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Archive for the ‘Microbiome and Responses to Cancer Therapy’ Category

Article SELECTION from Collection of Aviva Lev-Ari, PhD, RN Scientific Articles on PULSE on LinkedIn.com for Training Small Language Models (SLMs) in Domain-aware Content of Medical, Pharmaceutical, Life Sciences and Healthcare by 15 Subjects Matter

Posted in Alzheimer's Disease, Amino acids, Artificial Intelligence - Breakthroughs in Theories and Technologies, Artificial Intelligence Applications in Health Care, Artificial Intelligence in Health Care - Tools & Innovations, Artificial Intelligence in Medicine - Application for Diagnosis, Artificial Intelligence in Medicine - Applications in Therapeutics, Autophagosome, Big Data, Bio Instrumentation in Experimental Life Sciences Research, Biochemical pathways, Ca2+ triggered activation, Ca2+ triggered activation, Calcium, Calcium Signaling, Calmodulin Kinase and Contraction, CANCER BIOLOGY & Innovations in Cancer Therapy, cancer metabolism, Cancer-Immune Interactions, Cell Biology, Signaling & Cell Circuits, Cell Processing System in Cell Therapy Process Development, cell-based therapy, Chemical Biology and its relations to Metabolic Disease, Circulating Tumor Cells (CTC), combination immunotherapies., CT, Deep Learning, Echocardiography, Engineering Better T Cells, Enzymes and isoenzymes, Epigenetics and Environmental Factors, Exosomes, Genome Biology, Genomic Expression, Genomic Testing: Methodology for Diagnosis, Immune Engineering, Immune Modulatory, Immunotherapy, Intelligent Information Systems, Liquid Biopsy Chip detects an array of metastatic cancer cell markers in blood, LPBI Group, e-Scientific Media, DFP, R&D-M3DP, R&D-Drug Discovery, US Patents: SOPs and Team Management, Machine Learning, Mechanical Assist Devices: LVAD, RVAD, BiVAD, Artificial Heart, Medical Devices R&D Investment, Medical Imaging Technology, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Metabolic Immuno-Oncology, Metabolism, Microbiome and Responses to Cancer Therapy, Modulating Macrophages in Cancer Immunotherapy, MRI, mRNA, mRNA Therapeutics, Natural Language Processing (NLP), Neurodegenerative Diseases, NK Cell-Based Cancer Immunotherapy, Noninvasive Diagnostic Fractional Flow Reserve (FFR) CT, Nutrition, Nutrition and Phytochemistry, Nutrition Disorders, Nutritional Supplements: Atherogenesis, lipid metabolism, Pancreatic cancer, Patient-centered Medicine, PCI, Peripheral Arterial Disease & Peripheral Vascular Surgery, Personalized and Precision Medicine & Genomic Research, Precision Cancer Medicine, Prostate Cancer: Monitoring vs Treatment, Proteins, Proteomics, Robotic-assisted percutaneous coronary intervention, Robotically assisted Cardiothoracic Surgery, stem cell biology and patient-specific, Surgical Procedure, Synthetic Immunology: Hacking Immune Cells, Transcatheter Aortic Valve Replacement via the Transcarotid Access, tumor microenvironment, Ubiquitin, Ultra Sound, Variation in human protein-coding regions on January 10, 2026| Leave a Comment »

Article SELECTION from Collection of Aviva Lev-Ari, PhD, RN Scientific Articles on PULSE on LinkedIn.com for Training Small Language Models (SLMs) in Domain-aware Content of Medical, Pharmaceutical, Life Sciences and Healthcare by 15 Subjects Matter

Article selection: Aviva Lev-Ari, PhD, RN

 

#1 – February 20, 2016

Contributions to Personalized and Precision Medicine & Genomic Research

Author: Larry H. Bernstein, MD, FCAP

https://www.linkedin.com/pulse/contributions-personalized-precision-medicine-genomic-aviva/?trackingId=IXDBMmp4SR6vVYaXKPmfqQ%3D%3D

http://pharmaceuticalintelligence.com/contributors-biographies/members-of-the-board/larry-bernstein/

 

#2 – March 31, 2016

Nutrition: Articles of Note @PharmaceuticalIntelligence.com

Author and Curators: Larry H. Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN

https://www.linkedin.com/pulse/nutrition-articles-note-pharmaceuticalintelligencecom-aviva/?trackingId=IXDBMmp4SR6vVYaXKPmfqQ%3D%3D

 

#3 – March 31, 2016

Epigenetics, Environment and Cancer: Articles of Note @PharmaceuticalIntelligence.com

Author and Curators: Larry H. Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN

https://www.linkedin.com/pulse/epigenetics-environment-cancer-articles-note-aviva-lev-ari-phd-rn/?trackingId=IXDBMmp4SR6vVYaXKPmfqQ%3D%3D

 

#4 – April 5, 2016

Alzheimer’s Disease: Novel Therapeutical Approaches — Articles of Note @PharmaceuticalIntelligence.com

Curators: Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

https://www.linkedin.com/pulse/alzheimers-disease-novel-therapeutical-approaches-lev-ari-phd-rn/?trackingId=IXDBMmp4SR6vVYaXKPmfqQ%3D%3D

http://pharmaceuticalintelligence.com/2016/04/05/alzheimers-disease-novel-therapeutical-approaches-articles-of-note-pharmaceuticalintelligence-com/

 

#5 – April 5, 2016

Prostate Cancer: Diagnosis and Novel Treatment – Articles of Note  @PharmaceuticalIntelligence.com

Curators: Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

https://www.linkedin.com/pulse/prostate-cancer-diagnosis-novel-treatment-articles-lev-ari-phd-rn/?trackingId=IXDBMmp4SR6vVYaXKPmfqQ%3D%3D

http://pharmaceuticalintelligence.com/2016/04/05/prostate-cancer-diagnosis-and-novel-treatment-articles-of-note-pharmaceuticalintelligence-com/ 

 

#6 – May 1, 2016

Immune System Stimulants: Articles of Note @pharmaceuticalintelligence.com

Curators: Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

https://www.linkedin.com/pulse/immune-system-stimulants-articles-note-aviva-lev-ari-phd-rn/?trackingId=IXDBMmp4SR6vVYaXKPmfqQ%3D%3D

 

#7 – May 26, 2016

Pancreatic Cancer: Articles of Note @PharmaceuticalIntelligence.com

Curator: Aviva Lev-Ari, PhD, RN

https://www.linkedin.com/pulse/pancreatic-cancer-articles-note-aviva-lev-ari-phd-rn/?trackingId=0AT4eUwMQZiEXyEOqo58Ng%3D%3D

 

#8 – August 23, 2017

Proteomics, Metabolomics, Signaling Pathways, and Cell Regulation – Articles of Note, LPBI Group’s Scientists @ http://pharmaceuticalintelligence.com

Curators: Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

https://www.linkedin.com/pulse/proteomics-metabolomics-signaling-pathways-cell-lev-ari-phd-rn/?trackingId=0AT4eUwMQZiEXyEOqo58Ng%3D%3D

 

#9 – August 17, 2017

Articles of Note on Signaling and Metabolic Pathways published by the Team of LPBI Group in @pharmaceuticalintelligence.com

Curator: Aviva Lev-Ari, PhD, RN

https://www.linkedin.com/pulse/articles-note-signaling-metabolic-pathways-published-aviva/?trackingId=0AT4eUwMQZiEXyEOqo58Ng%3D%3D

 

#10 – October 8, 2017

What do we know on Exosomes?

Curator: Aviva Lev-Ari, PhD, RN

https://www.linkedin.com/pulse/what-do-we-know-exosomes-aviva-lev-ari-phd-rn/?trackingId=0AT4eUwMQZiEXyEOqo58Ng%3D%3D

 

#11 – September 1, 2017

Articles on Minimally Invasive Surgery (MIS) in Cardiovascular Diseases by the Team @Leaders in Pharmaceutical Business Intelligence (LPBI) Group

Curator: Aviva Lev-Ari, PhD, RN

https://www.linkedin.com/pulse/articles-minimally-invasive-surgery-mis-diseases-team-aviva/?trackingId=CPyrP0SNQq2X9N4pSubFxQ%3D%3D

 

#12 – August 13, 2018

MedTech & Medical Devices for Cardiovascular Repair – Contributions by LPBI Team to Cardiac Imaging, Cardiothoracic Surgical Procedures and PCI

Curator: Aviva Lev-Ari, PhD, RN

https://www.linkedin.com/pulse/medtech-medical-devices-cardiovascular-repair-lpbi-lev-ari-phd-rn/?trackingId=5EFVlg%2BQRLO5i%2FfGBEN2FQ%3D%3D

 

#13 – May 24, 2019

Resources on Artificial Intelligence in Health Care and in Medicine: Articles of Note at PharmaceuticalIntelligence.com @AVIVA1950 @pharma_BI

Curator: Aviva Lev-Ari, PhD, RN

https://www.linkedin.com/pulse/resources-artificial-intelligence-health-care-note-lev-ari-phd-rn/?trackingId=5EFVlg%2BQRLO5i%2FfGBEN2FQ%3D%3D

 

#14 – December 19, 2025

AI in Health: The Voice of Aviva Lev-Ari, PhD, RN

Curator: Aviva Lev-Ari, PhD, RN

https://www.linkedin.com/pulse/ai-health-voice-aviva-lev-ari-phd-rn-aviva-lev-ari-phd-rn-xgqie/?trackingId=5EFVlg%2BQRLO5i%2FfGBEN2FQ%3D%3D

 

#15 – January 7, 2026

NEW Foundation Multimodal Model in Healthcare: LPBI Group’s Domain-aware Corpus for 2025 Grok 4.1 Causal Reasoning & Novel Biomedical Relationships

Aviva Lev-Ari, PhD, RN, Founder of LPBI Group

https://www.linkedin.com/pulse/new-foundation-multimodal-model-healthcare-lpbi-2025-aviva-40h1e/?trackingId=5EFVlg%2BQRLO5i%2FfGBEN2FQ%3D%3D

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The Payload Revolution: Redefining the Future of Antibody-Drug Conjugates (ADCs)

Posted in Advanced Drug Manufacturing Technology, Antibody Responses Predict Antigen Exposure, “Antibody–enzyme conjugates”, Cancer Vaccines: Targeting Cancer Genes for Immunotherapy, Cell Biology, Signaling & Cell Circuits, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Carrier Design, Drug Delivery Platform Technology, Drug Development/Formulation using 3D Printing, Human Antibody Response, Human Circulating Antibody Repertoire, Human Immune System in Health and in Disease, Immuno-Oncology & Genomics, Immunology, Immunotherapy, Microbiome and Responses to Cancer Therapy, Modulating Macrophages in Cancer Immunotherapy, Monoclonal antibody therapy, Nanotechnology for Drug Delivery, Personal Health Applications: Tech Innovations serves HealhCare, Personalized and Precision Medicine & Genomic Research, Population Health Management, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Small Molecules in Development of Therapeutic Drugs, Synergistic Innate and Adaptive Immunotherapy, Transformative Technologies in Healthcare, Uncategorized, tagged , , , , , , on June 13, 2025| 1 Comment »

The Payload Revolution: Redefining the Future of Antibody-Drug Conjugates (ADCs)

Curator: Dr. Sudipta Saha, Ph. D.

 

Antibody-Drug Conjugates (ADCs) are at the forefront of targeted cancer therapy. While much attention has focused on antibody engineering and linker technology, the real breakthrough may lie in the payload—the cytotoxic compound delivered to tumor cells.

Historically, ADC payloads have relied on microtubule inhibitors like MMAE and MMAF, and topoisomerase I inhibitors such as SN-38 and Exatecan. These payloads are potent but limited in diversity, making differentiation difficult in a crowded therapeutic landscape.

The next wave of innovation introduces unconventional payloads with novel mechanisms:

  • ISACs (Immune-Stimulating ADCs) activate the immune system locally.
  • Protein degraders eliminate cancer-critical proteins without inhibiting them directly.
  • Urease-based and membrane-disrupting agents affect the tumor microenvironment.
  • RNA polymerase inhibitors and peptide-based payloads offer precision with reduced systemic toxicity.

This shift also places new demands on linker design. Linkers must now accommodate payloads with diverse chemical properties and release them selectively at the tumor site. A payload–linker mismatch could compromise both safety and efficacy.

Ultimately, the focus is shifting toward payloads not just as cytotoxins, but as precision-guided interventions. This evolution could redefine how ADCs are developed and positioned in treatment regimens, enabling breakthroughs in resistant and heterogeneous cancers. The ADC revolution is payload-powered—and the future belongs to those who can innovate at the molecular level.

References:

https://www.linkedin.com/posts/asmitasinghsharma_%F0%9D%97%A7%F0%9D%97%B5%F0%9D%97%B2-%F0%9D%97%99%F0%9D%98%82%F0%9D%98%81%F0%9D%98%82%F0%9D%97%BF%F0%9D%97%B2-activity-7336738434645901312-wfz1

https://www.nature.com/articles/s41573-022-00590-3

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10301933

https://www.cell.com/fulltext/S0092-8674(22)01299-7

https://ascopubs.org/doi/full/10.1200/JCO.22.02474

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257482

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Protein Switches: The Programmable Future of Bio-therapeutics

Posted in Autoimmune Inflammatory DIseases, Autologous Cell Therapy, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Cell Processing System in Cell Therapy Process Development, Human Immune System in Health and in Disease, Microbiome and Responses to Cancer Therapy, Personal Health Applications: Tech Innovations serves HealhCare, Pharmacotherapy and Cell Activity, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Proteins, Proteomics, Rapid automation of plasma protein pools, Transformative Technologies in Healthcare, Uncategorized, tagged , , , , on June 13, 2025| Leave a Comment »

Protein Switches: The Programmable Future of Bio-therapeutics

Curator: Dr. Sudipta Saha, Ph. D.

 

A PNAS paper entitled “A protein therapeutic modality founded on molecular regulation” presents a pioneering approach to creating protein switches—engineered enzymes that activate only in specific molecular environments. This design introduces a new class of context-dependent therapeutics for precision medicine.

Using domain-insertion techniques, researchers inserted ligand-binding domains into scaffold proteins like β-lactamase. These proteins remain inactive until encountering a specific small molecule, which triggers a conformational change and restores enzymatic activity. This offers precise spatiotemporal control—ideal for minimizing off-target effects.

One key innovation is the systematic insertional mutagenesis that identifies functional switch sites across the protein scaffold. This enables the construction of vast protein libraries, increasing the likelihood of finding optimal switch configurations. Furthermore, the approach is modular—different binding domains and enzymes can be combined to create switches tailored to specific clinical contexts.

These smart proteins can be programmed to respond to cancer biomarkers, metabolite levels, or disease-specific molecular cues. By activating only under disease conditions, they provide a blueprint for next-generation bio-therapeutics—potent, selective, and safer.

The method also opens avenues for drug delivery systems, diagnostics, and biosensors, where conditional activation is critical. Overall, this work represents a conceptual leap in synthetic biology and bioengineering, with implications spanning oncology, infectious disease, and regenerative medicine.

References:

https://www.pnas.org/doi/10.1073/pnas.1102803108

https://pubmed.ncbi.nlm.nih.gov/21646539

https://www.nature.com/articles/nchembio.581

https://pubs.acs.org/doi/10.1021/acs.biochem.8b00392

https://www.nature.com/articles/s41587-020-0585-5

https://www.frontiersin.org/articles/10.3389/fbioe.2022.870310/full

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Sleeping Threats: Immune System’s Watch on Dormant Cancer

Posted in Adaptive Immune Response to Biomaterials and Tissue Repair, Anticancer Resistance, Artificial Intelligence - General, Artificial Intelligence in CANCER, Breast Cancer - impalpable breast lesions, Cancer - General, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Genomics, cancer metabolism, Cancer Prevention: Research & Programs, Cancer Screening, cancer-general, Cancer-Immune Interactions, Funding Opportunities for Cancer Research, Human Immune System in Health and in Disease, Immune Engineering, Immunodiagnostics, Immunology, Immunotherapy, Innovation in Immunology Diagnostics, interventional oncology, Microbiome and Responses to Cancer Therapy, Modulating Macrophages in Cancer Immunotherapy, NK Cell-Based Cancer Immunotherapy, Population Health Management, Genetics & Pharmaceutical, Precision Cancer Medicine, Protection Against Autoimmune Disease, RNA Biology, Cancer and Therapeutics, Synthetic Immunology: Hacking Immune Cells, Uncategorized, tagged , , , , on June 6, 2025| Leave a Comment »

Sleeping Threats: Immune System’s Watch on Dormant Cancer

Curator: Dr. Sudipta Saha, Ph. D.

 

The immune system’s role in regulating dormant cancer cells has been increasingly elucidated, revealing a complex interplay that influences metastasis and cancer recurrence. Dormant cells, which enter a non-proliferative state, can evade immune detection and remain quiescent for prolonged periods.


Mechanisms of immune evasion include down-regulation of antigen presentation and residence within immune-privileged niches such as bone marrow. Both innate and adaptive immunity, particularly CD8+ T cells and natural killer cells, are involved in maintaining dormancy and preventing metastatic outgrowth.


Micro-environmental factors that modulate immune surveillance and dormancy status have been identified. Changes in cytokine profiles and inflammation can disrupt dormancy, leading to cancer cell reactivation and metastasis.


Therapeutic approaches to sustain dormancy or eliminate dormant cells are under development. These include immune checkpoint inhibitors, cancer vaccines, and cytokine modulators aimed at enhancing immune recognition and clearance.


By targeting dormant cancer cells through immune modulation, it is anticipated that metastasis can be delayed or prevented, significantly improving long-term patient outcomes and reducing cancer mortality.

References:

https://www.cancer.gov/news-events/cancer-currents-blog/2025/metastasis-dormant-cancer-cells-immune-system

https://www.nature.com/articles/nrc2256

https://pubmed.ncbi.nlm.nih.gov/33681821/

https://pubmed.ncbi.nlm.nih.gov/33811127/

https://www.nature.com/articles/nrc3910

https://pubmed.ncbi.nlm.nih.gov/27015306

 

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Armored CD7-CAR T Cells: A Fratricide-Resistant Solution for T-ALL Therapy

Posted in Anticancer Resistance, Autologous Cell Therapy, BioIT: BioInformatics, NGS, Clinical & Translational, Pharmaceutical R&D Informatics, Clinical Genomics, Cancer Informatics, Cancer - General, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Informatics, cancer metabolism, Cancer Prevention: Research & Programs, Cancer Screening, Cancer Vaccines: Targeting Cancer Genes for Immunotherapy, cancer-general, Cell Biology, Cell Biology, Signaling & Cell Circuits, Cell Level, Clinical Diagnostics, Hematology, interventional oncology, Microbiome and Responses to Cancer Therapy, MicroEngineering Cell-Tissue & Systems, Tissue Engineering, tagged , , , , , , , on September 10, 2024| Leave a Comment »

Armored CD7-CAR T Cells: A Fratricide-Resistant Solution for T-ALL Therapy

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

This research reported in Nature Medicine addresses the challenge of treating T-cell acute lymphoblastic leukemia (T-ALL) with CAR T-cell therapy, particularly focusing on CD7, a surface marker highly expressed on T-ALL cells. The authors develop a novel CAR T-cell therapy that targets CD7, but with a crucial innovation which is fratricide resistance.

Fratricide, a phenomenon where CAR T cells kill each other (killing sister cells) due to shared CD7 expression, has been a significant problem in using CD7-directed therapies. To overcome this, the researchers made CD7-negative CAR T cells (CD7-CAR T cells) by knocking out CD7 from the CAR T cells themselves, preventing them from attacking one another.

Their preclinical results show that these CD7-CAR T cells exhibit strong anti-leukemic activity in T-ALL models, both in vitro and in vivo.

  • The fratricide-resistant T cells not only maintain their potency but also display enhanced proliferation and persistence, crucial for sustained therapeutic effects. Additionally,
  • the study highlights the feasibility and safety of this approach by demonstrating no adverse off-target effects or side effects, making it a potentially promising treatment for T-ALL patients who have limited options.

The research presents a significant advancement in CAR T-cell therapy by addressing the challenge of fratricide, offering a new, effective, and safe therapeutic option for T-ALL patients. The development of fratricide-resistant CD7-CAR T cells could lead to more successful outcomes in clinical applications, revolutionizing the treatment for T-ALL patients.

References:

https://www.nature.com/articles/s41591-024-03228-8

https://pubmed.ncbi.nlm.nih.gov/39227445

https://pubmed.ncbi.nlm.nih.gov/36086817

https://pubmed.ncbi.nlm.nih.gov/35435984

https://pubmed.ncbi.nlm.nih.gov/28539325

https://pubmed.ncbi.nlm.nih.gov/29296885

 

Other articles on Acute Lymphoblastic Leukemia (ALL) published in this Open Access Journal include the following:

Inotuzumab Ozogamicin: Success in relapsed/refractory Acute Lymphoblastic Leukemia (ALL)

FDA: CAR-T therapy outweigh its risks tisagenlecleucel, manufactured by Novartis of Basel – 52 out of 63 participants — 82.5% — experienced overall remissions – young patients with Leukaemia [ALL]

Sunitinib brings Adult Acute Lymphoblastic Leukemia (ALL) to Remission – RNA Sequencing – FLT3 Receptor Blockade

 

Other articles on CAR-T cell Therapies published in this Open Access Journal include the following:

Alliance for Cancer Gene Therapy to honor Dr. Crystal Mackall with Edward Netter Leadership Award

Lessons on the Frontier of Gene & Cell Therapy – The Disruptive Dozen 12 #GCT Breakthroughs that are revolutionizing Healthcare

19th Annual Koch Institute Summer Symposium on Cancer Immunotherapy, June 12, 2020 at MIT’s Kresge Auditorium

2022 FDA Drug Approval List, 2022 Biological Approvals and Approved Cellular and Gene Therapy Products

Tweets at #WMIF2022 by @pharma_BI & @AVIVA1950 and all Retweets of these Tweets – 2022 World Medical Innovation Forum, GENE & CELL THERAPY • MAY 2–4, 2022 • BOSTON

 

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Gender affects the prevalence of the cancer type

Posted in Anti-tumor necrosis factor drugs (TNF inhibitors), Anticancer Resistance, BioIT: BioInformatics, NGS, Clinical & Translational, Pharmaceutical R&D Informatics, Clinical Genomics, Cancer Informatics, Breast Cancer - impalpable breast lesions, Cancer - General, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Genomics, Cancer Informatics, cancer metabolism, Cancer Prevention: Research & Programs, Cancer Screening, Cancer Vaccines: Targeting Cancer Genes for Immunotherapy, Cancer-Immune Interactions, Circulating Tumor Cells (CTC), Efficacy of Anti-Tumor T Cells, Funding Opportunities for Cancer Research, Imaging-based Cancer Patient Management, Liquid Biopsy Chip detects an array of metastatic cancer cell markers in blood, Liquid Biopsy: Circulating Tumor Cells in Urine and Blood, Microbiome and Responses to Cancer Therapy, Modulating Macrophages in Cancer Immunotherapy, NK Cell-Based Cancer Immunotherapy, Pancreatic cancer, Population Health Management, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Precision Cancer Medicine, Prostate Cancer: Monitoring vs Treatment, RNA Biology, Cancer and Therapeutics, tumor microenvironment, tagged , , , , , on April 2, 2019| Leave a Comment »

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.

 

References:

 

https://www.nature.com/articles/d41586-019-00562-7?utm_source=Nature+Briefing

 

https://www.nature.com/news/policy-nih-to-balance-sex-in-cell-and-animal-studies-1.15195

 

https://www.ncbi.nlm.nih.gov/pubmed/26296643

 

https://www.biorxiv.org/content/10.1101/507939v1

 

https://www.ncbi.nlm.nih.gov/pubmed/25985759

 

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Pancreatic cancer survival is determined by ratio of two enzymes

Posted in Anticancer Resistance, Biochemical pathways, BioIT: BioInformatics, NGS, Clinical & Translational, Pharmaceutical R&D Informatics, Clinical Genomics, Cancer Informatics, Breast Cancer - impalpable breast lesions, Cancer - General, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Genomics, Cancer Informatics, cancer metabolism, Cancer Prevention: Research & Programs, Cancer Screening, Cancer Vaccines: Targeting Cancer Genes for Immunotherapy, Cell Biology, Cell Biology, Signaling & Cell Circuits, Cell death pathways, Cell Processing System in Cell Therapy Process Development, Childhood cancer, Enzymes and isoenzymes, Imaging-based Cancer Patient Management, Microbiome and Responses to Cancer Therapy, Pancreatic cancer, PKC, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Precision Cancer Medicine, Proteomics, RNA Biology, Cancer and Therapeutics, Signaling & Cell Circuits, tagged , , , , , on March 29, 2019| Leave a Comment »

Pancreatic cancer survival is determined by ratio of two enzymes, 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.

 

Protein kinase C (PKC) isozymes function as tumor suppressors in increasing contexts. These enzymes are crucial for a number of cellular activities, including cell survival, proliferation and migration — functions that must be carefully controlled if cells get out of control and form a tumor. In contrast to oncogenic kinases, whose function is acutely regulated by transient phosphorylation, PKC is constitutively phosphorylated following biosynthesis to yield a stable, autoinhibited enzyme that is reversibly activated by second messengers. Researchers at University of California San Diego School of Medicine found that another enzyme, called PHLPP1, acts as a “proofreader” to keep careful tabs on PKC.

 

The researchers discovered that in pancreatic cancer high PHLPP1 levels lead to low PKC levels, which is associated with poor patient survival. They reported that the phosphatase PHLPP1 opposes PKC phosphorylation during maturation, leading to the degradation of aberrantly active species that do not become autoinhibited. They discovered that any time an over-active PKC is inadvertently produced, the PHLPP1 “proofreader” tags it for destruction. That means the amount of PHLPP1 in patient’s cells determines his amount of PKC and it turns out those enzyme levels are especially important in pancreatic cancer.

 

This team of researchers reversed a 30-year paradigm when they reported evidence that PKC actually suppresses, rather than promotes, tumors. For decades before this revelation, many researchers had attempted to develop drugs that inhibit PKC as a means to treat cancer. Their study implied that anti-cancer drugs would actually need to do the opposite — boost PKC activity. This study sets the stage for clinicians to one day use a pancreatic cancer patient’s PHLPP1/PKC levels as a predictor for prognosis, and for researchers to develop new therapeutic drugs that inhibit PHLPP1 and boost PKC as a means to treat the disease.

 

The ratio — high PHLPP1/low PKC — correlated with poor prognoses: no pancreatic patient with low PKC in the database survived longer than five-and-a-half years. On the flip side, 50 percent of the patients with low PHLPP1/high PKC survived longer than that. While still in the earliest stages, the researchers hope that this information might one day aid pancreatic diagnostics and treatment. The researchers are next planning to screen chemical compounds to find those that inhibit PHLPP1 and restore PKC levels in low-PKC-pancreatic cancer cells in the lab. These might form the basis of a new therapeutic drug for pancreatic cancer.

 

References:

 

https://health.ucsd.edu/news/releases/Pages/2019-03-20-two-enzymes-linked-to-pancreatic-cancer-survival.aspx?elqTrackId=b6864b278958402787f61dd7b7624666

 

https://www.ncbi.nlm.nih.gov/pubmed/30904392

 

https://www.ncbi.nlm.nih.gov/pubmed/29513138

 

https://www.ncbi.nlm.nih.gov/pubmed/18511290

 

https://www.ncbi.nlm.nih.gov/pubmed/28476658

 

https://www.ncbi.nlm.nih.gov/pubmed/28283201

 

https://www.ncbi.nlm.nih.gov/pubmed/24231509

 

https://www.ncbi.nlm.nih.gov/pubmed/28112438

 

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Immunoediting can be a constant defense in the cancer landscape

Posted in Anticancer Resistance, Apoptosis, BioIT: BioInformatics, NGS, Clinical & Translational, Pharmaceutical R&D Informatics, Clinical Genomics, Cancer Informatics, Breast Cancer - impalpable breast lesions, Cancer - General, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Genomics, Cancer Informatics, cancer metabolism, Cancer Prevention: Research & Programs, Cancer Screening, Cancer Surgery of the Heart, Cancer Vaccines: Targeting Cancer Genes for Immunotherapy, Cancer-Immune Interactions, Cell Biology, Cell Biology, Signaling & Cell Circuits, Cell death pathways, Cell Processing System in Cell Therapy Process Development, cell-based therapy, Childhood cancer, Circulating Tumor Cells (CTC), combination immunotherapies., Efficacy of Anti-Tumor T Cells, Engineering Better T Cells, Engineering Enhanced Cancer Vaccines, Funding Opportunities for Cancer Research, Human Immune System in Health and in Disease, Imaging-based Cancer Patient Management, Immune Modulatory, Immuno-Oncology & Genomics, Immunology, Immunotherapy, Infectious Disease Immunodiagnostics, Innovation in Immunology Diagnostics, Integrin-targeted Combination Immunotherapy, Liquid Biopsy Chip detects an array of metastatic cancer cell markers in blood, Liquid Biopsy: Circulating Tumor Cells in Urine and Blood, Metabolic Immuno-Oncology, Microbiome and Responses to Cancer Therapy, MicroEngineering Cell-Tissue & Systems, Modulating Macrophages in Cancer Immunotherapy, Monoclonal Immunotherapy, NK Cell-Based Cancer Immunotherapy, Pancreatic cancer, Pharmacotherapy and Cell Activity, Population Health Management, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Precision Cancer Medicine, Prostate Cancer: Monitoring vs Treatment, RNA Biology, Cancer and Therapeutics, Signaling & Cell Circuits, Single Cell Genomics, stem cell biology and patient-specific, Stem Cells for Regenerative Medicine, Synergistic Innate and Adaptive Immunotherapy, Synthetic Immunology: Hacking Immune Cells, Universal Immune Cell Therapies (uICT), Voices of Patients and Healthcare Providers, tagged , , , , on March 16, 2019| Leave a Comment »

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.

References:

 

https://www.linkedin.com/pulse/immunoediting-cancer-landscape-john-catanzaro/

 

https://www.cell.com/cell/fulltext/S0092-8674(16)31609-9

 

https://www.researchgate.net/publication/309432057_Circulating_tumor_cell_clusters_What_we_know_and_what_we_expect_Review

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190561/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840207/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593672/

 

https://www.frontiersin.org/articles/10.3389/fimmu.2018.00414/full

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593672/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190561/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4388310/

 

https://www.linkedin.com/pulse/cancer-hallmark-analytics-omics-data-pathway-studio-review-catanzaro/

 

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Knowing the genetic vulnerability of bladder cancer for therapeutic intervention

Posted in Anticancer Resistance, Apoptosis, BioIT: BioInformatics, NGS, Clinical & Translational, Pharmaceutical R&D Informatics, Clinical Genomics, Cancer Informatics, Biological Networks, Biological Networks, Gene Regulation and Evolution, Cancer - General, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Genomics, Cancer Informatics, cancer metabolism, Cancer Prevention: Research & Programs, Cancer Screening, Cancer Vaccines: Targeting Cancer Genes for Immunotherapy, Cell Biology, Cell Biology, Signaling & Cell Circuits, Cell death pathways, Cell Processing System in Cell Therapy Process Development, Childhood cancer, Clinical Diagnostics, Clinical Genomics, Gene Regulation, Gene Therapy & Gene Editing Development, Genome Biology, Genomic Endocrinology, interventional oncology, Metabolic Immuno-Oncology, Metastasis Process, Microbiome and Responses to Cancer Therapy, mRNA Therapeutics, Mutagenesis, Personalized and Precision Medicine & Genomic Research, Population genetics, Population Health Management, Population Health Management, Genetics & Pharmaceutical, RNA Biology, RNA Biology, Cancer and Therapeutics, Signaling, tagged , , , , , , on November 21, 2017| Leave a Comment »

Knowing the genetic vulnerability of bladder cancer for therapeutic intervention, 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)

Knowing the genetic vulnerability of bladder cancer for therapeutic intervention

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

 

A mutated gene called RAS gives rise to a signalling protein Ral which is involved in tumour growth in the bladder. Many researchers tried and failed to target and stop this wayward gene. Signalling proteins such as Ral usually shift between active and inactive states.

 

So, researchers next tried to stop Ral to get into active state. In inacvtive state Ral exposes a pocket which gets closed when active. After five years, the researchers found a small molecule dubbed BQU57 that can wedge itself into the pocket to prevent Ral from closing and becoming active. Now, BQU57 has been licensed for further development.

 

Researchers have a growing genetic data on bladder cancer, some of which threaten to overturn the supposed causes of bladder cancer. Genetics has also allowed bladder cancer to be reclassified from two categories into five distinct subtypes, each with different characteristics and weak spots. All these advances bode well for drug development and for improved diagnosis and prognosis.

 

Among the groups studying the genetics of bladder cancer are two large international teams: Uromol (named for urology and molecular biology), which is based at Aarhus University Hospital in Denmark, and The Cancer Genome Atlas (TCGA), based at institutions in Texas and Boston. Each team tackled a different type of cancer, based on the traditional classification of whether or not a tumour has grown into the muscle wall of the bladder. Uromol worked on the more common, earlier form, non-muscle-invasive bladder cancer, whereas TCGA is looking at muscle-invasive bladder cancer, which has a lower survival rate.

 

The Uromol team sought to identify people whose non-invasive tumours might return after treatment, becoming invasive or even metastatic. Bladder cancer has a high risk of recurrence, so people whose non-invasive cancer has been treated need to be monitored for many years, undergoing cystoscopy every few months. They looked for predictive genetic footprints in the transcriptome of the cancer, which contains all of a cell’s RNA and can tell researchers which genes are turned on or off.

 

They found three subgroups with distinct basal and luminal features, as proposed by other groups, each with different clinical outcomes in early-stage bladder cancer. These features sort bladder cancer into genetic categories that can help predict whether the cancer will return. The researchers also identified mutations that are linked to tumour progression. Mutations in the so-called APOBEC genes, which code for enzymes that modify RNA or DNA molecules. This effect could lead to cancer and cause it to be aggressive.

 

The second major research group, TCGA, led by the National Cancer Institute and the National Human Genome Research Institute, that involves thousands of researchers across USA. The project has already mapped genomic changes in 33 cancer types, including breast, skin and lung cancers. The TCGA researchers, who study muscle-invasive bladder cancer, have looked at tumours that were already identified as fast-growing and invasive.

 

The work by Uromol, TCGA and other labs has provided a clearer view of the genetic landscape of early- and late-stage bladder cancer. There are five subtypes for the muscle-invasive form: luminal, luminal–papillary, luminal–infiltrated, basal–squamous, and neuronal, each of which is genetically distinct and might require different therapeutic approaches.

 

Bladder cancer has the third-highest mutation rate of any cancer, behind only lung cancer and melanoma. The TCGA team has confirmed Uromol research showing that most bladder-cancer mutations occur in the APOBEC genes. It is not yet clear why APOBEC mutations are so common in bladder cancer, but studies of the mutations have yielded one startling implication. The APOBEC enzyme causes mutations early during the development of bladder cancer, and independent of cigarette smoke or other known exposures.

 

The TCGA researchers found a subset of bladder-cancer patients, those with the greatest number of APOBEC mutations, had an extremely high five-year survival rate of about 75%. Other patients with fewer APOBEC mutations fared less well which is pretty surprising.

 

This detailed knowledge of bladder-cancer genetics may help to pinpoint the specific vulnerabilities of cancer cells in different people. Over the past decade, Broad Institute researchers have identified more than 760 genes that cancer needs to grow and survive. Their genetic map might take another ten years to finish, but it will list every genetic vulnerability that can be exploited. The goal of cancer precision medicine is to take the patient’s tumour and decode the genetics, so the clinician can make a decision based on that information.

 

References:

 

https://www.ncbi.nlm.nih.gov/pubmed/29117162

 

https://www.ncbi.nlm.nih.gov/pubmed/27321955

 

https://www.ncbi.nlm.nih.gov/pubmed/28583312

 

https://www.ncbi.nlm.nih.gov/pubmed/24476821

 

https://www.ncbi.nlm.nih.gov/pubmed/28988769

 

https://www.ncbi.nlm.nih.gov/pubmed/28753430

 

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LIVE – OCTOBER 17 – DAY 2- Koch Institute Immune Engineering Symposium 2017, MIT, Kresge Auditorium

Posted in Antibody Responses Predict Antigen Exposure, Conference Coverage with Social Media, Cytokine Receptor Structure, Human Circulating Antibody Repertoire, Integrin-targeted Combination Immunotherapy, MHC Repertoires for Antigen Prediction, Microbiome and Responses to Cancer Therapy, Modulating Macrophages in Cancer Immunotherapy, Protection Against Autoimmune Disease, Synergistic Innate and Adaptive Immunotherapy on October 17, 2017| Leave a Comment »

LIVE – OCTOBER 17 – DAY 2- Koch Institute Immune Engineering Symposium 2017, MIT, Kresge Auditorium

Reporter: Aviva Lev-Ari, PhD, RN

 

 

Image Source:Koch Institute

Koch Institute

Immune Engineering Symposium 2017

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

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

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

@pharma_BI

@AVIVA1950

#IESYMPOSIUM

@KOCHINSTITUTE

  • The Immune System, Stress Signaling, Infectious Diseases and Therapeutic Implications: VOLUME 2: Infectious Diseases and Therapeutics and VOLUME 3: The Immune System and Therapeutics (Series D: BioMedicine & Immunology) Kindle Edition – on Amazon.com since September 4, 2017

https://www.amazon.com/dp/B075CXHY1B

SYMPOSIUM SCHEDULE

OCTOBER 17 – DAY 2

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
  1. Industrializing process
  2. 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:
  1. Braf/PTEN
  2. Braf/CAT
  3. 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
  • EBOV Vaccinee Peak ASCs (day 8) mining: Neutralization
  • Features of the Serum Antibody Repertoire to Vaccine ANtigens:The Serum IgG Repertoire is Highly Polarized
  • Each bar represents a distinct antibody lineage
  • Serum IgG Repertoire becomes increasingly polarized with AGE >50 – may be predictive of tumor development process
  • Human Norovirus – explosive Diarreha, chromically infected – HuNoV BNAb Discovery – Takeda 214 bivalent Vaccine – Binding antibodies binding to avccine antigen VLP
  • 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
  • Generation of immuno tolerance: SOruggable Mature RBCs: CRISPR mice expressing Kell-LPETG
  • Ovalbumin as Model Antigens:
  1. OBI B,
  2. OTI CD8 T cells
  3. OTII CD4 T cells
  4. OT-1
  5. OT-2
  • RBC induced peptides challenged and experiences apoptosis
  • Type I Diabetes in NOD mice
  • RBCs bearing InsB9-23 – prevented development of diabetes

Multiple sclerosis

  • MOG – Myelin Oligodend

Sai Reddy – ETH Zurich
Molecular Convergence Patterns in Antibody Responses Predict Antigen Exposure

  • Clonal diversity – estimating the size of antibody repertoire: 10 to power of 18 or 10 to 13
  • Clonal selection in antibody repertoire
  • Convergent selection in antibody repertoire
  • Convergent selection in TCR repertoire complex have restriction with MCH interactions
  • How molecular abundance of convergence predicts antigen exposure identify antigen-associated clusters #SaiReddy
  • molecular convergence 0 gene expression analysis, immunization scheme molecular bar coding to correct errors
  • Recoding antibody repertoire sequence space: Cross correlation reveals different clusters
  • Building a classifier model based on cluster frequency: Clones from immunized mice
  • epitope specificity is driving antibody repertoire response
  • deep learning,

K. Dane Wittrup – MIT, Koch Institute
Temporal Programming of Synergistic Innate and Adaptive Immunotherapy

  • Innate effector functions of anti-tumor antibodies
  • Innate & adaptive Immunotherapy
  • Innate mAb –>> tumor cell; adaptive CD8+ T cells
  • Chemokines Antigens
  • Cytokines Chemokines – back and forth innate Adaptive –> <— neutrophils impact
  • AIPV vaccine:
  • How anti-TAA mAbs helping T cell Immune response
  • Anti-TAA mAbs drive vaccinal T cell responses: NK cells
  • antibody drives T cells responses: alpha-TAA mAbs potentiate T cell therapies: ACT +MSA-IL-2 vs alphaPD-1 + vaccine
  • CD8+ T cells required for alpha TAA mAb efficacy- In absence of T cells Treatment does not work
  • Anti-TAA mAb +Fc/IL-2 induces intramural cytokine storm #KDaneWittrup
  • How to simplify and improve AIPV? Hypothesis: ALign dose schedule
  • Immune response to infection follwos a temporal progression: Innate … Adaptive
  • Antigenic material kill cells: Chemo, cell death Antigen presentation, T cell priming, T cell recirculation, Lymphocyte tumor infiltrate, TCR
  • IFN alpha 2 dys after mAb +Il-2: Curative: days post tumor injection
  • Necessary components: CD8+ T cells & DC, Macrophages,
  • Optimal IFNalpha coincides with max innate response vs Mature DCs after antigen loading #KDaneWittrup
  • Optimal timing od agent administration effect on Therapy Outcome: IL-2, IFNalpha, TAAmAb
  • Cytkine timing can be better than protein engineering #KDaneWittrup

11:30 – 1:00 Lunch Break

1:00 – 2:15 Session VII
Moderator: Michael Birnbaum | MIT, Koch Institute

Kai Wucherpfennig – Dana-Farber Cancer Institute
Discovery of Novel Targets for Cancer Immunotherapy

  • POSITIVE STRESS SIGNAL during malignant Transformation
  • NKG2G=D Receptor: MICA/B Results in Immune escape – Proteolytic cleavage  shedding of MICA/B present in serum, indication of tumor progression
  • Shed MICA vs Surface MICA/B – restore NK cell cytotoxicity and IFNgamma Production
  • Human NK cells express NKG2D and Fc Receptors
  • Synergistic NKG2D and CD16 signaling enhances NK cell cytootxicity: Control IgG vs Anti NKG2D
  • MICA Antibody induces Immunity Against Lung Metastases
  • NK cells are required to inhibit Growth of metastases: Anti-CD8beta,
  • Contribution to Therapeutic Efficacy: NKG2D and CD16 Receptors #KaiWucherpfennig
  • Strategy to analyze Pulmonary NK cells: Activation and expression
  • Single cell RNA-seq of lung NK cells Revealed higher infiltration of activated NK cells: Isotype vs 7C6-migG2a
  • Cytokines and Chemokines produce NK cells
  • MICA/B increaces NK
  •  Induction of Tumor cell Apoptosis
  • Xenotransplant Model with Human Melanoma Cel Line A2058
  • Lung metastasis, liver metastasis
  • Inhibition of human melanoma Metastases in NSG Mice Reconstitute with Human NK
  • Liver metastases are controlled by Myeloid Cells that include Kupffer cells

Michael Birnbaum – MIT, Koch Institute
An Unbiased Determination of pMHC Repertoires for Better Antigen Prediction

  • Vaccines TCR gene therapy adoptive T cel therapy
  • Tumor genone – Tumor pMHC repertoire = Tumor TCR repertoire T cell repertoire
  • Neoantigen vaccines as a personalized anti-cancer therapy
  • Tumor procurement – Target selection – personal vaccine production – vaccine administration
  • Prediction of neoantigen-MHC Binding due to polimorphism affecting recognition, rare in MHC Allells #Michael Birnbaum
  • Antigenicity – Chaperones HLA-DM sculp the peptide binding repertoire of MHC
  • Identification of loaded peptide ligands: pMHC mass spectroscopy of tissue
  • TCR recognition, pMHC yeast display: Cleave peptide-MHC linker, catalyze peptide exchange
  • 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
  • Targeting Integrin = universal target involved 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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