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Gender affects the prevalence of the cancer type, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 1: Next Generation Sequencing (NGS)
Reporter and Curator: Dr. Sudipta Saha, Ph.D.
Gender of a person can affect the kinds of cancer-causing mutations they develop, according to a genomic analysis spanning nearly 2,000 tumours and 28 types of cancer. The results show striking differences in the cancer-causing mutations found in people who are biologically male versus those who are biologically female — not only in the number of mutations lurking in their tumours, but also in the kinds of mutations found there.
Liver tumours from women were more likely to carry mutations caused by a faulty system of DNA mending called mismatch repair, for instance. And men with any type of cancer were more likely to exhibit DNA changes thought to be linked to a process that the body uses to repair DNA with two broken strands. These biases could point researchers to key biological differences in how tumours develop and evolve across sexes.
The data add to a growing realization that sex is important in cancer, and not only because of lifestyle differences. Lung and liver cancer, for example, are more common in men than in women — even after researchers control for disparities in smoking or alcohol consumption. The source of that bias, however, has remained unclear.
In 2014, the US National Institutes of Health began encouraging researchers to consider sex differences in preclinical research by, for example, including female animals and cell lines from women in their studies. And some studies have since found sex-linked biases in the frequency of mutations in protein-coding genes in certain cancer types, including some brain cancers and advanced melanoma.
But the present study is the most comprehensive study of sex differences in tumour genomes so far. It looks at mutations not only in genes that code for proteins, but also in the vast expanses of DNA that have other functions, such as controlling when genes are turned on or off. The study also compares male and female genomes across many different cancers, which can allow researchers to pick up on additional patterns of DNA mutations, in part by increasing the sample sizes.
Researchers analysed full genome sequences gathered by the International Cancer Genome Consortium. They looked at differences in the frequency of 174 mutations known to drive cancer, and found that some of these mutations occurred more frequently in men than in women, and vice versa. When they looked more broadly at the loss or duplication of DNA segments in the genome, they found 4,285 sex-biased genes spread across 15 chromosomes.
There were also differences found when some mutations seemed to arise during tumour development, suggesting that some cancers follow different evolutionary paths in men and women. Researchers also looked at particular patterns of DNA changes. Such patterns can, in some cases, reflect the source of the mutation. Tobacco smoke, for example, leaves behind a particular signature in the DNA.
Taken together, the results highlight the importance of accounting for sex, not only in clinical trials but also in preclinical studies. This could eventually allow researchers to pin down the sources of many of the differences found in this study. Liver cancer is roughly three times as common in men as in women in some populations, and its incidence is increasing in some countries. A better understanding of its aetiology may turn out to be really important for prevention strategies and treatments.
Immuno-editing can be a constant defense in the cancer landscape, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 1: Next Generation Sequencing (NGS)
Reporter and Curator: Dr. Sudipta Saha, Ph.D.
There are many considerations in the cancer immunoediting landscape of defense and regulation in the cancer hallmark biology. The cancer hallmark biology in concert with key controls of the HLA compatibility affinity mechanisms are pivotal in architecting a unique patient-centric therapeutic application. Selection of random immune products including neoantigens, antigens, antibodies and other vital immune elements creates a high level of uncertainty and risk of undesirable immune reactions. Immunoediting is a constant process. The human innate and adaptive forces can either trigger favorable or unfavorable immunoediting features. Cancer is a multi-disease entity. There are multi-factorial initiators in a certain disease process. Namely, environmental exposures, viral and / or microbiome exposure disequilibrium, direct harm to DNA, poor immune adaptability, inherent risk and an individual’s own vibration rhythm in life.
When a human single cell is crippled (Deranged DNA) with mixed up molecular behavior that is the initiator of the problem. A once normal cell now transitioned into full threatening molecular time bomb. In the modeling and creation of a tumor it all begins with the singular molecular crisis and crippling of a normal human cell. At this point it is either chop suey (mixed bit responses) or a productive defensive and regulation response and posture of the immune system. Mixed bits of normal DNA, cancer-laden DNA, circulating tumor DNA, circulating normal cells, circulating tumor cells, circulating immune defense cells, circulating immune inflammatory cells forming a moiety of normal and a moiety of mess. The challenge is to scavenge the mess and amplify the normal.
Immunoediting is a primary push-button feature that is definitely required to be hit when it comes to initiating immune defenses against cancer and an adaptation in favor of regression. As mentioned before that the tumor microenvironment is a “mixed bit” moiety, which includes elements of the immune system that can defend against circulating cancer cells and tumor growth. Personalized (Precision-Based) cancer vaccines must become the primary form of treatment in this case. Current treatment regimens in conventional therapy destroy immune defenses and regulation and create more serious complications observed in tumor progression, metastasis and survival. Commonly resistance to chemotherapeutic agents is observed. These personalized treatments will be developed in concert with cancer hallmark analytics and immunocentrics affinity and selection mapping. This mapping will demonstrate molecular pathway interface and HLA compatibility and adaptation with patientcentricity.
Immunotherapy may help in glioblastoma survival, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 1: Next Generation Sequencing (NGS)
Reporter and Curator: Dr. Sudipta Saha, Ph.D.
Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. But, in a glimmer of hope, a recent study found that a drug designed to unleash the immune system helped some patients live longer. Glioblastoma powerfully suppresses the immune system, both at the site of the cancer and throughout the body, which has made it difficult to find effective treatments. Such tumors are complex and differ widely in their behavior and characteristics.
A small randomized, multi-institution clinical trial was conducted and led by researchers at the University of California at Los Angeles involved patients who had a recurrence of glioblastoma, the most common central nervous system cancer. The aim was to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab (checkpoint inhibitor) in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone.
Neoadjuvant PD-1 blockade was associated with upregulation of T cell– and interferon-γ-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhanced both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.
Immunotherapy has not proved to be effective against glioblastoma. This small clinical trial explored the effect of PD-1 blockade on recurrent glioblastoma in relation to the timing of administration. A total of 35 patients undergoing resection of recurrent disease were randomized to either neoadjuvant or adjuvant pembrolizumab, and surgical specimens were compared between the two groups. Interestingly, the tumoral gene expression signature varied between the two groups, such that those who received neoadjuvant pembrolizumab displayed an INF-γ gene signature suggestive of T-cell activation as well as suppression of cell-cycle signaling, possibly consistent with growth arrest. Although the study was not powered for efficacy, the group found an increase in overall survival in patients receiving neoadjuvant pembrolizumab compared with adjuvant pembrolizumab of 13.7 months versus 7.5 months, respectively.
In this small pilot study, neoadjuvant PD-1 blockade followed by surgical resection was associated with intratumoral T-cell activation and inhibition of tumor growth as well as longer survival. How the drug works in glioblastoma has not been totally established. The researchers speculated that giving the drug before surgery prompted T-cells within the tumor, which had been impaired, to attack the cancer and extend lives. The drug didn’t spur such anti-cancer activity after the surgery because those T-cells were removed along with the tumor. The results are very important and very promising but would need to be validated in much larger trials.
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
Immune-Oncology Molecules In Development & Articles on Topic in @pharmaceuticalintelligence.com
Curators: Stephen J Williams, PhD and Aviva Lev-Ari, PhD, RN
UPDATED on 06/16/2026
Since 2020, the FDA has significantly expanded the immuno-oncology (IO) landscape, approving several novel agents and expanding existing immunotherapies (e.g., checkpoint inhibitors, CAR-T, bispecific antibodies) for early-stage and metastatic solid and hematologic tumors.
Major novel immuno-oncology drugs and foundational indication expansions include:
Tarlatamab-dlle {Imdelltra}: Approved in 2024 for extensive-stage small cell lung cancer (SCLC) that has progressed on or after platinum-based chemotherapy.
Epcoritamab {Epkinly}: Approved in 2023-2024 for relapsed/refractory follicular lymphoma and diffuse large B-cell lymphoma (DLBCL).
Teclistamab {Tecvayli}: Approved in 2022 as the first bispecific T-cell engager for heavily pretreated relapsed or refractory multiple myeloma.
Nivolumab + Relatlimab {Opdualag}: Approved in 2022, introducing a first-in-class dual checkpoint inhibitor combination (LAG-3 and PD-1 blockade) for advanced melanoma. [1, 2, 3, 4]
Pembrolizumab {Keytruda}+ Enfortumab Vedotin {Padcev} Approved for previously untreated, locally advanced, or metastatic urothelial cancer, redefining first-line therapy. [1]
Durvalumab {Imfinzi}: Saw significant label expansions, including perioperative use in early-stage non-small cell lung cancer (NSCLC) and for biliary tract cancer. [1]
3. Cellular Therapies (CAR-T)
Lisocabtagene maraleucel {Breyanzi}: A CD19-directed CAR-T cell therapy approved in 2021 for relapsed or refractory large B-cell lymphoma, and later expanded.
Ciltacabtagene autoleucel{Carvykti}: Approved in 2022 for relapsed or refractory multiple myeloma. [1, 2, 3, 4, 5]
4. Cytokine Therapies & New Formulations
Subcutaneous Immunotherapies: The FDA approved faster, subcutaneous (under the skin) injection formulations of established blockbusters, such as Tecentriq Hybreza (atezolizumab and hyaluronidase) and Darzalex Faspro (daratumumab and hyaluronidase)
Let’s see if Merck‘s acquisition history offers some clues!
Looking at 32 acquisitions over the past 20 years, one thing stands out:
It is not what Merck bought.
It is what Merck did NOT buy!
Despite Keytruda becoming one of the most successful oncology drugs in history, Merck has not made a major acquisition in several of the hottest post-Keytruda modalities:
• CAR-T
• T-cell engagers
• Radiopharmaceuticals
• Cell therapies
Instead, the company’s oncology acquisitions have largely focused on:
• Small molecules
• ADCs
• Cancer vaccines
• Immune-modulating platforms
Deals such as VelosBio, Tilos, Viralytics, Rigontec, Immune Design, and more recently, Terns Pharmaceuticals and Modifi Bio, expanded Merck’s oncology pipeline but were not obvious “next Keytruda” bets.
At the same time, Merck deployed significant capital outside oncology:
• Acceleron → Cardiovascular
• Prometheus → Immunology
• Verona → Pulmonology
• Cidara → Infectious Diseases
The acquisition record suggests a different strategy.
Rather than betting on a single successor to Keytruda, Merck appears to be building multiple future growth pillars across therapeutic areas and technologies.
Perhaps the real question is not:
“What will replace Keytruda?”
But:
“Does Merck even want a single replacement?”
UPDATED on 10/2/2018
2018 Nobel Prize in Physiology or Medicine for contributions to Cancer Immunotherapy to James P. Allison, Ph.D., of the University of Texas, M.D. Anderson Cancer Center, Houston, Texas. Dr. Allison shares the prize with Tasuku Honjo, M.D., Ph.D.,of Kyoto University Institute, Japan
FDA has approved the world’s first CAR-T therapy, Novartis for Kymriah (tisagenlecleucel) and Gilead’s $12 billion buy of Kite Pharma, no approved drug and Canakinumab for Lung Cancer (may be?)
Novartis’ Kymriah (tisagenlecleucel), FDA approved genetically engineered immune cells, would charge $475,000 per patient, will use Programs that Payers will pay only for Responding Patients
Kite Pharma ($KITE) climbs after Phase II data tee up FDA filing for CAR-T
Kite Pharma ($KITE) has posted an interim analysis of Phase II CAR-T data it thinks are strong enough to support regulatory approval. The CAR-T triggered complete remissions in 47% of patients with an aggressive form of non-Hodgkin lymphoma (NHL), although a dropoff in the number of responders over the first three months has raised questions about durability.
At the time of the interim analysis, Kite had administered its CD19-targeting CAR-T to 51 patients with chemorefractory diffuse large B-cell lymphoma (DLBCL). More than three quarters of patients experienced an objective response. Close to half experienced complete remission. When paired to stronger data from a small group of patients with transformed follicular lymphoma (TFL) and primary mediastinal B-cell lymphoma (PMBCL), Kite thinks the interim analysis boosts its prospects.
Amgen Announces Top-Line Results From Phase 3 KYPROLIS® (Carfilzomib) CLARION Study In Newly Diagnosed Multiple Myeloma Patients
Amgen to Hold Analyst Call Today at 8:30 a.m. ET
THOUSAND OAKS, Calif., Sept. 27, 2016 /PRNewswire/ — Amgen (NASDAQ:AMGN) today announced top-line results of the Phase 3 CLARION trial, which evaluated an investigational regimen of KYPROLIS® (carfilzomib), melphalan and prednisone (KMP) versus Velcade® (bortezomib), melphalan and prednisone (VMP) for 54 weeks in patients with newly diagnosed multiple myeloma who were ineligible for hematopoietic stem-cell transplant. The trial did not meet the primary endpoint of superiority in progression-free survival (PFS) (median PFS 22.3 months for KMP versus 22.1 months for VMP, HR = 0.91, 95 percent CI, 0.75 – 1.10). While the data for overall survival, a secondary endpoint, are not yet mature, the observed hazard ratio (KMP versus VMP) was 1.21 (95 percent CI, 0.90 – 1.64). Neither result was statistically significant.
Overall, the adverse events in the KMP arm were consistent with the known safety profile of KYPROLIS. The incidence of Grade 3 or higher adverse events was 74.7 percent in the KMP arm and 76.2 percent in the VMP arm. Fatal treatment-emergent adverse events occurred in 6.5 percent of KMP patients and 4.3 percent of VMP patients. The incidence of Grade 2 or higher peripheral neuropathy, a secondary endpoint, was 2.5 percent in the KMP arm and 35.1 percent in the VMP arm.
Cancer researchers see promise in giving patients combinations of multiple drugs that are proving more effective than one or two. But the strategy poses a dilemma for health insurers and patients: even higher prices.
Combination Drug Therapies for Cancer Show Promise at Higher Potential Cost
‘Group discounts’ suggested as one means of cutting cost of medicines in a combination regimen
2012pharmaceutical
sjwilliamspa
👑 𝗔𝗳𝘁𝗲𝗿 𝗞𝗲𝘆𝘁𝗿𝘂𝗱𝗮: 𝗪𝗵𝗲𝗿𝗲 𝗜𝘀 𝗠𝗲𝗿𝗰𝗸’𝘀 𝗡𝗲𝘅𝘁 𝗞𝗶𝗻𝗴?
Everyone talks about what comes after Keytruda.
Let’s see if Merck‘s acquisition history offers some clues!
Looking at 32 acquisitions over the past 20 years, one thing stands out:
It is not what Merck bought.
It is what Merck did NOT buy!
Despite Keytruda becoming one of the most successful oncology drugs in history, Merck has not made a major acquisition in several of the hottest post-Keytruda modalities:
• CAR-T
• T-cell engagers
• Radiopharmaceuticals
• Cell therapies
Instead, the company’s oncology acquisitions have largely focused on:
• Small molecules
• ADCs
• Cancer vaccines
• Immune-modulating platforms
Deals such as VelosBio, Tilos, Viralytics, Rigontec, Immune Design, and more recently, Terns Pharmaceuticals and Modifi Bio, expanded Merck’s oncology pipeline but were not obvious “next Keytruda” bets.
At the same time, Merck deployed significant capital outside oncology:
• Acceleron → Cardiovascular
• Prometheus → Immunology
• Verona → Pulmonology
• Cidara → Infectious Diseases
The acquisition record suggests a different strategy.
Rather than betting on a single successor to Keytruda, Merck appears to be building multiple future growth pillars across therapeutic areas and technologies.
Perhaps the real question is not:
“What will replace Keytruda?”
But:
“Does Merck even want a single replacement?”