Tag: immunology

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How Bacteria Store Information to Kill Viruses (But Not Themselves)

by Luis Melecio-Zambrano

A group of bacteriophages, viruses that infect bacteria, imaged using transmission electron microscopy. New research sheds light on how bacteria fight off these invaders without triggering an autoimmune response. (Image: ZEISS Microscopy, CC BY-NC-ND 2.0)

During the last few years, CRISPR has grabbed headlines for helping treat patients with conditions as varied as blindness and sickle cell disease. However, long before humans co-opted CRISPR to fight genetic disorders, bacteria were using CRISPR as an immune system to fight off viruses.

In bacteria, CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) works by stealing small pieces of DNA from infecting viruses and storing those chunks in the genes of the bacteria. These chunks of DNA, called spacers, are then copied to form little tags, which attach to proteins that float around until they find a matching piece of DNA. When they find a match, they recognize it as a virus and cut it up.

Now, a paper published in Current Biology by researchers from the University of Pennsylvania Department of Physics and Astronomy shows that the risk of autoimmunity plays a key role in shaping how CRISPR stores viral information, guiding how many spacers bacteria keep in their genes, and how long those spacers are.

Ideally, spacers should only match DNA belonging to the virus, but there is a small statistical chance that the spacer matches another chunk of DNA in the bacteria itself. That could spell death from an autoimmune response.

“The adaptive immune system in vertebrates can produce autoimmune disorders. They’re very serious and dangerous, but people hadn’t really considered that carefully for bacteria,” says Vijay Balasubramanian, principal investigator for the paper and the Cathy and Marc Lasry Professor of Physics in the School of Arts & Sciences.

Balancing this risk can put the bacteria in something of an evolutionary bind. Having more spacers means they can store more information and fend off more types of viruses, but it also increases the likelihood that one of the spacers might match the DNA in the bacteria and trigger an autoimmune response.

Read the full story in Penn Today.

Vijay Balasubramanian is the Cathy and Marc Lasry Professor of Physics at the Department of Physics and Astronomy of the University of Pennsylvania, a visiting professor at Vrije Universiteit Brussel, and a member of the Penn Bioengineering Graduate Group.

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FDA Approves Penn Pioneered CAR T Cell Therapy for Third Indication

The U.S. Food and Drug Administration has expanded its approval for Kymriah, a personalized cellular therapy developed at the Abramson Cancer Center, this time for the treatment of adults with relapsed/refractory follicular lymphoma who have received at least two lines of systemic therapy. “Patients with follicular lymphoma who relapse or don’t respond to treatment have a poor prognosis and may face a series of treatment options without a meaningful, lasting response,” said Stephen J. Schuster, the Robert and Margarita Louis-Dreyfus Professor in Chronic Lymphocytic Leukemia and Lymphoma in the Division of Hematology Oncology. It’s the third FDA approval for the “living drug,” which was the first of its kind to be approved, in 2017, and remains the only CAR T cell therapy approved for both adult and pediatric patients.

“In just over a decade, we have moved from treating the very first patients with CAR T cell therapy and seeing them live healthy lives beyond cancer to having three FDA-approved uses of these living drugs which have helped thousands of patients across the globe,” said Carl June, MD, the Richard W. Vague Professor in Immunotherapy in the department of Pathology and Laboratory Medicine in Penn’s Perelman School of Medicine and director of the Center for Cellular Immunotherapies in the Abramson Cancer Center and director of the Parker Institute for Cancer Immunotherapy at Penn. “Today’s news is new fuel for our work to define the future of cell therapy and set new standards in harnessing the immune system to treat cancer.”

Research from June, a member of the Penn Bioengineering Graduate Group, led to the initial FDA approval for the CAR T therapy (sold by Novartis as Kymriah) for treating acute lymphoblastic leukemia (ALL), one of the most common childhood cancers.

Read the full announcement in Penn Medicine News.

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Penn Engineers Develop a New Method that Could Enable a Patient’s Own Antibodies to Eliminate Their Tumors

Tsourkas
Andrew Tsourkas, Ph.D.

One of the reasons that cancer is notoriously difficult to treat is that it can look very different for each patient. As a result, most targeted therapies only work for a fraction of cancer patients. In many cases, patients will have tumors with no known markers that can be targeted, creating an incredible challenge in identifying effective treatments. A new study seeks to address this problem with the development of a simple methodology to help differentiate tumors from healthy, normal tissues.

This new study, published in Science Advances, was led by Andrew Tsourkas, Professor in Bioengineering and Co-Director of the Center for Targeted Therapeutics and Translational Nanomedicine (CT3N), who had what he describes as a “crazy idea” to use a patient’s antibodies to find and treat their own tumors, taking advantage of the immune system’s innate ability to identify tumors as foreign. This study, spearheaded by Burcin Altun, a former postdoctoral researcher in Tsourkas’s lab, and continued and completed by Fabiana Zappala, a former graduate student in Penn Bioengineering, details their new method for site-specifically labeling “off-the-shelf” and native serum autoantibodies with T cell–redirecting domains.

Researchers have known for some time that cancer patients will generate an antibody response to their own tumors. These anti-tumor antibodies are quite sophisticated in their ability to specifically identify cancer cells; however, they are not sufficiently potent to confer a therapeutic effect. In this study, Tsourkas’s team converted these antibodies into bispecific antibodies, thereby increasing their potency. T cell-redirecting bispecific antibodies are a new form of targeted therapeutic that forms a bridge between tumor cells and T cells which have been found to be as much as a thousand-times more potent than antibodies alone. By combining the specificity of a patient’s own antibodies with the potency of bispecific antibodies, researchers can effectively create a truly personalized therapeutic that is effective against tumors.

In order to test out this new targeted therapeutic approach, the Tsourkas lab had to develop an entirely new technology, allowing them to precisely label antibodies with T cell targeting domains, creating a highly homogeneous product.  Previously it has not been possible to convert native antibodies into bispecific antibodies, but Tsourkas’s Targeted Imaging Therapeutics and Nanomedicine or TITAN lab specializes in the creation of novel targeted imaging and therapeutic agents for detection and treatment of various diseases. “Much is yet to be done before this could be considered a practical clinical approach,” says Tsourkas. “But I hope at the very least this works stimulates new ideas in the way we think about personalized medicine.”

In their next phase, Tsourkas’s team will be working to separate anti-tumor antibodies from other antibodies found in patients’ serum (which could potentially redirect the bispecific antibodies to other locations in the body), as well as examining possible adverse reactions or unintended effects and immunogenicity caused by the treatment. However, this study is just the beginning of a promising new targeted therapeutic approach to cancer treatment.

This work was supported by Emerson Collective and the National Institutes of Health, National Cancer Institute (R01 CA241661).

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A New Way to Profile T Cells Can Aid in Personalized Immunotherapy

by Melissa Pappas

A scanning electron micrograph of a healthy human T cell. A better understanding the wide variety of antigen receptors that appear on the surfaces of these critical components of the immune system is necessary for improving a new class of therapies. (Credit: NIAID)

Our bodies are equipped with specialized white blood cells that protect us from foreign invaders, such as viruses and bacteria. These T cells identify threats using antigen receptors, proteins expressed on the surface of individual T cells that recognize specific amino acid sequences found in or on those invaders. Once a T cell’s antigen receptors bind to the corresponding antigen, it can directly kill infected cells or call for backup from the rest of the immune system.

We have hundreds of billions of T cells, each with unique receptors that recognize unique antigens, so profiling this T cell antigen specificity is essential in our understanding of the immune response. It is especially critical in developing targeted immunotherapies, which equip T cells with custom antigen receptors that recognize threats they would otherwise miss, such as the body’s own mutated cancer cells.

Jenny Jiang, Ph.D.

Jenny Jiang, Peter and Geri Skirkanich Associate Professor of Innovation in Bioengineering, along with lab members and colleagues at the University of Texas, Austin, recently published a study in Nature Immunology that describes their technology, which simultaneously provides information in four dimensions of T cell profiling. Ke-Yue Ma and Yu-Wan Guo, a former post doc and current graduate student in Jiang’s Penn Engineering lab, respectively, also contributed to this study.

This technology, called TetTCR-SeqHD, is the first to provide such detailed information about single T cells in a high-throughput manner, opening doors for personalized immune diagnostics and immunotherapy development.

There are many pieces of information needed to comprehensively understand the immune response of T cells, and gathering all of these measurements simultaneously has been a challenge in the field. Comprehensive profiling of T cells includes sequencing the antigen receptors, understanding how specific those receptors are in their recognition of invading antigens, and understanding T cell gene and protein expression. Current technologies only screen for one or two of these dimensions due to various constraints.

“Current technologies that measure T cell immune response all have limitations,” says Jiang. “Those that use cultured or engineered T cells cannot tell us about their original phenotype, because once you take a cell out of the body to culture, its gene and protein expression will change. The technologies that address T cell and antigen sequencing with mass spectrometry damage genetic information of the sample. And current technologies that do provide information on antigen specificity use a very expensive binding ligand that can cost more than a thousand dollars per antigen, so it is not feasible if we want to look at hundreds of antigens. There is clearly room for advancement here.”

The TetTCR-SeqHD technology combines Jiang’s previously developed T cell receptor sequencing tool, TetTCR-Seq, described in a Nature Biotechnology paper published in 2018, with the new ability of characterizing both gene and protein expression.

Read the full story in Penn Engineering Today.

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Penn Researchers Show ‘Encrypted’ Peptides Could be Wellspring of Natural Antibiotics

by Melissa Pappas

César de la Fuente, Ph.D.

While biologists and chemists race to develop new antibiotics to combat constantly mutating bacteria, predicted to lead to 10 million deaths by 2050, engineers are approaching the problem through a different lens: finding naturally occurring antibiotics in the human genome.

The billions of base pairs in the genome are essentially one long string of code that contains the instructions for making all of the molecules the body needs. The most basic of these molecules are amino acids, the building blocks for peptides, which in turn combine to form proteins. However, there is still much to learn about how — and where — a particular set of instructions are encoded.

Now, bringing a computer science approach to a life science problem, an interdisciplinary team of Penn researchers have used a carefully designed algorithm to discover a new suite of antimicrobial peptides, hiding deep within this code.

The study, published in Nature Biomedical Engineering, was led by César de la Fuente, Presidential Assistant Professor in Bioengineering, Microbiology, Psychiatry, and Chemical and Biomolecular Engineering, spanning both Penn Engineering and Penn Medicine, and his postdocs Marcelo Torres and Marcelo Melo. Collaborators Orlando Crescenzi and Eugenio Notomista of the University of Naples Federico II also contributed to this work.

“The human body is a treasure trove of information, a biological dataset. By using the right tools, we can mine for answers to some of the most challenging questions,” says de la Fuente. “We use the word ‘encrypted’ to describe the antimicrobial peptides we found because they are hidden within larger proteins that seem to have no connection to the immune system, the area where we expect to find this function.”

Read the full story in Penn Engineering Today.

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Penn Anti-Cancer Engineering Center Will Delve Into the Disease’s Physical Fundamentals

by Evan Lerner

A colorized microscope image of an osteosarcoma shows how cellular fibers can transfer physical force between neighboring nuclei, influencing genes. The Penn Anti-Cancer Engineering Center will study such forces, looking for mechanisms that could lead to new treatments or preventative therapies.

Advances in cell and molecular technologies are revolutionizing the treatment of cancer, with faster detection, targeted therapies and, in some cases, the ability to permanently retrain a patient’s own immune system to destroy malignant cells.

However, there are fundamental forces and associated challenges that determine how cancer grows and spreads. The pathological genes that give rise to tumors are regulated in part by a cell’s microenvironment, meaning that the physical push and pull of neighboring cells play a role alongside the chemical signals passed within and between them.

The Penn Anti-Cancer Engineering Center (PACE) will bring diverse research groups from the School of Engineering and Applied Science together with labs in the School of Arts & Sciences and the Perelman School of Medicine to understand these physical forces, leveraging their insights to develop new types of treatments and preventative therapies.

Supported by a series of grants from the NIH’s National Cancer Institute, the PACE Center is Penn’s new hub within the Physical Sciences in Oncology Network. It will draw upon Penn’s ecosystem of related research, including faculty members from the Abramson Cancer Center, Center for Targeted Therapeutics and Translational Nanomedicine, Center for Soft and Living Matter, Institute for Regenerative Medicine, Institute for Immunology and Center for Genome Integrity.

Dennis Discher and Ravi Radhakrishnan

The Center’s founding members are Dennis Discher, Robert D. Bent Professor with appointments in the Departments of Chemical and Biomolecular Engineering (CBE), Bioengineering (BE) and Mechanical Engineering and Applied Mechanics (MEAM), and Ravi Radhakrishnan, Professor and chair of BE with an appointment in CBE.

Discher, an expert in mechanobiology and in delivery of cells and nanoparticles to solid tumors, and Radhakrishnan, an expert on modeling physical forces that influence binding events, have long collaborated within the Physical Sciences in Oncology Network. This large network of physical scientists and engineers focuses on cancer mechanisms and develops new tools and trainee opportunities shared across the U.S. and around the world.

Lukasz Bugaj, Alex Hughes, Jenny Jiang, Bomyi Lim, Jennifer Lukes and Vivek Shenoy (Clockwise from upper left).

Additional Engineering faculty with growing efforts in the new Center include Lukasz Bugaj, Alex Hughes and Jenny Jiang (BE), Bomyi Lim (CBE), Jennifer Lukes (MEAM) and Vivek Shenoy (Materials Science and Engineering).

Among the PACE Center’s initial research efforts are studies of the genetic and immune mechanisms associated with whether a tumor is solid or liquid and investigations into how physical stresses influence cell signaling.

Originally posted in Penn Engineering Today.

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Ning Jenny Jiang Appointed Associate Professor in Penn Bioengineering

Jenny Jiang, Ph.D.

We are thrilled to announce the appointment of Ning Jenny Jiang, Ph.D. as the tenured Peter & Geri Skirkanich Associate Professor of Innovation in the Department of Bioengineering at the University of Pennsylvania. Dr. Jenny Jiang comes to Penn from the Department of Biomedical Engineering at the University of Texas at Austin. She obtained her Ph.D. from Georgia Institute of Technology and did her postdoctoral training at Stanford University.

Jiang’s research focuses on systems immunology by developing technologies that enable high-throughput, high-content, single cell profiling of T cells in health and disease and she is recognized as one of the leading authorities in systems immunology and immunoengineering. She is a pioneer in developing tools in biophysics, genomics, immunology, and informatics and applying them to study systems immunology in human diseases. Her early work on the development of the first high-throughput immune-repertoire sequencing technology opened up a brand new field of immune-repertoire profiling. Her laboratory developed the first high-throughput in situ T cell receptor affinity measurement technology and she pioneered the development of integrated single T cell profiling technologies. These technological innovations have changed the paradigm of T cell profiling in disease diagnosis and in immune engineering for therapeutics. Using these technologies, her laboratory has made many discoveries in immunology, from unexpected infants’ immunity in malaria infection to “holes” in T cell repertoire in aging immune systems in elderly, from dysregulated T cells in HIV infection to high-throughput identification of neoantigen-specific T cell receptor for cancer immunotherapy.

Dr. Jiang was also recently elected to the American Institute for Medical and Biological Engineering (AIMBE) College of Fellows for her outstanding contributions to the field of systems immunology and immunoengineering and devotion to the success of women in engineering. A virtual induction ceremony was held on March 26, 2021.

Additionally, Jiang is a recipient of numerous other awards, including the Damon Runyon-Rachleff Innovation Award, an NSF CAREER award, and a Chan Zuckerberg Initiative Neurodegeneration Challenge Network Ben Barres Early Career Acceleration Award. She was selected as one of National Academy of Medicine Emerging Leaders in Health and Medicine Scholars in 2019.

Jiang’s appointment will begin June 1, 2021. Welcome to Penn Bioengineering, Dr. Jiang!

N.B.: Edited 7/2/21 with full endowed chair title.

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Immunology/BE Seminar: “Engineering Next-Generation CAR-T Cells for Cancer Immunotherapy” (Yvonne Chen)

Yvonne Chen, PhD

This event is part of the Penn Institute for Immunology Colloquium seminar series in conjunction with the Department of Bioengineering.

Speaker: Yvonne Chen, Ph.D.
Associate Professor, Microbiology, Immunology & Molecular Genetics
University of California, Los Angeles

Date: Tuesday, November 17, 2020
Time: 4:00-5:00 PM EST
This event will be held virtually on Bluejeans.

Title: “Engineering Next-Generation CAR-T Cells for Cancer Immunotherapy”

Abstract:

The adoptive transfer of T cells expressing chimeric antigen receptors (CARs) has demonstrated clinical efficacy in the treatment of advanced cancers, with anti-CD19 CAR-T cells achieving up to 90% complete remission among patients with relapsed B-cell malignancies. However, challenges such as antigen escape and immunosuppression limit the long-term efficacy of adoptive T-cell therapy. Here, I will discuss the development of next-generation T cells that can target multiple cancer antigens and resist immunosuppression, thereby increasing the robustness of therapeutic T cells against tumor defense mechanisms. Specifically, I will discuss the development of multi-input receptors and T cells that can interrogate intracellular antigens. I will also discuss the engineering of T cells that can effectively convert TGF-beta from a potent immunosuppressive cytokine into a T-cell stimulant. This presentation will highlight the potential of synthetic biology in generating novel mammalian cell systems with multifunctional outputs for therapeutic applications.

Bio:

Dr. Yvonne Chen is an Associate Professor of Microbiology, Immunology, and Molecular Genetics at the University of California, Los Angeles. She is also a faculty, by courtesy, in the Department of Chemical and Biomolecular Engineering. The Chen Laboratory focuses on applying synthetic biology and biomolecular engineering techniques to the development of novel mammalian-cell systems. The Chen Lab’s work on engineering next-generation T-cell therapies for cancer has been recognized by the NIH Director’s Early Independence Award, the NSF CAREER Award, the Hellman Fellowship, the ACGT Young Investigator Award in Cell and Gene Therapy for Cancer, the Mark Foundation Emerging Leader Award, and the Cancer Research Institute Lloyd J. Old STAR Award. Prior to joining UCLA in 2013, Yvonne was a Junior Fellow in the Harvard Society of Fellows. She received postdoctoral training at the Center for Childhood Cancer Research within the Seattle Children’s Research Institute, and in the Department of Systems Biology at Harvard Medical School. Yvonne received her B.S. in Chemical Engineering from Stanford University and her Ph.D. in Chemical Engineering from the California Institute of Technology.

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The Optimal Immune Repertoire for Bacteria

by Erica K. Brockmeier

Transmission electron micrograph of multiple bacteriophages, viruses that infect bacteria, attached to a cell wall. New research describes how bacteria can optimize their “memory” of past viral infections in order to launch an effective immune response against a new invader. (Image: Graham Beards)

Before CRISPR became a household name as a tool for gene editing, researchers had been studying this unique family of DNA sequences and its role in the bacterial immune response to viruses. The region of the bacterial genome known as the CRISPR cassette contains pieces of viral genomes, a genomic “memory” of previous infections. But what was surprising to researchers is that rather than storing remnants of every single virus encountered, bacteria only keep a small portion of what they could hold within their relatively large genomes.

Work published in the Proceedings of the National Academy of Sciences provides a new physical model that explains this phenomenon as a tradeoff between how much memory bacteria can keep versus how efficiently they can respond to new viral infections. Conducted by researchers at the American Physical Society, Max Planck Institute, University of Pennsylvania, and University of Toronto, the model found an optimal size for a bacteria’s immune repertoire and provides fundamental theoretical insights into how CRISPR works.

In recent years, CRISPR has become the go-to biotechnology platform, with the potential to transform medicine and bioengineering. In bacteria, CRISPR is a heritable and adaptive immune system that allows cells to fight viral infections: As bacteria come into contact with viruses, they acquire chunks of viral DNA called spacers that are incorporated into the bacteria’s genome. When the bacteria are attacked by a new virus, spacers are copied from the genome and linked onto molecular machines known as Cas proteins. If the attached sequence matches that of the viral invader, the Cas proteins will destroy the virus.

Bacteria have a different type of immune system than vertebrates, explains senior author Vijay Balasubramanian, but studying bacteria is an opportunity for researchers to learn more about the fundamentals of adaptive immunity. “Bacteria are simpler, so if you want to understand the logic of immune systems, the way to do that would be in bacteria,” he says. “We may be able to understand the statistical principles of effective immunity within the broader question of how to organize an immune system.”

Read more on Penn Today.

Vijay Balasubramanian is the Cathy and Marc Lasry Professor in the Department of Physics and Astronomy in the School of Arts & Sciences at the University of Pennsylvania and a member of the Department of Bioengineering Graduate Group. 

This research was supported by the Simons Foundation (Grant 400425) and National Science Foundation Center for the Physics of Biological Function (Grant PHY-1734030). 

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Daniel A. Hammer and Miriam Wattenbarger to Offer Summer Course on COVID-19

Daniel A. Hammer and Miriam Wattenbarger

As researchers hunt for a solution to the coronavirus outbreak, Daniel A. Hammer, Alfred G. and Meta A. Ennis Professor in Bioengineering and in Chemical and Biomolecular Engineering (CBE), is bringing lessons from the fight for a vaccine to the classroom.

Hammer will offer a course on COVID-19 and the coronavirus pandemic during Penn’s Summer II session, which will be held online this year. The course will be co-taught with Miriam Wattenbarger, senior lecturer in CBE.

The course, “Biotechnology, Immunology, and COVID-19,” will culminate with a case study of the coronavirus pandemic including the types of drugs proposed and their mechanism of action, as well as the process of vaccine development.

“Obviously, the pandemic has been a life-altering event, causing an immense dislocation for everyone in our community, especially the students. Between me and Miriam, who has been trumpeting the importance of vaccines for some time in her graduate-level CBE courses, we have the expertise to inform students about this disease and how we might combat it,” says Hammer.

For more than ten years, Wattenbarger has run courses and labs focused on drug delivery and biotechnology, key elements of the vaccine development process.

“I invite both researchers and industry speakers to meet with my students,” Wattenbarger says, “so that they learn the crucial role engineers play in both vaccine development and manufacturing.”

Beyond studying the interactions between the immune system and viruses — including HIV, influenza, adenovirus and coronavirus — students will cover a variety of biotechnological techniques relevant to tracking and defending against them, including recombinant DNA technology, polymerase chain reaction, DNA sequencing, gene therapy, CRISPR-Cas9 editing, drug discovery, small molecule inhibitors, vaccines and the clinical trial process.

Students will also learn the mathematical principles used to quantify biomolecular interactions, as well as those found behind simple epidemiological models and methods for making and purifying drugs and vaccines.

“We all have to contribute in the ways that we can. Having taught biotechnology to freshmen for the past decade, this is something that I can do that can both inform and build community,” says Hammer. “Never has it been more important to have an informed and scientifically literate community that can fight this or any future pandemic.”

Originally posted on the Penn Engineering blog. Media contact Evan Lerner. For more on BE’s COVID-19 projects, read our recent blog post.