Children's immune response more effective against COVID-19 -- ScienceDaily

Understanding how to improve antibodies targeting OX40 for the treatment of cancer — ScienceDaily

  • January 13, 2021

Scientists at the University of Southampton’s Centre for Cancer Immunology have gained new insight into how the immune system can be better used to find and kill cancer cells.

Working with BioInvent International, a team led by Professor Mark Cragg and Dr Jane Willoughby from the Antibody and Vaccine Group, based at the Centre, have shown that antibodies, designed to target the molecule OX40, give a more active immune response when they bind closer to the cell membrane and can be modified to attack cancer in different ways.

OX40 is a ‘co-receptor’ that helps to stimulate the production of helper and killer T-cells during an immune response. One of the ways cancer avoids detection is by suppressing immune responses to stop functional tumour specific T-cells from being produced.

In the study, which has been published in Journal for ImmunoTherapy of Cancer, the team also discovered that switching the antibody’s isotype (the part of the antibody that engages with cells of the immune system) could change the way the antibody worked.

When the mIgG2a isotype was used, the antibody could delete cells called Treg cells which are suppressive in the immune system. When the mIgG1 isotype was present, the antibody could stimulate killer T-cells to increase and therefore kill more cancer cells.

Professor Cragg said: “Clinical trials with anti-OX40 antibodies have shown that the body can tolerate these drugs but unfortunately have also shown disappointing clinical responses. We need to understand why this is.

“This new data shows us that when there is a cancer with lots of Tregs we could use the equivalent of the m2IgGa isotype and in patients where we feel we need better cytotoxic T cells we could use the equivalent of a mIgG1 isotype to boost the immune response. This information is important for developing the next generation of OX40 antibodies that we hope will be more effective in treating patients with cancer.”

Story Source:

Materials provided by University of Southampton. Note: Content may be edited for style and length.

Researchers develop new technique to more efficiently isolate and identify rare T cells

New technique may enable researchers to more efficiently isolate and identify rare T cells

  • January 13, 2021

Scientists from the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA have developed a technique that will enable researchers to more efficiently isolate and identify rare T cells that are capable of targeting viruses, cancer and other diseases.

The approach could increase scientists’ understanding of how these critical immune cells respond to a wide range of illnesses and advance the development of T cell therapies. This includes immunotherapies that aim to boost the function and quantity of cancer or virus-targeting T cells and therapies intended to regulate the activity of T cells that are overactive in autoimmune diseases such as diabetes and multiple sclerosis.

The study, published today in Proceedings of the National Academy of Sciences, describes how the new method, called CLInt-Seq, combines and improves upon existing techniques to collect and genetically sequence rare T cells.

“T cells are critical for protecting the body against both infections and cancers,” said Pavlo Nesterenko, first author of the new paper and a graduate student in the lab of Dr. Owen Witte. “They’re both the effectors and organizers of the body’s adaptive immune response, which means they can be used as therapeutics and studying their dynamics can shed light on overall immune activity.”

T cells stand out from other immune cells because they are equipped with molecules on their surfaces called T-cell receptors that recognize fragments of foreign proteins called antigens.

Our bodies produce millions and millions of T cells per day and each of these cells has its own distinct set of receptors. Every T-cell receptor is capable of recognizing one specific antigen. One T-cell receptor might recognize an antigen from the virus that causes the common cold while another might recognize an antigen from breast cancer, for example.

When a T cell encounters an antigen its receptor recognizes, it springs to action, producing large numbers of copies of itself and instructing other parts of the immune system to attack cells bearing that antigen.

Researchers around the world are exploring methods to collect T cells with receptors targeting cancer or other illnesses like the SARS-CoV-2 virus from patients, expand those cells in the lab and then return this larger population of targeted T cells to patients to boost their immune response.

The problem is that in most populations of cells we have access to, whether it be from peripheral blood or samples taken from other parts of the human body, T cells with receptors of interest are found in very low numbers. Existing methods for capturing and identifying these T cells are labor-intensive and need improvement.”


Dr. Owen Witte, Senior Author and Founding Director, UCLA Broad Stem Cell Research Center

Part of the reason this process is inefficient is that when T cells recognize the antigen for which they have the corresponding receptor, they send out signals that prompt other cells nearby to partially activate.

“These so-called bystander cells are excited by the activity around them, but are not really capable of reacting to the antigen that provoked the immune response,” said Witte, who holds the presidential chair in developmental immunology in the department of microbiology, immunology and molecular genetics and is a member of the UCLA Jonsson Comprehensive Cancer Center.

When researchers attempt to isolate T cells with specific receptors using traditional methods, they end up capturing many of these bystander cells. CLInt-Seq alleviates this problem by incorporating a technique that enables researchers to distinguish T cells with receptors of interest from most bystander cells.

Isolating T cells with specific receptors is only the first step. In order for these isolated cells to be useful, they need to be analyzed using droplet-based mRNA sequencing, also known as Drop-seq, which can measure messenger RNA expression in thousands of individual cells at once.

“Once you know the sequence of a T-cell receptor of interest, you can use that information to develop therapies that either make more of that cell in the case of fighting cancer and viruses or introduce regulatory T cells with this receptor sequence to curb an overactive immune response in a given area,” Nesterenko said.

The process of isolating T cells with specific receptors requires that the cells’ contents are fixed in place using chemicals that form bonds between the proteins inside each cell and their surroundings – this technique is known as cross-linking. Unfortunately, cross-linking degrades the T cells’ RNA, which makes Drop-seq analysis very challenging. CLInt-Seq overcomes this hurdle by utilizing a method of cross-linking that is reversible and thus preserves the T cells’ RNA.

“The innovation of this system is that it combines an improved method that identifies T-cell receptors with more specificity with a chemical adaptation that makes this process compatible with droplet-based mRNA sequencing,” Witte said. “This addresses challenges at the heart of finding T-cell receptors for treating cancer and other diseases as well as viral infections – from acute viruses like the virus that causes COVID-19 to chronic viruses like Epstein Barr or herpes.”

Moving forward, the Witte lab is utilizing this technology to address a number of scientific questions, including identifying T-cell receptors that react to the SARS-CoV-2 virus and developing T-cell therapies for prostate cancer.

Source:

Journal reference:

Nesterenko, P.A., et al. (2021) Droplet-based mRNA sequencing of fixed and permeabilized cells by CLInt-seq allows for antigen-specific TCR cloning. PNAS. doi.org/10.1073/pnas.2021190118.

Researchers develop new technique to more efficiently isolate and identify rare T cells

Researchers develop new technique to more efficiently isolate and identify rare T cells

  • January 12, 2021

Scientists from the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA have developed a technique that will enable researchers to more efficiently isolate and identify rare T cells that are capable of targeting viruses, cancer and other diseases.

The approach could increase scientists’ understanding of how these critical immune cells respond to a wide range of illnesses and advance the development of T cell therapies. This includes immunotherapies that aim to boost the function and quantity of cancer or virus-targeting T cells and therapies intended to regulate the activity of T cells that are overactive in autoimmune diseases such as diabetes and multiple sclerosis.

The study, published today in Proceedings of the National Academy of Sciences, describes how the new method, called CLInt-Seq, combines and improves upon existing techniques to collect and genetically sequence rare T cells.

“T cells are critical for protecting the body against both infections and cancers,” said Pavlo Nesterenko, first author of the new paper and a graduate student in the lab of Dr. Owen Witte. “They’re both the effectors and organizers of the body’s adaptive immune response, which means they can be used as therapeutics and studying their dynamics can shed light on overall immune activity.”

T cells stand out from other immune cells because they are equipped with molecules on their surfaces called T-cell receptors that recognize fragments of foreign proteins called antigens.

Our bodies produce millions and millions of T cells per day and each of these cells has its own distinct set of receptors. Every T-cell receptor is capable of recognizing one specific antigen. One T-cell receptor might recognize an antigen from the virus that causes the common cold while another might recognize an antigen from breast cancer, for example.

When a T cell encounters an antigen its receptor recognizes, it springs to action, producing large numbers of copies of itself and instructing other parts of the immune system to attack cells bearing that antigen.

Researchers around the world are exploring methods to collect T cells with receptors targeting cancer or other illnesses like the SARS-CoV-2 virus from patients, expand those cells in the lab and then return this larger population of targeted T cells to patients to boost their immune response.

The problem is that in most populations of cells we have access to, whether it be from peripheral blood or samples taken from other parts of the human body, T cells with receptors of interest are found in very low numbers. Existing methods for capturing and identifying these T cells are labor-intensive and need improvement.”


Dr. Owen Witte, Study Senior Author and Founding Director, Broad Stem Cell Research Center, University of California, Los Angeles

Part of the reason this process is inefficient is that when T cells recognize the antigen for which they have the corresponding receptor, they send out signals that prompt other cells nearby to partially activate.

“These so-called bystander cells are excited by the activity around them, but are not really capable of reacting to the antigen that provoked the immune response,” said Witte, who holds the presidential chair in developmental immunology in the department of microbiology, immunology and molecular genetics and is a member of the UCLA Jonsson Comprehensive Cancer Center.

When researchers attempt to isolate T cells with specific receptors using traditional methods, they end up capturing many of these bystander cells. CLInt-Seq alleviates this problem by incorporating a technique that enables researchers to distinguish T cells with receptors of interest from most bystander cells.

Isolating T cells with specific receptors is only the first step. In order for these isolated cells to be useful, they need to be analyzed using droplet-based mRNA sequencing, also known as Drop-seq, which can measure messenger RNA expression in thousands of individual cells at once.

“Once you know the sequence of a T-cell receptor of interest, you can use that information to develop therapies that either make more of that cell in the case of fighting cancer and viruses or introduce regulatory T cells with this receptor sequence to curb an overactive immune response in a given area,” Nesterenko said.

The process of isolating T cells with specific receptors requires that the cells’ contents are fixed in place using chemicals that form bonds between the proteins inside each cell and their surroundings – this technique is known as cross-linking. Unfortunately, cross-linking degrades the T cells’ RNA, which makes Drop-seq analysis very challenging. CLInt-Seq overcomes this hurdle by utilizing a method of cross-linking that is reversible and thus preserves the T cells’ RNA.

“The innovation of this system is that it combines an improved method that identifies T-cell receptors with more specificity with a chemical adaptation that makes this process compatible with droplet-based mRNA sequencing,” Witte said. “This addresses challenges at the heart of finding T-cell receptors for treating cancer and other diseases as well as viral infections – from acute viruses like the virus that causes COVID-19 to chronic viruses like Epstein Barr or herpes.”

Source:

Journal reference:

Nesterenko, P.A., et al. (2021) Droplet-based mRNA sequencing of fixed and permeabilized cells by CLInt-seq allows for antigen-specific TCR cloning. Proceedings of the National Academy of Sciences. doi.org/10.1073/pnas.2021190118.

Freiburg researchers receive ERC funding to develop and test immunostimulatory drug candidates

Freiburg researchers receive ERC funding to develop and test immunostimulatory drug candidates

  • January 12, 2021

With the Proof of Concept funding line, the ERC grants recipients of ERC frontier research funds (Starting, Consolidator, Advanced or Synergy grants) with 150.000 Euro to develop promising ideas with commercial or societal potential to the proof of concept stage. With this funding, Olaf Groß and his team in the Metabolism and Inflammation Group at the Institute of Neuropathology of the Medical Center – University of Freiburg will test whether a new class of immune activating drugs they discovered can boost the effectiveness of cancer immunotherapies or vaccines against infectious diseases.

Groß studies a protein complex called the inflammasome within macrophages, specialized cells of the body’s defense system that patrol tissues for signs of danger. When their inflammasome is activated, macrophages sound the alarm by releasing of potent factors called cytokines. These cytokines alert other cells in the body, initiating an inflammatory response that helps other immune cells attack cancer cells or infections, explains Groß. Within the context of his ERC Starting Grant, he and his team discovered a new class of small molecules that potently and specifically activate the inflammasome, acting like turbo boosters for the immune system.

“There has been great excitement surrounding the development of inflammasome inhibitors for the treatment of inflammatory diseases”, Groß explains. “But we think that in the right clinical setting inflammasome activators might be just as valuable”, he adds. During the proof of concept phase, Groß and his team will test whether his IMMUNOSTIM compounds improve the efficacy of cancer treatment and vaccines.

We will also be looking for commercial partners for further development of this promising new class of immunotherapeutics.”


Olaf Groß, University of Freiburg

Groß received his doctorate at Technical University of Munich in 2008. Following postdoctoral research at the University of Lausanne in Switzerland he established an independent research group focused on the inflammasome at Klinikum rechts der Isar in Munich. Since 2017, Groß is Professor at the University of Freiburg in the Institute of Neuropathology of the University Medical Center. He is a Speaker of the University of Freiburg’s Emerging Field in Metabolism Research and member of the Cluster of Excellence CIBSS – the Centre for Integrative Biological Signalling Studies. Within CIBSS he studies the signaling mechanisms responsible for inflammasome activation by the IMMUNOSTIM compounds and screens for new molecules that modulate metabolic and immune signaling processes.

UCLA scientists develop method to more efficiently isolate and identify rare T cells

UCLA scientists develop method to more efficiently isolate and identify rare T cells

  • January 11, 2021

Newswise — Scientists from the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA have developed a technique that will enable researchers to more efficiently isolate and identify rare T cells that are capable of targeting viruses, cancer and other diseases.

The approach could increase scientists’ understanding of how these critical immune cells respond to a wide range of illnesses and advance the development of T cell therapies. This includes immunotherapies that aim to boost the function and quantity of cancer or virus-targeting T cells and therapies intended to regulate the activity of T cells that are overactive in autoimmune diseases such as diabetes and multiple sclerosis.

The study, published today in Proceedings of the National Academy of Sciences, describes how the new method, called CLInt-Seq, combines and improves upon existing techniques to collect and genetically sequence rare T cells.

“T cells are critical for protecting the body against both infections and cancers,” said Pavlo Nesterenko, first author of the new paper and a graduate student in the lab of Dr. Owen Witte. “They’re both the effectors and organizers of the body’s adaptive immune response, which means they can be used as therapeutics and studying their dynamics can shed light on overall immune activity.” 

T cells stand out from other immune cells because they are equipped with molecules on their surfaces called T-cell receptors that recognize fragments of foreign proteins called antigens.

Our bodies produce millions and millions of T cells per day and each of these cells has its own distinct set of receptors. Every T-cell receptor is capable of recognizing one specific antigen. One T-cell receptor might recognize an antigen from the virus that causes the common cold while another might recognize an antigen from breast cancer, for example.

When a T cell encounters an antigen its receptor recognizes, it springs to action, producing large numbers of copies of itself and instructing other parts of the immune system to attack cells bearing that antigen.

Researchers around the world are exploring methods to collect T cells with receptors targeting cancer or other illnesses like the SARS-CoV-2 virus from patients, expand those cells in the lab and then return this larger population of targeted T cells to patients to boost their immune response.

“The problem is that in most populations of cells we have access to, whether it be from peripheral blood or samples taken from other parts of the human body, T cells with receptors of interest are found in very low numbers,” said Witte, senior author of the paper and founding director of the UCLA Broad Stem Cell Research Center. “Existing methods for capturing and identifying these T cells are labor-intensive and need improvement.”

Part of the reason this process is inefficient is that when T cells recognize the antigen for which they have the corresponding receptor, they send out signals that prompt other cells nearby to partially activate.

“These so-called bystander cells are excited by the activity around them, but are not really capable of reacting to the antigen that provoked the immune response,” said Witte, who holds the presidential chair in developmental immunology in the department of microbiology, immunology and molecular genetics and is a member of the UCLA Jonsson Comprehensive Cancer Center.

When researchers attempt to isolate T cells with specific receptors using traditional methods, they end up capturing many of these bystander cells. CLInt-Seq alleviates this problem by incorporating a technique that enables researchers to distinguish T cells with receptors of interest from most bystander cells.

Isolating T cells with specific receptors is only the first step. In order for these isolated cells to be useful, they need to be analyzed using droplet-based mRNA sequencing, also known as Drop-seq, which can measure messenger RNA expression in thousands of individual cells at once.

“Once you know the sequence of a T-cell receptor of interest, you can use that information to develop therapies that either make more of that cell in the case of fighting cancer and viruses or introduce regulatory T cells with this receptor sequence to curb an overactive immune response in a given area,” Nesterenko said. 

The process of  isolating T cells with specific receptors requires that the cells’ contents are fixed in place using chemicals that form bonds between the proteins inside each cell and their surroundings – this technique is known as cross-linking. Unfortunately, cross-linking  degrades the T cells’ RNA, which makes Drop-seq analysis very challenging. CLInt-Seq overcomes this hurdle by utilizing a method of cross-linking that is reversible and thus preserves the T cells’ RNA.

“The innovation of this system is that it combines an improved method that identifies T-cell receptors with more specificity with a chemical adaptation that makes this process compatible with droplet-based mRNA sequencing,” Witte said. “This addresses challenges at the heart of finding T-cell receptors for treating cancer and other diseases as well as viral infections – from acute viruses like the virus that causes COVID-19 to chronic viruses like Epstein Barr or herpes.”

Moving forward, the Witte lab is utilizing this technology to address a number of scientific questions, including identifying T-cell receptors that react to the SARS-CoV-2 virus and developing T-cell therapies for prostate cancer.

This research was funded by the National Cancer Institute, the Parker Institute for Cancer Immunotherapy, a UCLA Tumor Immunology Training Grant and the UCLA Broad Stem Cell Research Center, including support from the Hal Gaba Director’s Fund for Cancer Stem Cell Research.

Researchers Discover Way to Boost Immunotherapy Against Breast Cancer

Researchers Discover Way to Boost Immunotherapy Against Breast Cancer

  • January 10, 2021
Strategies to Enhance the Activity of CAR T Cells Against Breast Cancer

A diagram showing the various strategies that could enhance the activity of CAR T cells against breast cancer. Credit: © 2020 Xu et al. Originally published in Journal of Experimental Medicine. DOI: 10.1084/jem.20200844

Boosting immune system T cells to effectively attack solid tumors, such as breast cancers, can be done by adding a small molecule to a treatment procedure called chimeric antigen receptor-T (CAR-T) cell therapy, according to a study by researchers at the UNC Lineberger Comprehensive Cancer Center. The boost helps recruit more immune cells into battle at the tumor site. The findings are published today (December 31, 2020) in the Journal of Experimental Medicine.

CAR-T immunotherapy, in which T cells are modified in the laboratory to express chimeric antigen receptors, CARs, that in turn target surface proteins on cancer cells, has been most effective in the treatment of patients with B-cell leukemia or lymphoma. But this new research, conducted in mouse models, points to the potential for using CAR-T therapy effectively against solid tumors as well.

“We know that CAR T cells are safe for patients with solid tumors but so far they have not been able to cause significant tumor regression in the overwhelming majority of people treated,” said Jonathan S. Serody, MD, the Elizabeth Thomas Professor of Medicine, Microbiology and Immunology and director of the Immunotherapy Program at UNC Lineberger. “Now we may have a new approach to make CAR T cells work in solid tumors, which we think could be a game-changer for therapies aimed at an appreciable number of cancers.”

Jonathan Serody

UNC Lineberger Comprehensive Cancer Center’s Jonathan S. Serody, MD, and colleagues report that adding a small molecule to a chimeric antigen receptor-T (CAR-T) cell therapy can help immune system T cells to effectively attack solid tumors, such as breast cancers. The boost helps recruit more immune cells into battle at the tumor site, according to the study published in the Journal of Experimental Medicine. Credit: UNC Lineberger Comprehensive Cancer Center

Serody is the paper’s corresponding author and Nuo Xu, PhD, formerly a graduate student at UNC Lineberger and UNC School of Medicine, is the first author.

For CAR-T cell therapy to be effective, T cells infused back into patients have to be able to migrate to the site of a tumor. In treating patients with non-solid tumors, such as lymphomas, CAR T cells home in on bone marrow and other organs that make up the lymphatic system. But for solid tumors, such as breast cancer, that is usually not the case. Even if they do migrate to the tumor, they don’t persist and expand well there due to the nature of the microenvironment surrounding such tumors, noted Serody.

So Serody and colleagues looked for ways to direct the lab-expanded cells toward the site of solid tumors. They focused on Th17 and Tc17 cells, which are known to have longer persistence in the micro-environment that surrounds a tumor, in part due to their better survival capabilities. To boost accumulation of Th17 and Tc17 cells near solid tumors, they turned to two small molecules that can activate an immune response: the stimulator of interferon genes (STING) agonists DMXAA and cGAMP.

DMXAA, which worked well in the investigator’s mouse studies, has not provided benefit in human clinical trials as it does not activate human STING. The other STING agonist however, cGAMP, does activate human STING and is known to boost the human immune system. It also works well in mice.

In Serody’s experiments, mice injected with cGAMP exhibited enhanced proliferation of T cells and those cells migrated to the tumor site. The end result was a significant decrease in tumor growth and enhanced survival.

“We hope to be able to study cGAMP in humans fairly soon,” concluded Serody. “We will look to see if we can produce improvements in the treatment of head and neck cancers first, and if that proves promising, move into other forms of cancer by using CAR T cells generated by one of our colleagues here at UNC.”

UNC Lineberger is one of a select few academic centers in the United States with the scientific, technical and clinical capabilities to develop and deliver CAR-T immunotherapy to patients. The cancer center currently has nine CAR-T clinical trials open and is developing new trials to treat a number of solid tumors, including ovarian and head and neck cancer. It also offers patients commercially available CAR-T therapies.

Reference: “STING agonist promotes CAR T cell trafficking and persistence in breast cancer” by Nuo Xu, Douglas C. Palmer, Alexander C. Robeson, Peishun Shou, Hemamalini Bommiasamy, Sonia J. Laurie, Caryn Willis, Gianpietro Dotti, Benjamin G. Vincent, Nicholas P. Restifo and Jonathan S. Serody, 31 December 2020, Journal of Experimental Medicine.
DOI: 10.1084/jem.20200844

In addition to Serody and Xu, the paper’s other authors are Alexander C. Robeson, PhD, Peishun Shou, PhD, Hemamalini Bommiasamy, PhD, Sonia J. Laurie, PhD, Caryn Willis, MS, Gianpietro Dotti, MD, and Benjamin Vincent, MD, UNC Lineberger and UNC School of Medicine; Douglas C. Palmer, PhD, National Cancer Institute; and Nicholas P. Restifo, MD, Lyell Immunophara, Inc., formerly of the National Cancer Institute.

This work was supported by grants from the National Cancer Institute (P50-CA058223) and the University Cancer Research Fund.

UCSF researchers discover a new way to control immune system's 'natural killer' cells

UCSF researchers discover a new way to control immune system’s ‘natural killer’ cells

  • January 10, 2021

UC San Francisco scientists have discovered a new way to control the immune system’s “natural killer” (NK) cells, a finding with implications for novel cell therapies and tissue implants that can evade immune rejection. The findings could also be used to enhance the ability of cancer immunotherapies to detect and destroy lurking tumors.

The study, published January 8, 2021 in the Journal of Experimental Medicine, addresses a major challenge for the field of regenerative medicine, said lead author Tobias Deuse, MD, the Julien I.E. Hoffman, MD, Endowed Chair in Cardiac Surgery in the UCSF Department of Surgery.

“As a cardiac surgeon, I would love to put myself out of business by being able to implant healthy cardiac cells to repair heart disease,” said Deuse, who is interim chair and director of minimally invasive cardiac surgery in the Division of Adult Cardiothoracic Surgery. “And there are tremendous hopes to one day have the ability to implant insulin-producing cells in patients with diabetes or to inject cancer patients with immune cells engineered to seek and destroy tumors. The major obstacle is how to do this in a way that avoids immediate rejection by the immune system.”

Deuse and Sonja Schrepfer, MD, PhD, also a professor in the Department of Surgery’s Transplant and Stem Cell Immunobiology Laboratory, study the immunobiology of stem cells. They are world leaders in a growing scientific subfield working to produce “hypoimmune” lab-grown cells and tissues — capable of evading detection and rejection by the immune system. One of the key methods for doing this is to engineer cells with molecular passcodes that activate immune cell “off switches” called immune checkpoints, which normally help prevent the immune system from attacking the body’s own cells and modulate the intensity of immune responses to avoid excess collateral damage.

Schrepfer and Deuse recently used gene modification tools to engineer hypoimmune stem cells in the lab that are effectively invisible to the immune system. Notably, as well as avoiding the body’s learned or “adaptive” immune responses, these cells could also evade the body’s automatic “innate” immune response against potential pathogens.

To achieve this, the researchers adapted a strategy used by cancer cells to keep innate immune cells at bay: They engineered their cells to express significant levels of a protein called CD47, which shuts down certain innate immune cells by avtivating a molecular switch found on these cells, called SIRPα. Their success became part of the founding technology of Sana Biotechnology, Inc, a company co-founded by Schrepfer, who now directs a team developing a platform based on these hypoimmune cells for clinical use.

But the researchers were left with a mystery on their hands — the technique was more successful than predicted. In particular, the field was puzzled that such engineered hypoimmune cells were able to deftly evade detection by NK cells, a type of innate immune cell that isn’t supposed to express a SIRPα checkpoint at all.

NK cells are a type of white blood cell that acts as an immunological first responder, quickly detecting and destroying any cells without proper molecular ID proving they are “self” — native body cells or at least permanent residents — which takes the form of highly individualized molecules called MHC class I (MHC-I).

When MHC-I is artificially knocked out to prevent transplant rejection, the cells become susceptible to accelerated NK cell killing, an immunological rejection that no one in the field had yet succeeded in inhibiting fully. Deuse and Schrepfer’s 2019 data, published in Nature Biotechnology, suggested they might have stumbled upon an off switch that could be used for that purpose.

All the literature said that NK cells don’t have this checkpoint, but when we looked at cells from human patients in the lab we found SIRPα there, clear as day. We can clearly demonstrate that stem cells we engineer to overexpress CD47 are able to shut down NK cells through this pathway.”


Sonja Schrepfer, MD, PhD, Professor, Department of Surgery’s Transplant and Stem Cell Immunobiology Laboratory

To explore their data, Deuse and Schrepfer approached Lewis Lanier, PhD, a world expert in NK cell biology. At first Lanier was sure there must be some mistake, because several groups had looked for SIRPα in NK cells already and it wasn’t there. But Schrepfer was confident in her team’s data.

“Finally it hit me,” Schrepfer said. “Most studies looking for checkpoints in NK cells were done in immortalized lab-grown cell lines, but we were studying primary cells directly from human patients. I knew that must be the difference.”

Further examination revealed that NK cells only begin to express SIRPα after they are activated by certain immune signaling molecules called cytokines. As a result, the researchers realized, this inducible immune checkpoint comes into effect only in already inflammatory environments and likely functions to modulate the intensity of NK cells’ attack on cells without proper MHC class I identification.

“NK cells have been a major barrier to the field’s growing interest in developing universal cell therapy products that can be transplanted “off the shelf” without rejection, so these results are extremely promising,” said Lanier, chair and J. Michael Bishop Distinguished Professor in the Department of Microbiology and Immunology.

In collaboration with Lanier, Deuse and Schrepfer comprehensively documented how CD47-expressing cells can silence NK cells via SIRPα. While other approaches can silence some NK cells, this was the first time anyone has been able to inhibit them completely. Notably, the team found that NK cells’ sensitivity to inhibition by CD47 is highly species-specific, in line with its function in distinguishing “self” from potentially dangerous “other”.

As a demonstration of this principle, the team engineered adult human stem cells with the rhesus macaque version of CD47, then implanted them into rhesus monkeys, where they successfully activated SIRPα in the monkeys’ NK cells, and avoided killing the transplanted human cells. In the future the same procedure could be performed in reverse, expressing human CD47 in pig cardiac cells, for instance, to prevent them from activating NK cells when transplanted into human patients.

“Currently engineered CAR T cell therapies for cancer and fledgling forms of regenerative medicine all rely on being able to extract cells from the patient, modify them in the lab, and then put them back in the patient. This avoids rejection of foreign cells, but is extremely laborious and expensive,” Schrepfer said. “Our goal in establishing a hypoimmune cell platform is to create off-the shelf products that can be used to treat disease in all patients everywhere.”

The findings could also have implications for cancer immunotherapy, as a way of boosting existing therapies that attempt to overcoming the immune checkpoints cancers use to evade immune detection. “Many tumors have low levels of self-identifying MHC-I protein and some compensate by overexpressing CD47 to keep immune cells at bay,” said Lanier, who is director of the Parker Institute for Cancer Immunotherapy at the UCSF Helen Diller Family Comprehensive Cancer Center. “This might be the sweet spot for antibody therapies that target CD47.”

Scientists gain new insight into how the immune system can be better used to destroy cancer cells

Scientists gain new insight into how the immune system can be better used to destroy cancer cells

  • January 10, 2021

Scientists at the University of Southampton’s Centre for Cancer Immunology have gained new insight into how the immune system can be better used to find and kill cancer cells.

Working with BioInvent International, a team led by Professor Mark Cragg and Dr Jane Willoughby from the Antibody and Vaccine Group, based at the Centre, have shown that antibodies, designed to target the molecule OX40, give a more active immune response when they bind closer to the cell membrane and can be modified to attack cancer in different ways.

OX40 is a ‘co-receptor’ that helps to stimulate the production of helper and killer T-cells during an immune response. One of the ways cancer avoids detection is by suppressing immune responses to stop functional tumour specific T-cells from being produced.

In the study, which has been published in Journal for ImmunoTherapy of Cancer, the team also discovered that switching the antibody’s isotype (the part of the antibody that engages with cells of the immune system) could change the way the antibody worked.

When the mIgG2a isotype was used, the antibody could delete cells called Treg cells which are suppressive in the immune system. When the mIgG1 isotype was present, the antibody could stimulate killer T-cells to increase and therefore kill more cancer cells.

Clinical trials with anti-OX40 antibodies have shown that the body can tolerate these drugs but unfortunately have also shown disappointing clinical responses. We need to understand why this is.


This new data shows us that when there is a cancer with lots of Tregs we could use the equivalent of the m2IgGa isotype and in patients where we feel we need better cytotoxic T cells we could use the equivalent of a mIgG1 isotype to boost the immune response. This information is important for developing the next generation of OX40 antibodies that we hope will be more effective in treating patients with cancer.”


Mark Cragg, Professor, University of Southampton

Source:

Journal reference:

Griffiths, J., et al. (2020) Domain binding and isotype dictate the activity of anti-human OX40 antibodies. Journal for ImmunoTherapy of Cancer. doi.org/10.1136/jitc-2020-001557.

Understanding how to improve antibodies targeting OX40 for the treatment of cancer

Understanding how to improve antibodies targeting OX40 for the treatment of cancer

  • January 8, 2021

IMAGE

IMAGE: Human T-Cell
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Credit: NIAID

Scientists at the University of Southampton’s Centre for Cancer Immunology have gained new insight into how the immune system can be better used to find and kill cancer cells.

Working with BioInvent International, a team led by Professor Mark Cragg and Dr Jane Willoughby from the Antibody and Vaccine Group, based at the Centre, have shown that antibodies, designed to target the molecule OX40, give a more active immune response when they bind closer to the cell membrane and can be modified to attack cancer in different ways.

OX40 is a ‘co-receptor’ that helps to stimulate the production of helper and killer T-cells during an immune response. One of the ways cancer avoids detection is by suppressing immune responses to stop functional tumour specific T-cells from being produced.

In the study, which has been published in Journal for ImmunoTherapy of Cancer, the team also discovered that switching the antibody’s isotype (the part of the antibody that engages with cells of the immune system) could change the way the antibody worked.

When the mIgG2a isotype was used, the antibody could delete cells called Treg cells which are suppressive in the immune system. When the mIgG1 isotype was present, the antibody could stimulate killer T-cells to increase and therefore kill more cancer cells.

Professor Cragg said: “Clinical trials with anti-OX40 antibodies have shown that the body can tolerate these drugs but unfortunately have also shown disappointing clinical responses. We need to understand why this is.

“This new data shows us that when there is a cancer with lots of Tregs we could use the equivalent of the m2IgGa isotype and in patients where we feel we need better cytotoxic T cells we could use the equivalent of a mIgG1 isotype to boost the immune response. This information is important for developing the next generation of OX40 antibodies that we hope will be more effective in treating patients with cancer.”

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Notes to Editors

1) Contact Peter Franklin, Media Realtions, University of Southampton. Tel: 07748 321087 Email: p.franklin@soton.ac.uk.

2) Reference: Jane E Willoughby, Mark S Cragg et al, Domain Binding and Isotype Dictate the Activity of Anti-human OX40 Antibodies; Journal for ImmunoTherapy of Cancer, https://jitc.bmj.com/content/8/2/e001557

3) For more about the University of Southampton’s Centre for Cancer Immunology visit: https://www.southampton.ac.uk/youreit/

4) The University of Southampton drives original thinking, turns knowledge into action and impact, and creates solutions to the world’s challenges. We are among the top 100 institutions globally (QS World University Rankings 2021). Our academics are leaders in their fields, forging links with high-profile international businesses and organisations, and inspiring a 22,000-strong community of exceptional students, from over 135 countries worldwide. Through our high-quality education, the University helps students on a journey of discovery to realise their potential and join our global network of over 200,000 alumni. http://www.southampton.ac.uk

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Astragalus helps fight cancer: Turkish scientists

Astragalus helps fight cancer: Turkish scientists

  • January 5, 2021

IZMIR, Turkey

Astragalus has shown to boost the immune system of cancer patients, Turkish scientists said Tuesday. 

Long-term studies observed that some of the molecules obtained from the herb increase the number of cytokines and strongly stimulate immunity.

A patent application made by a team for the discovery titled “A method to obtain Saponin molecules and using active molecules as immunomodulators” was registered by the Turkish Patent and Trademark Office.

Experts believe the discovery, whose international patent application is expected to be approved shortly, will make a significant contribution to cancer immunotherapy. 

Molecules stimulate immunity’

Erdal Bedir, a professor of bioengineering at the Izmir Institute of Technology, told Anadolu Agency that the team started the study based on the use of a kind of astragalus by cancer patients in southeastern Turkey.

His team of researchers saw that the herb does not have a direct effect on cancer cells, but it did boost the immune system, he said.

 

“We found that some of the molecules we obtained increase the amount of some important cytokines and stimulate immunity strongly. The patent obtained by our team includes molecules and derivatives obtained from a type of Astragalus,” he said. “We have demonstrated that the molecules presented in this patent can be used as powerful adjuvant candidates in vaccine formulations and even in cancer vaccines because they trigger the immune system at the cellular level.”

He emphasized that molecules are also ideal adjuvant candidates for vaccine formulations developed for the coronavirus.  

Researchers from the Izmir Institute of Technology also included chemistry professor Ali Cagir, Ph.D. candidate Nilgun Yakubogullari and Duygu Sag from the Biomedicine and Genome Center. 

*Writing by Seda Sevencan in Ankara



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