Feeds:
Posts
Comments

Archive for the ‘Universal Immune Cell Therapies (uICT)’ Category


Predicting the Protein Structure of Coronavirus: Inhibition of Nsp15 can slow viral replication and Cryo-EM – Spike protein structure (experimentally verified) vs AI-predicted protein structures (not experimentally verified) of DeepMind (Parent: Google) aka AlphaFold

 

Curators: Stephen J. Williams, PhD and Aviva Lev-Ari, PhD, RN

This illustration, created at the Centers for Disease Control and Prevention (CDC), reveals ultrastructural morphology exhibited by coronaviruses. Note the spikes that adorn the outer surface of the virus, which impart the look of a corona surrounding the virion, when viewed electron microscopically. A novel coronavirus virus was identified as the cause of an outbreak of respiratory illness first detected in Wuhan, China in 2019.

Image and Caption Credit: Alissa Eckert, MS; Dan Higgins, MAM available at https://phil.cdc.gov/Details.aspx?pid=23311

 

UPDATED on 8/9/2020

 

UPDATED on 3/11/2020

Coronaviruses

According to the World Health Organization, coronaviruses make up a large family of viruses named for the crown-like spikes found on their surface (Figure 1). They carry their genetic material in single strands of RNA and cause respiratory problems and fever. Like HIV, coronaviruses can be transmitted between animals and humans.  Coronaviruses have been responsible for the Severe Acute Respiratory Syndrome (SARS) pandemic in the early 2000s and the Middle East Respiratory Syndrome (MERS) outbreak in South Korea in 2015. While the most recent coronavirus, COVID-19, has caused international concern, accessible and inexpensive sequencing is helping us understand COVID-19 and respond to the outbreak quickly.

Figure 1. Coronaviruses with the characteristic spikes as seen under a microscope.

First studies that explore genetic susceptibility to COVID-19 are now being published. The first results indicate that COVID-19 infects cells using the ACE2 cell-surface receptor. Genetic variants in the ACE2 receptor gene are thus likely to influence how effectively COVID-19 can enter the cells in our bodies. Researchers hope to discover genetic variants that confer resistance to a COVID-19 infection, similar to how some variants in the CCR5 receptor gene make people immune to HIV. At Nebula Genomics, we are monitoring the latest COVID-19 research and will add any relevant discoveries to the Nebula Research Library in a timely manner.

The Role of Genomics in Responding to COVID-19

Scientists in China sequenced COVID-19’s genome just a few weeks after the first case was reported in Wuhan. This stands in contrast to SARS, which was discovered in late 2002 but was not sequenced until April of 2003. It is through inexpensive genome-sequencing that many scientists across the globe are learning and sharing information about COVID-19, allowing us to track the evolution of COVID-19 in real-time. Ultimately, sequencing can help remove the fear of the unknown and allow scientists and health professionals to prepare to combat the spread of COVID-19.

Next-generation DNA sequencing technology has enabled us to understand COVID-19 is ~30,000 bases long. Moreover, researchers in China determined that COVID-19 is also almost identical to a coronavirus found in bats and is very similar to SARS. These insights have been critical in aiding in the development of diagnostics and vaccines. For example, the Centers for Disease Control and Prevention developed a diagnostic test to detect COVID-19 RNA from nose or mouth swabs.

Moreover, a number of different government agencies and pharmaceutical companies are in the process of developing COVID-19 vaccines to stop the COVID-19 from infecting more people. To protect humans from infection inactivated virus particles or parts of the virus (e.g. viral proteins) can be injected into humans. The immune system will recognize the inactivated virus as foreign, priming the body to build immunity against possible future infection. Of note, Moderna Inc., the National Institute of Allergy and Infectious Diseases, and Coalition for Epidemic Preparedness Innovations identified a COVID-19 vaccine candidate in a record 42 days. This vaccine will be tested in human clinical trials starting in April.

For more information about COVID-19, please refer to the World Health Organization website.

SOURCE

https://blog.nebula.org/role-of-genomics-coronavirus-covid-19/?utm_source=Nebula%20Genomics&utm_medium=email&utm_campaign=COVID-19

Aviva Lev-Ari
13.3K Tweets

Aviva Lev-Ari
@AVIVA1950

My BIO lnkd.in/eEyn69r MediaPharma ex-SRI ex-MITRE ex-McGraw-Hill Followed by

Aviva Lev-Ari
@AVIVA1950

Predicting the #ProteinStructure of #Coronavirus: #Inhibition of #Nsp15 #Cryo-EM – #spike #protein structure (#experimentally verified) vs #AI-predicted protein structures (not verified) of

(

) #AlphaFold

Quote Tweet
Eric Topol
@EricTopol
·
The problem w/ visionaries is that we don’t recognize them in a timely manner (too late) Ralph Baric @UNCpublichealth and Vineet Menachery deserve recognition for being 5 yrs ahead of #COVID19 nature.com/articles/nm.39 @NatureMedicine pnas.org/content/113/11 @PNASNews via @hoondy

Image

Image

Image

Image

 

 

Senior, A.W., Evans, R., Jumper, J. et al. Improved protein structure prediction using potentials from deep learningNature 577, 706–710 (2020)https://doi.org/10.1038/s41586-019-1923-7

Abstract

Protein structure prediction can be used to determine the three-dimensional shape of a protein from its amino acid sequence1. This problem is of fundamental importance as the structure of a protein largely determines its function2; however, protein structures can be difficult to determine experimentally. Considerable progress has recently been made by leveraging genetic information. It is possible to infer which amino acid residues are in contact by analysing covariation in homologous sequences, which aids in the prediction of protein structures3. Here we show that we can train a neural network to make accurate predictions of the distances between pairs of residues, which convey more information about the structure than contact predictions. Using this information, we construct a potential of mean force4 that can accurately describe the shape of a protein. We find that the resulting potential can be optimized by a simple gradient descent algorithm to generate structures without complex sampling procedures. The resulting system, named AlphaFold, achieves high accuracy, even for sequences with fewer homologous sequences. In the recent Critical Assessment of Protein Structure Prediction5 (CASP13)—a blind assessment of the state of the field—AlphaFold created high-accuracy structures (with template modelling (TM) scores6 of 0.7 or higher) for 24 out of 43 free modelling domains, whereas the next best method, which used sampling and contact information, achieved such accuracy for only 14 out of 43 domains. AlphaFold represents a considerable advance in protein-structure prediction. We expect this increased accuracy to enable insights into the function and malfunction of proteins, especially in cases for which no structures for homologous proteins have been experimentally determined7. https://doi.org/10.1038/s41586-019-1923-7

[ALA added bold face]

COVID-19 outbreak

The scientific community has galvanised in response to the recent COVID-19 outbreak, building on decades of basic research characterising this virus family. Labs at the forefront of the outbreak response shared genomes of the virus in open access databases, which enabled researchers to rapidly develop tests for this novel pathogen. Other labs have shared experimentally-determined and computationally-predicted structures of some of the viral proteins, and still others have shared epidemiological data. We hope to contribute to the scientific effort using the latest version of our AlphaFold system by releasing structure predictions of several under-studied proteins associated with SARS-CoV-2, the virus that causes COVID-19. We emphasise that these structure predictions have not been experimentally verified, but hope they may contribute to the scientific community’s interrogation of how the virus functions, and serve as a hypothesis generation platform for future experimental work in developing therapeutics. We’re indebted to the work of many other labs: this work wouldn’t be possible without the efforts of researchers across the globe who have responded to the COVID-19 outbreak with incredible agility.

Knowing a protein’s structure provides an important resource for understanding how it functions, but experiments to determine the structure can take months or longer, and some prove to be intractable. For this reason, researchers have been developing computational methods to predict protein structure from the amino acid sequence.  In cases where the structure of a similar protein has already been experimentally determined, algorithms based on “template modelling” are able to provide accurate predictions of the protein structure. AlphaFold, our recently published deep learning system, focuses on predicting protein structure accurately when no structures of similar proteins are available, called “free modelling”.  We’ve continued to improve these methods since that publication and want to provide the most useful predictions, so we’re sharing predicted structures for some of the proteins in SARS-CoV-2 generated using our newly-developed methods.

It’s important to note that our structure prediction system is still in development and we can’t be certain of the accuracy of the structures we are providing, although we are confident that the system is more accurate than our earlier CASP13 system. We confirmed that our system provided an accurate prediction for the experimentally determined SARS-CoV-2 spike protein structure shared in the Protein Data Bank, and this gave us confidence that our model predictions on other proteins may be useful. We recently shared our results with several colleagues at the Francis Crick Institute in the UK, including structural biologists and virologists, who encouraged us to release our structures to the general scientific community now. Our models include per-residue confidence scores to help indicate which parts of the structure are more likely to be correct. We have only provided predictions for proteins which lack suitable templates or are otherwise difficult for template modeling.  While these understudied proteins are not the main focus of current therapeutic efforts, they may add to researchers’ understanding of SARS-CoV-2.

Normally we’d wait to publish this work until it had been peer-reviewed for an academic journal. However, given the potential seriousness and time-sensitivity of the situation, we’re releasing the predicted structures as we have them now, under an open license so that anyone can make use of them.

Interested researchers can download the structures here, and can read more technical details about these predictions in a document included with the data. The protein structure predictions we’re releasing are for SARS-CoV-2 membrane protein, protein 3a, Nsp2, Nsp4, Nsp6, and Papain-like proteinase (C terminal domain). To emphasise, these are predicted structures which have not been experimentally verified. Work on the system continues for us, and we hope to share more about it in due course.

Citation:  John Jumper, Kathryn Tunyasuvunakool, Pushmeet Kohli, Demis Hassabis, and the AlphaFold Team, “Computational predictions of protein structures associated with COVID-19”, DeepMind website, 5 March 2020, https://deepmind.com/research/open-source/computational-predictions-of-protein-structures-associated-with-COVID-19

SARS-COV-2 MEMBRANE PROTEIN: A RENDERING OF ONE OF OUR PROTEIN STRUCTURE PREDICTIONS

SOURCES

Computational predictions of protein structures associated with COVID-19

https://deepmind.com/research/open-source/computational-predictions-of-protein-structures-associated-with-COVID-19

AlphaFold: Using AI for scientific discovery 

https://deepmind.com/blog/article/AlphaFold-Using-AI-for-scientific-discovery

 

DeepMind has shared its results with researchers at the Francis Crick Institute, a biomedical research lab in the UK, as well as offering it for download from its website.

“Normally we’d wait to publish this work until it had been peer-reviewed for an academic journal. However, given the potential seriousness and time-sensitivity of the situation, we’re releasing the predicted structures as we have them now, under an open license so that anyone can make use of them,” it said. [ALA added bold face]

There are 93,090 cases of COVID-19, and 3,198 deaths, spread across 76 countries, according to the latest report from the World Health Organization at time of writing. ®

SOURCE

https://www.theregister.co.uk/2020/03/06/deepmind_covid19_outbreak/

 

  • MHC content – The spike protein is thought to be the key to binding to cells via the angiotensin II receptor, the major mechanism the immune system uses to distinguish self from non-self

Preliminary Identification of Potential Vaccine Targets for the COVID-19 Coronavirus (SARS-CoV-2) Based on SARS-CoV Immunological Studies

Syed Faraz Ahmed 1,† , Ahmed A. Quadeer 1, *,† and Matthew R. McKay 1,2, *

1 Department of Electronic and Computer Engineering, The Hong Kong University of Science and

Technology, Hong Kong, China; sfahmed@connect.ust.hk

2 Department of Chemical and Biological Engineering, The Hong Kong University of Science and

Technology, Hong Kong, China

* Correspondence: eeaaquadeer@ust.hk.com (A.A.Q.); m.mckay@ust.hk (M.R.M.)

These authors contributed equally to this work.

Received: 9 February 2020; Accepted: 24 February 2020; Published: 25 February 2020

Abstract:

The beginning of 2020 has seen the emergence of COVID-19 outbreak caused by a novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). There is an imminent need to better understand this new virus and to develop ways to control its spread. In this study, we sought to gain insights for vaccine design against SARS-CoV-2 by considering the high genetic similarity between SARS-CoV-2 and SARS-CoV, which caused the outbreak in 2003, and leveraging existing immunological studies of SARS-CoV. By screening the experimentally determined SARS-CoV-derived B cell and T cell epitopes in the immunogenic structural proteins of SARS-CoV, we identified a set of B cell and T cell epitopes derived from the spike (S) and nucleocapsid (N) proteins that map identically to SARS-CoV-2 proteins. As no mutation has been observed in these identified epitopes among the 120 available SARS-CoV-2 sequences (as of 21 February 2020), immune targeting of these epitopes may potentially offer protection against this novel virus. For the T cell epitopes, we performed a population coverage analysis of the associated MHC alleles and proposed a set of epitopes that is estimated to provide broad coverage globally, as well as in China. Our findings provide a screened set of epitopes that can help guide experimental efforts towards the development of vaccines against SARS-CoV-2.

Keywords: Coronavirus; 2019-nCoV; 2019 novel coronavirus; SARS-CoV-2; COVID-19; SARS-CoV; MERS-CoV; T cell epitopes; B cell epitopes; vaccine [ALA added bold face]

SOURCE

https://www.mdpi.com/1999-4915/12/3/254/pdf

 

Selected Online COMMENTS to

https://forums.theregister.co.uk/forum/all/2020/03/06/deepmind_covid19_outbreak/

MuscleguySilver badge

Re: Protein structure prediction has been done for ages…

Not quite, Natural Selection does not measure methods, it measures outputs, usually at the organism level.

Sure correct folding is necessary for much protein function and we have prions and chaperone proteins to get it wrong and right.

The only way NS measures methods and mechanisms is if they are very energetically wasteful. But there are some very wasteful ones out there. Beta-Catenin at the end of point of Wnt signalling comes particularly to mind.

Chemist

Re: Does not matter at all

“Determining the structure of the virus proteins might also help in developing a molecule that disrupts the operation of just those proteins, and not anything else in the human body.”

Well it might, but predicting whether a ‘drug’ will NOT interact with any other of the 20000+ protein in complex organisms is well beyond current science. If we could do that we could predict/avoid toxicity and other non-mechanism related side-effects & mostly we can’t.

rob miller

Title

There are 480 structures on PDBe resulting from a search on ‘coronavirus,’ the top hits from MERS and SARS. PR stunt or not, they did win the most recent CASP ‘competition’, so arguably it’s probably our best shot right now – and I am certainly not satisfied that they have been sufficiently open in explaining their algorithms though I have not checked in the last few months. No one is betting anyone’s health on this, and it is not like making one wrong turn in a series of car directions. Latest prediction algorithms incorporate contact map predictions, so it’s not like a wrong dihedral angle sends the chain off in the wrong direction. A decent model would give something to run docking algorithms against with a series of already approved drugs, then we take that shortlist into the lab. A confirmed hit could be an instantly available treatment, no two year wait as currently estimated. [ALA added bold face]

jelabarre59Silver badge

Re: these structure predictions have not been experimentally verified

Naaaah. Can’t possibly be a stupid marketing stunt.

Well yes, a good possibility. But it can also be trying to build on the open-source model of putting it out there for others to build and improve upon. Essentially opening that “peer review” to a larger audience quicker. [ALA added bold face]

We shall see.

Anonymous Coward

Anonymous CowardWhat bothers me, besides the obvious PR stunt, is that they say this prediction is licensed. How can a prediction from software be protected by, I presume, patents? And if this can be protected without even verifying which predictions actually work, what’s to stop someone spitting out millions of random, untested predictions just in case they can claim ownership later when one of them is proven to work? [ALA added bold face]

 

 

SOURCES

 

  • AI-predicted protein structures could unlock vaccine for Wuhan coronavirus… if correct… after clinical trials It’s not quite DeepMind’s ‘Come with me if you want to live’ moment, but it’s close, maybe

Experimentally derived by a group of scientists at the University of Texas at Austin and the National Institute of Allergy and Infectious Diseases, an agency under the US National Institute of Health. They both feature a “Spike protein structure.”

  • Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation

See all authors and affiliations

Science  19 Feb 2020:
eabb2507
DOI: 10.1126/science.abb2507

 

  • Israeli scientists: We have developed a coronavirus vaccine

https://www.fromthegrapevine.com/health/coronavirus-vaccine-israel-migal-research-institute-david-zigdon

Other related articles published in this Open Access Online Scientific Journal include the following:

 

  • Group of Researchers @ University of California, Riverside, the University of Chicago, the U.S. Department of Energy’s Argonne National Laboratory, and Northwestern University solve COVID-19 Structure and Map Potential Therapeutics

Reporters: Stephen J Williams, PhD and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2020/03/06/group-of-researchers-solve-covid-19-structure-and-map-potential-therapeutic/

 

  • Is It Time for the Virtual Scientific Conference?: Coronavirus, Travel Restrictions, Conferences Cancelled Curator:

Stephen J. Williams, PhD

https://pharmaceuticalintelligence.com/2020/03/06/is-it-time-for-the-virtual-scientific-conference-coronavirus-travel-restrictions-conferences-cancelled/

Read Full Post »


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

 

Effective humoral immune responses to infection and immunization are defined by high-affinity antibodies generated as a result of B cell differentiation and selection that occurs within germinal centers (GC). Within the GC, B cells undergo affinity maturation, an iterative and competitive process wherein B cells mutate their immunoglobulin genes (somatic hypermutation) and undergo clonal selection by competing for T cell help. Balancing the decision to remain within the GC and continue participating in affinity maturation or to exit the GC as a plasma cell (PC) or memory B cell (MBC) is critical for achieving optimal antibody avidity, antibody quantity, and establishing immunological memory in response to immunization or infection. Humoral immune responses during chronic infections are often dysregulated and characterized by hypergammaglobulinemia, decreased affinity maturation, and delayed development of neutralizing antibodies. Previous studies have suggested that poor antibody quality is in part due to deletion of B cells prior to establishment of the GC response.

 

In fact the impact of chronic infections on B cell fate decisions in the GC remains poorly understood. To address this question, researchers used single-cell transcriptional profiling of virus-specific GC B cells to test the hypothesis that chronic viral infection disrupted GC B cell fate decisions leading to suboptimal humoral immunity. These studies revealed a critical GC differentiation checkpoint that is disrupted by chronic infection, specifically at the point of dark zone re-entry. During chronic viral infection, virus-specific GC B cells were shunted towards terminal plasma cell (PC) or memory B cell (MBC) fates at the expense of continued participation in the GC. Early GC exit was associated with decreased B cell mutational burden and antibody quality. Persisting antigen and inflammation independently drove facets of dysregulation, with a key role for inflammation in directing premature terminal GC B cell differentiation and GC exit. Thus, the present research defines GC defects during chronic viral infection and identify a critical GC checkpoint that is short-circuited, preventing optimal maturation of humoral immunity.

 

Together, these studies identify a key GC B cell differentiation checkpoint that is dysregulated during chronic infection. Further, it was found that the chronic inflammatory environment, rather than persistent antigen, is sufficient to drive altered GC B cell differentiation during chronic infection even against unrelated antigens. However, the data also indicate that inflammatory circuits are likely linked to perception of antigen stimulation. Nevertheless, this study reveals a B cell-intrinsic program of transcriptional skewing in chronic viral infection that results in shunting out of the cyclic GC B cell process and early GC exit with consequences for antibody quality and hypergammaglobulinemia. These findings have implications for vaccination in individuals with pre-existing chronic infections where antibody responses are often ineffective and suggest that modulation of inflammatory pathways may be therapeutically useful to overcome impaired humoral immunity and foster affinity maturation during chronic viral infections.

 

References:

 

https://www.biorxiv.org/content/10.1101/849844v1

 

https://www.ncbi.nlm.nih.gov/pubmed/25656706

 

https://www.ncbi.nlm.nih.gov/pubmed/27653600

 

https://www.ncbi.nlm.nih.gov/pubmed/26912368

 

https://www.ncbi.nlm.nih.gov/pubmed/26799208

 

https://www.ncbi.nlm.nih.gov/pubmed/23001146

 

Read Full Post »


Newly Found Functions of B Cell

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

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

 

Other advances that are providing insight include:

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

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

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

 

References:

 

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

 

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

 

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

 

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

 

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

 

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

 

Read Full Post »

Immunoediting can be a constant defense in the cancer landscape


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/

 

Read Full Post »

Immunotherapy may help in glioblastoma survival


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.

 

References:

 

https://www.washingtonpost.com/health/2019/02/11/immunotherapy-may-help-patients-with-kind-cancer-that-killed-john-mccain/?noredirect=on&utm_term=.e1b2e6fffccc

 

https://www.ncbi.nlm.nih.gov/pubmed/30742122

 

https://www.practiceupdate.com/content/neoadjuvant-anti-pd-1-immunotherapy-promotes-immune-responses-in-recurrent-gbm/79742/37/12/1

 

https://www.esmo.org/Oncology-News/Neoadjuvant-PD-1-Blockade-in-Glioblastoma

 

https://neurosciencenews.com/immunotherapy-glioblastoma-cancer-10722/

 

Read Full Post »


CHI’s NK Cell-Based Cancer Immunotherapy Symposium, September 19 in Boston

Reporter: Aviva Lev-Ari, PhD, RN

 

Announcement from LPBI Group: key code LPBI16 for Exclusive Discount to attend Boston’s Discovery on Target (September 2016)

https://pharmaceuticalintelligence.com/2016/05/13/announcement-from-lpbi-group-key-code-lpbi16-for-exclusive-discount-to-attend-bostons-discovery-on-target-september-2016/

DOT-150x150

DOT-NCT-700x150

FEATURED SESSION:

Natural killer (NK) cells have been known to have advantages over T cells, yet their therapeutic potential in the clinic has been largely unexplored.

Cambridge Healthtech Institute’s NK Cell-Based Cancer Immunotherapy Symposium, September 19 in Boston, is dedicated to the exploration of utilizing NK cells for new adoptive cell therapies, including updates from ongoing clinical studies.

NK CELL IMMUNO-ONCOLOGY AND CLINICAL STUDIES

Harnessing Adaptive NK Cells in Cancer Therapy

Karl-Johan Malmberg, M.D., Ph.D., Professor, Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital

  • We have recently completed a Phase I/II clinical trial with transfer of haploidentical NK cells to patients with high-risk myelodysplastic syndrome. Six of the 16 treated patients achieved morphological complete remission and five of these underwent allogeneic stem cell transplantation resulting in long-term survival in four patients. The quality and number of infused NK cells as well as their transient engraftment in the recipient correlated with decrease in mutational burden and clinical outcomes. These results suggest that adoptive transfer of allogeneic NK cells may hold utility as a bridge to transplant in patients who are refractory to induction therapy. Current efforts to selectively expand metabolically optimized adaptive NK cells for the next generation NK cell cancer immunotherapy will be discussed.

Update on Systemic and Locoregional Cancer Immunotherapy with IL-21-Expanded NK Cells

Dean Anthony Lee, M.D., Ph.D., Professor, Pediatrics; Director, Cellular Therapy and Cancer Immunotherapy Program, Nationwide Children’s Hospital; James Comprehensive Cancer Center/Solove Research Institute, The Ohio State University

  • The ability to generate clinical-grade NK cell products of sufficient purity, number, and function has enabled broader application of adoptive NK cell therapy in clinical trials. We translated our IL-21-based NK cell expansion platform to clinical grade and scale and initiated 7 clinical trials that administer NK cell immunotherapy with high cell doses or repeated dosing in transplant, adjuvant, or stand-alone settings. These trials have collectively delivered approximately 150 infusions to over 60 patients at doses of up to 10e8/kg. We will discuss the importance of STAT3 signaling in this setting, describe early outcome and correlative data from these studies, and present preclinical data supporting future clinical trials that build on this platform.

REGISTER

BY AUGUST 12 TO

SAVE UP TO $200

VISIT

WEBSITE

DOWNLOAD PDF AGENDA

Suggested Event Package

SYMPOSIUM

NK Cell-Based Cancer Immunotherapy

SEPT. 19

CONFERENCE

Antibodies Against Membrane Protein Targets (Part One)

SEPT. 20-21

CONFERENCE

Antibodies Against Membrane Protein Targets (Part Two)

SEPT. 21-22

The exhibit hall was sold out in 2015, so please contact us early to reserve your place. To customize your sponsorship or exhibit package for 2016, contact:

Jon Stroup

Sr. Business Development Manager

P: 781-972-5483

E: jstroup@healthtech.com

Sponsorship/Exhibitor Information >>

 

DiscoveryOnTarget.com | Register by August 12 to SAVE up to $200 | Download PDF Agenda

Cambridge Healthtech Institute | 250 First Avenue, Suite 300, Needham, MA 02494 | www.healthtech.com | 781-972-5400

SOURCE

From: NK Cell Symposium <heidio@healthtech.com>

Date: Tuesday, August 9, 2016 at 1:40 PM

To: Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu>

Subject: NK Cells for Adoptive Therapies: The Future of Cancer Immunotherapy?

Read Full Post »


AGENDA for Personalized Immunotherapy – Personalized Oncology in the Genomic Era: Expanding the Druggable Space CHI’S 4TH ANNUAL IMMUNO-ONCOLOGY SUMMIT – AUGUST 30-31, 2016 | Marriott Long Wharf Hotel – Boston, MA

 

Personalized Immunotherapy Personalized Oncology in the Genomic Era: Expanding the Druggable Space

http://www.immuno-oncologysummit.com/uploadedFiles/Immuno_Oncology_Summit/Agenda/16/2016-The-Immuno-Oncology-Summit-Brochure.pdf

 

TUESDAY, AUGUST 30 & WED, AUGUST 31

 

TUESDAY, AUGUST 30

12:00 pm Registration

TUMOR NEOANTIGENS FOR PERSONALIZED IMMUNOTHERAPY

1:15 Chairperson’s Opening Remarks

Pramod K. Srivastava, M.D., Ph.D., Professor, Immunology and Medicine, Director, Carole and Ray Neag Comprehensive Cancer Center, University of Connecticut School of Medicine

1:20 Basics of Personalized Immunotherapy: What Is a Good Antigen? Pramod K. Srivastava, M.D., Ph.D., Professor, Immunology and Medicine, Director, Carole and Ray Neag Comprehensive Cancer Center, University of Connecticut School of Medicine

The definition of host-protective immunogenic antigen(s) of any human cancer of non-viral origin is still an enigma. New approaches in cancer genomics and bioinformatics are now offering a plethora of candidate antigens, whose role in cancer immunity, and specifically in host-protective cancer immunity, is under extensive testing. Outlines of some broad rules are emerging and some of these shall be discussed.

1:50 Novel Antibodies against Immunogenic Neoantigens

Philip M. Arlen, M.D., President & CEO, Precision Biologics, Inc.

Two novel antibodies, NEO-102 (ensituximab) and NEO- 201, were developed from an allogeneic colorectal cancer vaccine that had previously shown activity in patients with metastatic colorectal cancer This vaccine was derived from an immunogenic component of the cell membrane from pooled surgical specimens from both primary and metastatic colon cancer. Patients who benefited from the vaccine in the prior clinical trial produced and sustained high levels of serum IgG against the vaccine. Several thousand candidate antibodies were screened against this vaccine and NEO- 102 and NEO-201 were candidates that demonstrated the ability to bind to colon cancer vs. normal tissue.

2:20 PD-1 Blockade in Tumors with Mismatch-Repair Deficiency

Luis Alberto Diaz, M.D., Associate Professor, Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center

Somatic mutations have the potential to encode “non-self” immunogenic antigens. Tumors with a large number of somatic mutations due to mismatch-repair defects appear to be highly susceptible to immune checkpoint blockade. This presentation will summarize the clinical and genomic data of using mutations as neoantigens.

2:50 Sponsored Presentations (Opportunities Available)

3:20 Refreshment Break in the Exhibit Hall with Poster Viewing

4:00 PLENARY KEYNOTE SESSION See Keynotes for details.

4:00 A New Era of Personalized Therapy: Using Tumor Neoantigens to Unlock the Immune System Matthew J. Goldstein, M.D., Ph.D., Director, Translational Medicine, Neon Therapeutics, Inc.

Neon Therapeutics, Inc. launched in 2015 to focus on advancing neoantigen biology to improve cancer patient care. A neoantigen-based product engine will allow Neon to develop further treatment modalities including next-generation vaccines and T cell therapies targeting both personalized as well as shared neoantigens. The company’s first trial will launch later this year investigating the combination of a personalized, vaccine with nivolumab in advanced Melanoma, NSCLC, and Bladder Cancer.

4:30 Emerging Innate Immune Targets for Enhancing Adaptive Anti-Tumor Responses

Michael Rosenzweig, Ph.D., Executive Director, Biology-Discovery, IMR Early Discovery, Merck Research Laboratories

Novel cancer immunotherapies targeting T cell checkpoint proteins have emerged as powerful tools to induce profound, durable regression and remission of many types of cancer. Despite these advances, multiple studies have demonstrated that not all patients respond to these therapies, and the ability to predict which patients may respond is limited. Harnessing the innate immune system to augment the adaptive anti-tumor response represents an attractive target for therapy, which has the potential to enhance both the percentage and rate of response to checkpoint blockade.

5:00 Reading Tea Leaves: The Dilemma of Prediction and Prognosis in Immunotherapy

Morganna Freeman, D.O., Associate Director, Melanoma & Cutaneous Oncology Program, The Angeles Clinic and Research Institute

With the rapid expansion of immunotherapeutics in oncology, scientifically significant advances have been made with both the depth and duration of antitumor responses. However, not all patients benefit, or quickly relapse, thus much scientific inquiry has been devoted to appropriate patient selection and how such obstacles might be overcome. While more is known about potential biomarkers, accurate prognostication persists as a knowledge gap, and efforts to bridge it will be discussed here.

5:30 Welcome Reception in the Exhibit Hall with Poster Viewing

 

WEDNESDAY, AUGUST 31

 

8:00 am Morning Coffee

PERSONALIZED IMMUNOTHERAPY WITH CANCER VACCINES

8:25 Chairperson’s Remarks

Ravi Madan, M.D., Clinical Director, Genitourinary Malignancies Branch, National Cancer Institute, National Institutes of Health

8:30 Cancer Vaccines in the Era of Checkpoint Inhibitors

Keith L. Knutson, Ph.D., Professor, Immunology, Mayo Clinic

Vaccination has been one of the most successful approaches to reduce incidence and mortality rates of infectious diseases and more recently cancer, including cervical cancer. Our goal is to develop vaccine strategies that can be delivered to breast cancer patients to boost host immune defenses following conventional treatments (e.g., surgery, chemotherapy, and radiation), in order to prevent recurrence of treatment resistant tumors. We believe that one of the better approaches is to vaccinate against abnormally expressed ‘self’ (non-mutated) antigens that contribute to the cancer initiation and progression.

9:00 Developing Therapeutic Cancer Vaccine Strategies for Prostate Cancer

Ravi Madan, M.D., Clinical Director, Genitourinary Malignancies Branch, National Cancer Institute, National Institutes of Health

The development of immunotherapy strategies has become the primary focus in oncology. This lecture will provide prostate cancer as a template to demonstrate synergies between immune-based therapies and chemotherapy, radiopharmaceuticals and hormonal therapies.

9:30 Getting Very Personal: Fully Individualized Tumor Neoantigen-Based Vaccine Approaches to Cancer Therapy

Karin Jooss, Ph.D., CSO, Gritstone Oncology

Genetic instability in tumors generates tumor-specific neoantigens which have been identified as the targets of new T cells in patients responding to checkpoint inhibitor therapy. Predicting neoantigens by sequencing routine clinical biopsy material, and then incorporating them into therapeutic cancer vaccines is an attractive concept being developed by Gritstone Oncology. The complexities of neoantigen prediction will be discussed, together with insights into how vaccine vectors are selected and designed.

10:00 Approaches to Assess Tumor Mutation Load for Selecting Patients for Cancer Immunotherapy

John Simmons, Ph.D., Manager, Research Services, Personal Genome

Diagnostics Tests to identify patients who are most likely to benefit from cancer immunotherapies are urgently needed. Here we discuss PGDx approaches to assess tumor mutation load as a potential predictor of clinical benefit for checkpoint inhibitors in multiple cancer types.

10:15 Sponsored Presentation (Opportunity Available)

10:30 Coffee Break in the Exhibit Hall with Poster Viewing

11:15 In situ Vaccination for Lymphoma

Joshua Brody, M.D., Director, Lymphoma Immunotherapy Program, Icahn School of Medicine at Mount Sinai

Prior ex vivo combinations of dendritic cells (DC) with tumor antigens have yielded immunologic and clinical responses. Intratumoral immunomodulation may bypass the need for ex vivo production of vaccine. In situ vaccination combines: intratumoral Flt3L to recruit DC, low dose radiotherapy to load DC with tumor antigens, and intratumoral TLR agonist to activate tumor-antigen-loaded DC. Preliminary results demonstrate DC recruitment and activation, systemic tumor regressions, and induction of neoantigen specific CD8 T cell responses after vaccination.

11:45 Immunotherapy Using Ad5 [E1-, E2b-] Vector Vaccines in the Cancer MoonShot 2020 Program

Frank R. Jones, Ph.D., Chairman & CEO, Etubics Corporation

The Cancer MoonShot 2020 project intends to design, initiate and complete randomized clinical trials at all stages of cancer in up to 20 tumor types in as many as 20,000 patients by the year 2020. Etubics is participating in the Cancer MoonShot 2020 program by providing its proprietary viral platform, known as Ad5 [E1-, E2b-] as a treatment agent in several of the program’s immunotherapeutic vaccination initiatives and trials.

12:15 pm Sponsored Presentations (Opportunities Available)

12:45 Luncheon Presentation to be Announced

Robert G. Petit, Ph.D., Executive Vice President & CSO, Advaxis Immunotherapies

1:15 Session Break

PERSONALIZED CELL THERAPY

1:55 Chairperson’s Remarks

Andrew M. Evens, D.O., Professor and Chief, Hematology/Oncology, Tufts University School of Medicine; Director, Tufts Cancer Center

2:00 Integration of Natural Killer-Based Therapy into the Treatment of Lymphoma Andrew M. Evens, D.O., Professor and Chief, Hematology/Oncology, Tufts University School of Medicine; Director, Tufts Cancer Center

Targeting signaling pathways or epitopes with small molecules and antibody-based immunotherapeutic agents is a leading strategy for cancer therapy. Promising immunotherapy agents being examined for the treatment of lymphoma include monoclonal antibodies, immunomodulatory agents, PD-1 inhibitors, chimeric antigen receptor (CAR) T-cells, and NK-based therapies. The optimum combinations or sequences of these therapeutics continue to be defined. Additionally, understanding tumor and patient/host heterogeneity is desired in order to optimize personalized medicine.

2:30 Dendritic Cells: Personalized Cancer Vaccines and Inducers of Multi-Epitope Specific T Cells for Adoptive Cell Therapy

Pawel Kalinski, M.D., Ph.D., Professor, Surgery, Immunology, and Bioengineering, University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute

Conditions of dendritic cell (DC) maturation affect their ability to cross-present cancer cell-derived antigens and induce clonal expansion and effector functions of responding T cells. We will discuss the pathways of DC maturation which promote their preferential interaction with naïve, memory and effector T cells, cross-presentation of antigens from dead cancer cells, and induction of large numbers of type-1 CD4+ and CD8+ T cells specific for multiple tumor-associated antigens ex vivo and in vivo.

3:00 Mesothelin-Targeted CAR T-Cell Therapy for Solid Tumors

Prasad S. Adusumilli, M.D., FACS, Deputy Chief of Translational & Clinical Research, Thoracic Surgery, Memorial Sloan-Kettering Cancer Center

Mesothelin, a cell-surface antigen, provides an exciting prospect based on its higher expression in a majority of solid tumors (estimated annual incidence of 340,000 and prevalence of 2 million patients in the U.S.), limited expression in normal tissues and its association with tumor aggressiveness. CAR T-cell therapy with second generation mesothelin-targeted CARs has been translated to clinical trials targeting mesothelioma, non-small cell lung cancer, triple-negative breast cancer, and other solid tumors.

3:30 Refreshment Break with Exhibit and Poster Viewing

4:15 Synthetic Regulation of T Cell Therapies Adds Safety and Enhanced Efficacy to Previously Unpredicted Therapies

David M. Spencer, Ph.D., CSO, Bellicum Pharmaceuticals

CAR- and TCR-based T cell therapies have had some spectacular successes in a handful of malignancies, but safety and efficacy concerns still impede broader adoption of these new technologies. Bellicum Pharmaceuticals has developed a suite of synthetic ligand-inducible switches to rapidly and rigorously regulate T cell therapies. These potent switches address both safety and anti-tumor efficacy and promise to further expand the reach of immunotherapy.

4:45 Long-Term Relapse-Free Survival of Patients with Acute Myeloid Leukemia (AML) Receiving a Telomerase- Engineered Dendritic Cell Immunotherapy

Jane Lebkowski, Ph.D., President & CSO, Research and Development, Asterias Biotherapeutics

There are few treatment options for patients with intermediate and high risk AML, and remission and relapse rates are dismal, especially in patients ≥ 60 years old. A Phase II clinical trial was conducted in subjects with AML to assess a dendritic cell immunotherapy (ASTVAC1) engineered to express a modified form of telomerase that is processed through both the MHC Class I and II antigen presentation pathways. The results suggest that immunotherapy with AST-VAC1 is safe, can stimulate immune responses to telomerase, and may extend relapse-free survival even in patients with high risk AML.

5:15 Activated and Exhausted Tumor Infiltrating B Cells in Non-Small Cell Lung Cancer Patients Present Antigen and Influence the Phenotype of CD4 Tumor Infiltrating T Cells

Tullia Bruno, Ph.D., Research Assistant Professor, Immunology, University of Pittsburgh

The focus of immunotherapy has been on subsets of CD8 and CD4 tumor infiltrating lymphocytes (TILs), however, tumor infiltrating B cells (TIL-Bs) have been reported in tertiary lymphoid structures (TLS) with CD4 TILs, and both TIL-Bs and TLS correlate with NSCLC patient survival. While TIL-Bs have been identified in NSCLC patients, their function in the tumor microenvironment has been understudied with no focus on their role as antigen presenting cells (APCs) and their influence on CD8 and CD4 TILs. Here, we demonstrate that TIL-Bs can efficiently present antigen to CD4 TILs and influence CD4 TIL phenotype depending on their exhaustion profile.

5:30 Dinner Short Course Registration

5:45 Close of Personalized Immunotherapy Conference

 

Read Full Post »


Next-generation Universal Cell Immunotherapy startup Adicet Bio, Menlo Park, CA is launched with $51M Funding by OrbiMed

Reporter: Aviva Lev-Ari, PhD, RN

On 1/27/2016 Adicet Bio announced the acquisition of Applied Immune Technologies (AIT)

Applied Immune Technologies (AIT) was acquired by Adicet, 1/27/2016.

AIT is a drug development company specializing in T-Cell Receptor-Like (TCRL) antibodies that are targeted to intracellular-derived peptides for a variety of therapeutic and diagnostic applications. AIT is also focused on identification and validation of novel therapeutic targets.

Therapeutic Antibodies
AIT’s core technology platforms encompass the identification and validation of novel MHC-based targets, as well as development of therapeutic Human Recombinant T-Cell Receptor-Like (TCRL) antibodies with the unique ability to bind with these intracellular peptide/MHC complexes with the specificity of cytotoxic T-cell killer cells.
AIT’s technologies enable the generation of a rich pipeline of therapeutic TCRL antibodies for intracellularly-derived, disease-specific targets which normally are not accessible to conventional antibodies. TCRL antibodies also have diagnostic applications in vaccine design, validation and monitoring, as well as analysis of antigen presentation in disease.

Immune System Explained 

Our immune system is composed of two arms: antibodies and T cells.

Soluble antibody molecules can bind to cell surface expressed proteins with high affinity and specificity. Upon binding, they can recruit effector cells of the immune system such as macrophages and Natural Killer (NK) cells, or mediate a biological signal into cells. Antibodies constitute today the most important class of targeted therapeutics in the bio-pharmaceutical industry.HOWEVER, analysis of the human proteome reveals that only 20% of human proteins are expressed on the cell surface. The remaining 80% of the human proteome is intracellular, and is therefore not accessible by conventional antibodies for therapeutic targeting clinical applications. Thus, there is an urgent need for the development of novel therapeutic antibodies against these intracellular based targets.

T cells mediate cellular immunity. CD8+ Cytotoxic T cells (CTLs) are the most potent effector cells of the immune system because they can recognize and kill diseased cells in a highly specific manner. They recognize intracellular proteins due to their ability to bind to the cell surface-expressed MHC-peptide complex, which presents peptides derived from intracellular proteins. Upon specific recognition of the MHC-peptide complex by the T-cell receptor (TCR), the CTLs undergo activation, proliferation and expansion, leading to destruction of the target diseased cells. HOWEVER, T cells are very difficult to manipulate for therapeutic applications and thus their advantage in recognizing intracellular targets is very difficult to apply for clinical therapeutic purposes.

 SOURCE

http://www.tcrl.co.il/home/doc.aspx?mCatID=57466Publications

AIT – Technology

TCRL™ Antibodies

AIT’s innovative solution is a platform technology for the development of human recombinant T-Cell Receptor-Like (TCRL) antibodies capable of targeting intracellular-derived peptides. These 3rd generation antibodies combine the advantages of both arms of the immune system. They are capable of binding to targets with high affinity and specificity like conventional antibodies. In addition, they can recognize and bind to intracellular-derived peptides presented on the MHC complex with the same degree of specificity as T cells, but without being limited by the regulatory mechanisms imposed on T cells.

TCRL antibodies enable us to identify and validate intracellular-expressed disease-specific targets and make them available for cell surface targeting. AIT’s platform technology further enables the generation of highly specific therapeutic antibodies against these intracellular-derived targets, which can bind to them on the cell surface and kill the diseased cells only, without effecting healthy cells. Thus, disease-specific targets that are expressed inside diseased cells are transformed into targets that can be recognized by soluble antibodies on the cell surface.

This breakthrough harnesses the power of the cellular arm of the immune system to attack diseased cells with soluble, readily made human monoclonal antibodies. Distinct from conventional monoclonal approaches that only attack cell surface-associated proteins, AIT’s TCRL technology addresses the far more abundant intracellular proteome. The combination of these features opens up entirely new vistas for the development of highly specific 3rdgeneration antibodies for the treatment of cancer, viral, and autoimmune diseases.

SOURCE

http://www.tcrl.co.il/home/doc.aspx?mCatID=27142

EpiTarget™ Discovery

EpiTarget is a unique approach for the discovery and validation of novel therapeutic MHC-based targets that can be applied to the isolation and characterization of new TCRL antibodies against a variety of disease-related intracellular targets.

The EpiTarget approach combines bioinformatic analysis and mass spectroscopy strategies to identify target peptides presented on MHC molecules that are differentially expressed on diseased cells of various histological origins.

The large intracellular proteome, which is not accessible for antibody-based recognition, can serve as a huge pool for new target discovery and a strong pipeline for therapeutic and diagnostic TCRL antibodies by integration of proteomic strategies with the TCRL technology.

SOURCE

http://www.tcrl.co.il/home/doc.aspx?mCatID=27130

Publications

Makler, O., Oved, K., Netzer, N., Wolf, D., Reiter, Y. Direct visualization of the dynamics of antigen presentation in human cells infected with cytomegalovirus revealed by antibodies mimicking TCR specificity. Eur. J. Immunol. 40: 1552-1562, 2010.

Klechevsky, E., Flamar, A.L., Cao, Y., Liu, M., Thompson-Snipes, L., O’Bar, A., Zurawski, S., Reiter, Y., Zurawski, G., Banchereau, J. Cross-priming CD8+ T cells by  targeting antigens to human dendritic cells through DCIR. Blood 116:1685-97, 2010.

Dahan, R., Tabul, M., Chou, Y.K., Meza-Romero, R., Andrew, S., Ferro, A.J., Burrows, G.G., Offner, H., Vandenbark, A.A., Reiter, Y. TCR-like antibodies distinguish conformational and functional differences in auto-reactive idiotopes present on two vs. four-domain MHC class II/peptide complexes. Eur. J. Immunol. 41:1465-79,2011.

Dahan, R, Reiter, Y. T-cell-receptor-like antibodies – generation, function and applications. Expert Rev Mol Med. 14:e6, 2012.

Noy, R., Epel, M., Haus-Cohen, M., Klechevsky, E., Makler, O., Michaeli, Y., Denkberg, G., Reiter, Y. T-cell receptor-like antibodies: novel reagents for clinical cancer immunology and immunotherapy. Exp. Rev. Anticancer Ther. 5(3) 2005.

Michaeli, Y., Sinik, K., Cohen, M., Reiter, Y:. Protein Instability and Aberrant Intracellular Processing of Tyrosinase Lead to High Presentation of HLA-A2/Tyrosinase Complexes on the Surface of Melanoma Cells. Eur. J. Immunol. In press 2012.

SOURCE

http://www.tcrl.co.il/home/doc.aspx?mCatID=27120

Next-generation immunotherapy startup Adicet is launched with $51M Funding by OrbiMed

Reporter: Aviva Lev-Ari, PhD, RN

 

biotech investing JP Morgan 2016Aya Jakobovits, former founder and CEO of Kite Pharma and current venture partner at OrbiMed, is heading up a new, next-gen immunotherapy startup – backed by an impressive $51 million Series A.

The Bay Area upstart, called Adicet Bio, is keeping very quiet about its underlying platform. Jakobovits emphasized in a phone interview, however, that the platform is meant to develop “universal immune cell therapy” – meaning it should be broadly applicable for a number of diseases, including cancer, autoimmune disease and inflammation.

It’s launching with news of an acquisition, however: Adicet just bought Israeli immunotherapy company Applied Immune Technologies, which focuses on the intracellular proteome.

“There’s a very good correlation between AIT and Adicet,” Jakobovits said.

AIT develops T-Cell Receptor-like antibodies that are targeted, through the Major Histocompatibility Complex (MHC), toward disease-linked peptides in cells. Adicet’s plan is to generate monoclonal antibodies that have affinity and high specificity to this MHC complex, she said.

Jakobovits said there’s no correlation or link between Kite Pharma and Adicet – in technology or in business dealings.

The financing round was led by OrbiMed with participation from Novartis Venture Fund and Pontifax.

SOURCE

http://medcitynews.com/2016/01/orbimed-launches-next-gen-immunotherapy-startup-adicet-with-51m/?utm_source=MedCity+News+Subscribers&utm_campaign=62cc8e78f9-MCN+Startups+Weekly&utm_medium=email&utm_term=0_5092836c41-62cc8e78f9-408919493

Adicet Bio Announces Closing of $51 Million Series A Financing and Acquisition of

Applied Immune Technologies

Menlo Park, CA (January 27, 2016): Adicet Bio, Inc. (“Adicet”), a biopharmaceutical company focused on the development of next-generation cell immunotherapies, announced today that it closed a $51 million Series A financing. Adicet also announced the acquisition of Applied Immune Technologies, Ltd. (“AIT”), an Israel-based company that develops immunotherapies directed to the intracellular proteome.

The financing was led by OrbiMed and also included Novartis Venture Fund and Pontifax.

“These significant financial resources will allow Adicet to progress its universal immune cell therapy (“uICT”) platform technology and related products and advance AIT’s programs and product pipeline,” said Aya Jakobovits, Ph.D., Founder, President and Chief Executive Officer of Adicet. “AIT’s technologies, capabilities, and intellectual property highly complement those of Adicet and position the combined company to become a leader in next-generation immunotherapy products for cancer and other indications.

Adicet was founded by Aya Jakobovits and OrbiMed. Previously, Dr. Jakobovits served as the President and founding CEO of Kite Pharma, Inc. Before joining Kite Pharma, she served as Executive Vice President, Head of Research and Development at Agensys, Inc., which became an affiliate of Astellas Pharma Inc. in a deal valued at up to $537 million. Before its acquisition, she served as Agensys’ Senior Vice President, Technology and Corporate Development and Chief Scientific Officer. Prior to Agensys, Dr. Jakobovits served as the Director, Discovery Research and Principal Scientist at Abgenix, Inc., which was spun out of Cell Genesys, Inc. and based on the XenoMouse® technology developed under her leadership. Abgenix was acquired by Amgen Inc. for $2.2 billion.

AIT specializes in generating and developing T-Cell Receptor-Like (“TCRL”) antibodies with high affinity and specificity to disease-specific intracellular peptides presented on the cell surface by the major histocompatibility complex (“MHC”). AIT also established Epitarget, a proprietary technology to identify and validate novel disease-specific peptide targets. AIT technology is based on work by Prof. Yoram Reiter, a world leader in the research of immunotherapies directed to the intracellular proteome. AIT will continue its operations in Israel as Adicet’s wholly-owned subsidiary.

Following the financing and acquisition, the Adicet Board of Directors will include Jonathan Silverstein and Carl Gordon, General Partners and Co-Heads of Global Private Equity at OrbiMed, Aya Jakobovits, Florent Gros, Managing Director at Novartis Venture Fund, and Erez Chimovits, Managing Director at OrbiMed Israel.

“We are excited to join forces again with Aya, a prominent figure in the field of immunotherapy with a track record of growing successful biotechnology companies,” said Carl Gordon.

“We look forward to building a leading immunotherapy company,” said Jonathan Silverstein. “The AIT acquisition expands Adicet’s platform technologies and its product pipeline.”

About Applied Immune Technologies, Ltd.

Applied Immune Technologies Ltd. (“AIT”) pioneered and advanced the generation and development of TCRLs for therapeutic and diagnostic applications in cancer, inflammation, autoimmune, and infectious diseases. AIT’s TCRLs are directed to disease-specific peptide-MHC complexes and are aimed at delivering potent payloads specifically to the diseased cells. AIT’s pipeline includes TCRLs directed to different disease indications. AIT also established a robust and proprietary technology for identification and validation of novel MHC-based targets. AIT was founded in 2006 by Prof. Yoram Reiter, Head of the Laboratory of Molecular Immunology at the Technion, Israel Institute of Technology, and Mira Peled-Kamar, Ph.D., AIT Chief Executive Officer. AIT is located in Haifa, Israel.

About Adicet Bio, Inc.

Adicet Bio, Inc. is a privately held, pre-clinical stage biotechnology company engaged in the design and development of cutting-edge immunotherapies for cancer and other disease indications, with a focus on novel universal immune cell therapies (uICT).  Adicet Bio is located in Menlo Park, California.

# # #

Contact:

Aya Jakobovits, Ph.D.
President and Chief Executive Officer
Adicet Bio, Inc.
Tel 310.990.3832
ajakobovits@adicetbio.com

For Media:

Joan Kureczka
Kureczka/Martin Associates
Tel 415.821.2413
Mobile 415.690.0210
joan@kureczka-martin.com

SOURCE

http://www.adicetbio.com/pr-012716.html

 

 

ATI Management

Management
Mira Peled-Kamar, PhD – Chief Executive Officer

Dr. Peled-Kamar, AIT’s Co-Founder and CEO, has extensive academic and biotech research experience in basic sciences as well as biotechnology and biomedical devices. Dr. Peled has worked for leading Israeli biotech companies including Biotechnology General and Interpharm, was the Co-Founder and CEO of BioMimic Pharma, and has been involved in the establishment of a number of start-ups. Dr. Peled received her PhD in Biochemistry and Molecular Biology from the Weizmann Institute of Science and completed her post doctorate at the University of California, Berkeley.
Yoram Reiter, PhD – Chief Scientific Officer

AIT Co-Founder and CSO, Professor Reiter is a world leader in the isolation of human TCRL molecules. Head of the Laboratory of Molecular Immunology at the Technion Institute, Prof. Reiter established a cutting-edge research program in the molecular immunology of cancer. His major work involves the development of novel immunotherapeutic approaches, as well as the study of molecular mechanisms in anti-tumor and anti-viral immunity. Prof. Reiter received his PhD from the Department of Immunology at the Weizmann Institute and subsequently spent 5 years at the NCI Laboratory of Molecular Biology headed by Dr. Ira Pastan, where he developed new approaches in antibody engineering. Prof. Reiter has published over 100 scientific papers and reviews, and holds 15 patents. He currently serves as an advisor to several pharmaceutical and biotechnology companies.

Galit Denkberg, PhD – R&D Manager

Dr. Denkberg leads AIT’s TCRL development team. A  graduate of the Technion’s Faculty of Biology, she worked with Prof. Yoram Reiter on the design and construction of the single-chain MHC molecules and was the first in the group to isolate TCRL antibodies from both immunized and naïve phage-display libraries. Through the years Dr. Denkberg has mastered a variety of molecular immunology, cellular immunology and molecular biology techniques and has become an expert in design, application, and characterization of TCRL antibodies. Dr. Denkberg is the author of 16 scientific papers related to the TCRL technology in leading peer-reviewed journals.

SOURCE

http://www.tcrl.co.il/home/doc.aspx?mCatID=27137

Read Full Post »