, in the drug discovery and development programs that bring better therapies.
Based on cutting edge technologies, trained on data that would normally be impossible to access, and steered by leading biological and data science researchers, our approach is underpinned by three core principles:
Science is the backbone of our methodologies and applications, and must stand the test of scientific scrutiny. To date we have 16 research papers published in top quality peer-reviewed scientific journals, including four in 2018 alone – 3 of which were published in journals from the Nature group
Shen-Orr told Forbes in an article published late last month that CytoReason’s tech is able to calculate immune age in one of two ways: “Via cell-subset composition nearest neighbor approach or based on a gene expression signature where the genes are predictive of the cell-subsets composition, and they test for their enrichment in the gene expression pattern of the sample. The immune profiles of individuals are used to predict immune changes based on a machine learning methodology deployed on data on a range of cell-subsets. ”
“The immune age is a biological clock that will help to identify, the decline and progress in immunity that occurs in old age, to determine preventive measures and develop new treatment modalities to minimize chronic disease and death,” he added.
CytoReason’s tech has so far yielded two pending patents, 10 commercial and scientific collaborations, and 16 peer-reviewed publications.
Harel says it was a combination of forces that made CytoReason’s immune-focused methodology work: Big Data, machine learning, and biology. He describes it as “the intersection of computer science and biology.”
Professor Magdassi tells NoCamels that with 3D printing of hydrogels, molecules that are soluble in water, scientists can improve the performance of the drug through its delivery. For example, “the hydrogel once ingested can be designed to swell, releasing two, or three, or four drugs at a time [or with a delay] or it can be designed not to swell, depending on what we are trying to achieve.”
“The drug can be tailored to the patient because of the unique shape or structure of the hydrogel and/or its release behavior,” Professor Magdassi explains.
Last January, CytoReason announced an agreement with Pfizer, in which the latter will leverage the former’s technology to create cell-based models of the immune system. According to the agreement, CytoReason will receive an undisclosed amount in the low double-digit millions of U.S. dollars from Pfizer in access fees, research support and success-based payments. Prof. Shen-Orr concluded, “The immune age is a biological clock that will help to identify, the decline and progress in immunity that occurs in old age, to determine preventive measures and develop new treatment modalities to minimize chronic disease and death.”
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
2.1.3.4 TWEETS by @pharma_BI and @AVIVA1950 at #IESYMPOSIUM – @kochinstitute 2019 #Immune #Engineering #Symposium, 1/28/2019 – 1/29/2019, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 2: CRISPR for Gene Editing and DNA Repair
eProceedings for Day 1 and Day 2
LIVE Day One – Koch Institute 2019 Immune Engineering Symposium, January 28, 2019, Kresge Auditorium, MIT
#IESYMPOSIUM@pharma_BI@AVIVA1950 Aviv Regev @kochinstitute 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
#IESYMPOSIUM@pharma_BI@AVIVA1950 Diane Mathis @HMS 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
#IESYMPOSIUM@pharma_BI@AVIVA1950 Martin LaFleur @HMS 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
#IESYMPOSIUM@pharma_BI@AVIVA1950 Alex Shalek @MIT@kochinstitute 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
#IESYMPOSIUM@pharma_BI@AVIVA1950 Glenn Dranoff @Novartis 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
#IESYMPOSIUM@pharma_BI@AVIVA1950 Glenn Dranoff @Novartis 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
#IESYMPOSIUM@pharma_BI@AVIVA1950 Yvonne Chen @UCLA 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”
#IESYMPOSIUM@pharma_BI@AVIVA1950 Yvonne Chen @UCLA “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)
Ending the 1st session is Cathy Wu of @DanaFarber detailing some amazing work on vaccination strategies for melanoma and glioblastoma patients. They use long peptides engineered from tumor sequencing data. #iesymposium
Some fancy imaging: Duggan gives a nice demo of how dSTORM imaging works using a micropatterend image of Kennedy Institute for Rheumatology! yay! #iesymposium
Lots of interesting talks in the second session of the #iesymposium – effects of lymphoangiogenesis on anti-tumor immune responses, nanoparticle based strategies to improve bNAbs titers/affinity for HIV therapy, and IAPi cancer immunotherapy
Looking forward to another day of the #iesymposium. One more highlight from yesterday – @nm0min from our own lab showcased her work developing cytokine fusions that bind to collagen, boosting efficacy while drastically reducing toxicities
#IESYMPOSIUM@pharma_BI@AVIVA1950 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
#IESYMPOSIUM@pharma_BI@AVIVA1950 Bryan Bryson @MIT 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
#IESYMPOSIUM@pharma_BI@AVIVA1950 Bryan Bryson @MIT 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
#IESYMPOSIUM@pharma_BI@AVIVA1950 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
#IESYMPOSIUM@pharma_BI@AVIVA1950 Michael Dustin @UniofOxford 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
#IESYMPOSIUM@pharma_BI@AVIVA1950 Michael Dustin @Oxford 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
#IESYMPOSIUM@pharma_BI@AVIVA1950 Michael Dustin @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 Invadipodia
#IESYMPOSIUM@pharma_BI@AVIVA1950 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
#IESYMPOSIUM@pharma_BI@AVIVA1950 Stefani Spranger @MIT 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
#IESYMPOSIUM@pharma_BI@AVIVA1950 Max Krummel @UCSF Gene expression association between two genes: #NK and #cDC1 numbers are tightly linked to response to checkpoint blockage IMMUNE “ACCOMODATION” ARCHYTYPES: MYELOID TUNING OF ARCHITYPES Myeloid function and composition
#IESYMPOSIUM@pharma_BI@AVIVA1950 Noor Momin, MIT Lumican-cytokines improve control of distant lesions – Lumican-fusion potentiates systemic anti-tumor immunity
#IESYMPOSIUM@pharma_BI@AVIVA1950 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
excited to attend the @kochinstitute@MIT immune engineering symposium #iesymposium this week! find me there to chat about @CellCellPress and whether your paper could be a good fit for us!
April Pawluk added,
Koch Institute at MITVerified account@kochinstitute
Join leading immunology researchers at our Immune Engineering Symposium on Jan. 28 & 29. Register now: http://bit.ly/2AOUWH6#iesymposium
Bob Schreiber and Tyler Jacks kicked off the #iesymposium 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
Scott Wilson from @UChicago 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 @MITChemE faculty talk! #iesymposium
Spending the (literal) first day of my fellowship at the @kochinstitute#iesymposium! @DanaFarber Cathy Wu talking about the use of neoantigen targeting cancer vaccines for the treatment of ‘cold’ glioblastoma tumors in pts
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 @pharma_BI@AVIVA1950
Aviva Lev-Ari added,
Anne E Deconinck@AEDeconinck
My boss, @kochinstitute director Tyler Jacks, presenting beautiful, unpublished work at our 3rd #iesymposium.
#IESYMPOSIUM@pharma_BI@AVIVA1950 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
#IESYMPOSIUM@pharma_BI@AVIVA1950 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
#IESYMPOSIUM@pharma_BI@AVIVA1950 Cathy Wu @MGH breakthrough for Brain Tumor #vaccine 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
#IESYMPOSIUM@pharma_BI@AVIVA1950 Cathy Wu (Massachusetts General Hospital) – CoFounder of NEON Enduring complete radiographic responses after #Neovax + alpha-PD-1 treatment (anti-PD-1) NeoVax vs IVAC Mutanome for melanoma and Glioblastoma clinical trials
#IESYMPOSIUM@pharma_BI@AVIVA1950@TylerJacks@MIT 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
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.
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
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
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
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
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
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.
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
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
8:30 – 9:45 Session V Moderator: Stefani Spranger | MIT, Koch Institute
K. Christopher Garcia – Stanford University Exploiting T Cell and Cytokine Receptor Structure and Mechanism to Develop New Immunotherapeutic Strategies
T Cell Receptor, peptide-MHC, 10 to the power of 10 is combinatorics – Library for selection to determine enrichment possibilities
Ligand identification for orphan TCRs
Industrializing process
use pMHC
IL-2 – Receptor Signaling Complex
Effector cells (NK, T)
Engineered T Cell – Tunable expansion, ligand-Receptor interface
Randomize IL-2RBeta interface: Orthogonal receptor vs wild type
In Vivo adoptive transfer model: to quantify orthogonality ratio
CD4, CD8, Treg,C57BL/6J
Ligand discovery
Orthogonal IL-2
Stefani Spranger – MIT, Koch Institute Batf3-DC as Mediators of the T Cell-Inflamed Tumor Microenvironment
Melanoma – solid cancer and other types, Immune inhibitory regulatory pathway patient with Immune response present
T cell-inflamed Tumor vs Non-T cell-inflamed Tumor
identify oncogenic pathways differentially activated between T cell-inflamed and non-Tcell-inflamed infiltration
If on Tumor:
Braf/PTEN
Braf/CAT
Braf/PTEN/CAT
The role of T cell priming – lack of initial
Beta-catenin-expressing tumors fail to prime 2C TCR-transgenic T cells
Deficiency in number of CD8+ and CD103+ dendritic cells
CD103+ DC are essential for T cell Priming and T cell-inflammation #StefaniSpranger
Adoptive transfer of effector 2C T cells fails to control Beta-catenin+ tumors
Vaccination induced anti-gen specific T cell memory fails to control Beta-catenin+ tumors
What cell type in tumor microenvironment effect monilization of T cell
CD103+ Dendritic cellsare source chymokine
Recruitment of effector T cells: Reconstitution od Beta-catenin-expressing SIY+
Are Batf3-DC within the tumor required for the recruitment of effector T cells?
Tumor-residing Batf3-drive CD103+ DC are required for the recruitment of effector T cells
Gene spore for correlation with recturment of effector cells
T cell Priming – CD103+ DC are essential for effector T cells
George Georgiou – University of Texas at Austin The Human Circulating Antibody Repertoire in Infection, Vaccination or Cancer
Serological Antibody Repertoire: in blood or in secretions
Antibody in serum – is difficult sequence identity
Serum IgG – 7-17 mg/ml if less immune deficient if more hyper globular
antibodies produced in long lived plasma cells in the bone marrow — experimentally inaccessible
Discovery of antibodies from the serological repertoire – not B cells
BM-PCs
Serum antibodies function via Fc effector mechanism – complement activation
Ig-SEQ – BCR-SEQ
Repertoire-wide computational modelling of antibody structures
En masse analysis & Mining of the Human Native Antibody Repertoire
hypervariable – High-Throughput Single B Cell VH:VL (or TCRalpha, beta) sequencing
HuNoV causes 800 death in the US per year of immune deficient
Influenza Trivalent Vaccine: Antibodies to hemaggiutinin: H1, H3, and B COmponenet
Abundant H1 +H3 Serum IgGs do not neutralize but confer Protection toInfluenza challenge with Live Virus #GeorgeGeorgiou
Non-Neutralizing Antibodies: The role of Complement in Protection
9:45 – 10:15 Break
10:15 – 11:30 Session VI Moderator: K. Dane Wittrup | MIT, Koch Institute
Harvey Lodish – Whitehead Institute and Koch Institute Engineered Erythrocytes Covalently Linked to Antigenic Peptides Can Protect Against Autoimmune Disease
Modified Red blood cells are microparticles for introducing therapeutics & diagnostics into the human body
Bool transfusion is widely used therapeutics
Covalently linking unique functional modalities to mouse or human red cells produced in cell culture:
PRODUCTION OF HUMAN RED BLOD CELLS EXPRESSING A FOREIN PROTEIN: CD34+ stem/progenitor cells that generates normal enucleated RBC.
PPAR-alpha and glucocorticoticoid receptor
Norman morphology: Sortase A is a bactrial transpeptidase that covalently links a “donor”
Engineering Normal Human RBC biotin-LPETG
Covelantely – Glycophorin A with camelid VHHs specific for Botulinum toxin A or B
HLA-DR4 library design and selection to enrich HLA-DM: Amino Acid vs Peptide position: Depleted vs Enriched – relative to expected for NNK codon
6852 _ predicted to bind vs 220 Non-binding peptides
HLA polymorphism: repertoire differences caused by
Antigen – T cell-driven antigen discovery: engaging Innate and Adaptive Immune response
Sorting TIL and select: FOcus of T cell-driven antigen discovery
T cell-driven antigen discovery: TCR
Jennifer R. Cochran – Stanford University Innate and Adaptive Integrin-targeted Combination Immunotherapy
alpa-TAA
TargetingIntegrin = universal targetinvolved in binding to several receptors: brest, lung, pancreatic, brain tumors arising by mutations – used as a handle for binding to agents
NOD201 Peptide-Fc Fusion: A Psudo Ab
Handle the therapeutics: NOD201 + alphaPD1
NOD201 effectively combines with alphaPD-L1, alphaCTLA-4, and alpha4-1BB/CD137
Corresponding monotherapies vs ComboTherapy invoking Innate and Adaptive Immune System
Microphages, CD8+ are critical vs CD4+ Neutrophils, NK cells, B cells #JenniferR. Cochran
Macrophages activation is critical – Day 4, 4 and 5
NOD201 + alphaPD1 combo increases M1 macrophages
Who are the best responders to PD1 – genes that are differentially expressed
NOD201 deives T cells reaponses through a “vaccinal” effect
CAncer Immune CYcle
Integrin – localization
Prelim NOD201 toxicity studies: no significant effects
Targeting multiple integrins vs antibodies RJ9 – minimal effect
NOD201 – manufacturability – NEW AGENT in Preclinical stage
2:15 – 2:45 Break
2:45 – 3:35 Session VIII Moderator: Jianzhu Chen | MIT, Koch Institute
Jennifer Wargo – MD Anderson Cancer Center Understanding Responses to Cancer Therapy: The Tissue is the Issue, but the Scoop is in the Poop
Optimize Targeted Treatment response
Translational research in patients on targeted therapy revealed molecular and immune mechanisms of response and resistance
Molecular mechanisms – T cell infiltrate after one week of therapy
Role of tumor stroma in mediating resistance to targeted therapy
Tumor microenvironment
Intra-tumoral bacteria identified in patients with Pancreatic Cancer
Translational research in patients on immune checkpoint blockade revealed molecualr and immune mechanism of response and resistance
Biomarkers not found
SYstemic Immunity and environment (temperature) on response to checkpoint blockade – what is the role?
Role of mIcrobiome in shaping response to checkpoint blockade in Melanoma
Microbime and GI Cancer
Diversity of the gut microbiome is associated with differential outcomes in the setting of stem cell transplant in AML
Oral and gut fecal microbiome in large cohort patient with metastatic melanoma undergoing systemic therapy
Repeat oral & gut AFTER chemo
WGSeq – Diversity of microbiome and response (responders vs non-responders to anti PD-1 – High diversity of microbiome have prolonged survival to PD-1 blockade
Anti tumor Immunity and composition of gut microbiome in patient on anti-PD-1 favorable AND higher survival #JenniferWargo
Enhance therapeutic responses in lang and renal carcinoma: If on antibiotic – poorer survival
sharing data important across institutions
Jianzhu Chen – MIT, Koch Institute Modulating Macrophages in Cancer Immunotherapy
Humanized mouth vs de novo human cancer
B cell hyperplasia
double hit lymphoma
AML
Overexpression of Bcl-2 & Myc in B cells leads to double-hit lymphoma
antiCD52 – CLL
Spleen, Bone marrow, Brain
Microphages are required to kill Ab-bound lymphoma cells in vivo #JianzhuChen
COmbinatorial chemo-Immunotherapy works for solid tumors: treating breast cancer in humanized mice
Infiltration of monocytic cells in the bone marrow
Cyclophosphophamide-antibody synergy extending to solid tumor and different antibodies #JianzhuChen
Polarization of macrophages it is dosage-dependent M1 and M2
Antibiotic induces expression of M1 polarizing supresses development and function of tumor-associated macrophages (TAM)
Antibiotic inhibits melanoma growth by activating macrophages in vivo #JianzhuChen
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