Tag: immunoengineering

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Lipid Nanoparticles That Deliver mRNA to T Cells Hold Promise for Autoimmune Diseases

by Janelle Weaver

Ajay Thatte, Benjamin Nachod, Rohan Palanki, Kelsey Swingle, Alex Hamilton, and Michael Mitchell (Left to Right – Courtesy of the Mitchell Lab) 

Autoimmune disorders are among the most prevalent chronic diseases across the globe, affecting approximately 5-7% of the world’s population. Emerging treatments for autoimmune disorders focus on “adoptive cell therapies,” or those using cells from a patient’s own body to achieve immunosuppression. These therapeutic cells are recognized by the patient’s body as ‘self,’ therefore limiting side effects, and are specifically engineered to localize the intended therapeutic effect.

In treating autoimmune diseases, current adoptive cell therapies have largely centered around the regulatory T cell (Treg), which is defined by the expression of the Forkhead box protein 3, orFoxp3. Although Tregs offer great potential, using them for therapeutic purposes remains a major challenge. In particular, current delivery methods result in inefficient engineering of T cells.

Tregs only compose approximately 5-10% of circulating peripheral blood mononuclear cells. Furthermore, Tregs lack more specific surface markers that differentiate them from other T cell populations. These hurdles make it difficult to harvest, purify and grow Tregs to therapeutically relevant numbers. Although there are additional tissue-resident Tregs in non-lymphoid organs such as in skeletal muscle and visceral adipose tissue, these Tregs are severely inaccessible and low in number.

Now, a research team led by Michael Mitchell, Associate Professor in Bioengineering in the School of Engineering and Applied Science at the University of Pennsylvania, has developed a lipid nanoparticle (LNP) platform to deliver Foxp3 messenger RNA (mRNA) to T cells for applications in autoimmunity. Their findings are published in the journal Nano Letters.

“The major challenges associated with ex vivo (outside the body) cell engineering are efficiency, toxicity, and scale-up: our mRNA lipid nanoparticles (mRNA LNPs) allow us to overcome all of these issues,” says Mitchell. “Our work’s novelty comes from three major components: first, the use of mRNA, which allows for the generation of transient immunosuppressive cells; second, the use of LNPs, which allow for effective delivery of mRNA and efficient cell engineering; and last, the ex vivo engineering of primary human T cells for autoimmune diseases, offering the most direct pipeline for clinical translation of this therapy from bench to bedside.”

“To our knowledge, this is one of the first mRNA LNP platforms that has been used to engineer T cells for autoimmune therapies,” he continues. “Broadly, this platform can be used to engineer adoptive cell therapies for specific autoimmune diseases and can potentially be used to create therapeutic avenues for allergies, organ transplantation and beyond.”

Delivering the Foxp3 protein to T cells has been difficult because proteins do not readily cross the cell membrane. “The mRNA encodes for Foxp3 protein, which is a transcription factor that makes the T cells immunosuppressive rather than active,” explains first author Ajay Thatte, a doctoral student in Bioengineering and NSF Fellow in the Mitchell Lab. “These engineered T cells can suppress effector T cell function, which is important as T cell hyperactivity is a common phenotype in autoimmune diseases.”

Read the full story in Penn Engineering Today.

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Penn Bioengineering Alumnus Joshua Doloff Seeks a Pain-free Treatment for Diabetes

Person taking a finger stick blood test.
Credit: Darryl Leja, NHGRI Flickr

Joshua C. Doloff, Assistant Professor of Biomedical Engineering and Materials Science & Engineering at Johns Hopkins University, featured in The Jewish News Syndicate for his work on “Hope,” a new technology which offers pain- and injection-free treatment to people with Type 1 or “juvenile” diabetes. Doloff is an alumnus of Penn Bioengineering, Class of 2004:

“Doloff received his bachelor’s degree from the University of Pennsylvania and his graduate degrees from Boston University. In addition to his post in Johns Hopkins’ Department of Biomedical Engineering, he is a member of the Translational Tissue Engineering Center at Johns Hopkins University School of Medicine. His lab is interested in systems biology with an emphasis on engineering improved therapies in the fields of cancer, autoimmunity, transplantation medicine, including Type 1 diabetes and ophthalmology.”

Read “Technion researchers offer ‘Hope’ for treating diabetes, minus the painful jabs” in the Jewish News Syndicate.

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Penn Bioengineering Student is a Hertz Fellowship Finalist

Savan Patel (Class of 2023)

Savan Patel, a fourth year Penn Bioengineering student, is one of 42 finalists competing for a 2023 Hertz Fellowship in applied science, mathematics, and engineering, one of the most prestigious Ph.D. fellowships in the United States. Chosen annually, the Hertz Fellowship is awarded to the nation’s most promising graduate students in science and technology.

From the Hertz Foundation website:

“Since 1963, the Hertz Foundation has granted fellowships empowering the nation’s most promising young minds in science and technology. Hertz Fellows receive five years of funding valued at up to $250,000, which offers flexibility from the traditional constraints of graduate training and the independence needed to pursue research that best advances our security and economic vitality […]

Over the foundation’s 60-year history of awarding fellowships, more than 1200 Hertz Fellows have established a remarkable track record of accomplishments. Their ranks include two Nobel laureates; recipients of 10 Breakthrough Prizes and three MacArthur Foundation “genius awards”; and winners of the Turing Award, the Fields Medal, the National Medal of Technology, and the National Medal of Science. In addition, 50 are members of the National Academies of Sciences, Engineering and Medicine, and 34 are fellows of the American Association for the Advancement of Science. Hertz Fellows hold over 3,000 patents, have founded more than 375 companies and have created hundreds of thousands of science and technology jobs.”

Patel is studying Bioengineering and Finance in the Jerome Fisher Program in Management and Technology (M&T), an interdisciplinary dual degree program coordinated by Penn Engineering and the Wharton School of Business. He is currently a member of the lab of Michael J. Mitchell, J. Peter and Geri Skirkanich Assistant Professor of Innovation in Bioengineering. Patel’s research interests lie at the interface of drug delivery and immunoengineering. His current project involves the use of modified cholesterol molecules to induce shifts in the biodistribution of ionizable lipid nanoparticles (LNPs). Following graduation, he intends to pursue a Ph.D. in bioengineering in which hopes to develop translatable immunotherapies and drug delivery platforms.

If chosen, the Hertz Fellowship will fund Patel’s graduate studies. Selected from over 750 applicants, Patel is one of fifteen undergraduates and one of two bioengineering students to make the final round of interviews. After a culminating round of interviews, the 2023 Class of Hertz Fellows will be announced in May.

Learn more about the Hertz Fellowship and read the full list of finalists here.

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Inside the Mitchell Lab: Crossing Biological Barriers

by Olivia J. McMahon

Black and white photo of Mike Mitchell working in the lab.
Mike Mitchell, Ph.D.

Engineers in the Center for Precision Engineering for Health (CPE4H) are focusing on innovations in diagnostics and delivery, cellular and tissue engineering, and the development of new devices that integrate novel materials with human tissues. Below is an excerpt from “Going Small to Win Big: Engineering Personalized Medicine,” featuring the research from the laboratory of Michael Mitchell, J. Peter and Geri Skirkanich Assistant Professor of Innovation in Bioengineering.

The Challenge

Solid tumors evade the immune system’s ability to attack them in part due to the tumors’ tough, fibrous biological barriers that circulating immune cells can’t cross. Researchers need to identify ways to deliver individualized treatments that can better target these tumors without causing damage to healthy tissues or affecting overall quality of life.

The Status Quo

Current cancer treatments typically involve surgery, radiation or chemo- therapy to eliminate solid tumors. These treatments are invasive and can cause numerous negative downstream effects. Newer treatments involve engineering a patient’s immune system to recognize and fight cancerous cells, but are so far only effective against certain “liquid” cancers, where the mutated cells circulate freely in the blood and bone marrow and are small enough to be picked off by the patient’s upgraded T cells. Additionally, existing methods can also require that the cell engineering take place in a lab rather than directly inside the body.

The Mitchell Lab’s Fix

Members of the lab of Michael Mitchell, J. Peter and Geri Skirkanich Assistant Professor of Innovation in Bioengineering, are looking to utilize nanoparticle delivery technology developed by their lab to engineer a different type of immune cell, the macrophage, in order to fight solid- tumor cancers from the inside.

The Mitchell lab is using lipid nanoparticles (LNPs) to carry mRNA and DNA sequences inside of macrophages, a type of immune cell that can consume tumor cells if engineered correctly. In theory, a patient would receive an injection carrying the LNP payload, and the macrophages, whose name literally means “big eaters,” would take up the genetic sequence, alter their function and be able to recognize a patient’s own unique tumor cells in the body.

Because of the way macrophages operate, they could cross the tumor’s biological barrier and attack the cells, destroying the tumor from the inside. An added benefit of the Mitchell Lab’s technology is that the destroyed tumor cells would then also allow other immune cells to present their antigens to circulating T cells, which could then learn to fight those same cancer cells in the future.

“One of the longstanding challenges that we face in the context of cancer and immunotherapies is that every tumor has unique antigens that are specific to patients,” says Mitchell. “This is why we’ve had a lot of trouble developing targeted therapies. Personalizing an approach by harnessing an individual’s immune system gives each patient a greater chance of a positive outcome.”

Read the full story in Penn Engineering magazine.

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Inside the Jiang Lab: An Inventory of Immunity

by Olivia J. McMahon

Black and white photo of Jenny Jiang working in her lab on a laptop.
Jenny Jiang, Ph.D.

Engineers in the Center for Precision Engineering for Health (CPE4H) are focusing on innovations in diagnostics and delivery, cellular and tissue engineering, and the development of new devices that integrate novel materials with human tissues. Below is an excerpt from “Going Small to Win Big: Engineering Personalized Medicine,” featuring the research from the laboratory of Jenny Jiang, J. Peter and Geri Skirkanich Associate Professor of Innovation in Bioengineering.

The Challenge

In order to create personalized immune therapies, researchers need to untangle what is happening between an individual patient’s immune cells and the antigens that they interact with on a molecular level. Immune cell-antigen interactions need to be understood in four different areas in order to create a full picture: the unique genetic sequence of the T cell’s antigen receptors, the antigen specificity of that cell, and both the gene and protein expression of the same cell.

The Status Quo

Prior methods of understanding interactions between T cells and antigens could only get a picture of one or two of these four elements because of technology constraints. Other roadblocks included that cells cultured or engineered in a laboratory setting are not in a natural environment so they won’t express genes or proteins in the way T cells would in the body, and technologies that assess the antigen specificity of T cells were not cost-effective for looking at large numbers of antigens.

The Jiang Lab’s Fix

The lab of Jenny Jiang, J. Peter and Geri Skirkanich Associate Professor of Innovation in Bioengineering, developed a technology called TetTCR-SeqHD, which solves these problems. Using this technology, scientists can now simultaneously profile samples of large numbers of single T cells in the four dimensions using high- throughput screening.

The Jiang Lab’s technology is essentially a method for getting a “full-body scan” of an individual’s T cells and creates a catalog of the different types of T cells and the antigens they respond (or don’t respond) to, paving the way for the ability to better target immune therapies to an individual patient.

“Individual T cells are unique, and that’s the challenge of using one treatment to fit all,” says Jiang. “Identifying antigen specificity and creating therapies that target that specificity in an individual’s T cells will be key to truly personalizing immune therapies in the future.”

Read the full story in Penn Engineering magazine.

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2022 Career Award Recipient: Michael Mitchell

by Melissa Pappas

Michael Mitchell (Illustration by Melissa Pappas)

Michael Mitchell, J. Peter and Geri Skirkanich Assistant Professor of Innovation in the Department of Bioengineering, is one of this year’s recipients of the National Science Foundation’s CAREER Award. The award is given to early-career faculty researchers who demonstrate the potential to be role models in their field and invest in the outreach and education of their work.

Mitchell’s award will fund research on techniques for “immunoengineering” macrophages. By providing new instructions to these cells via nanoparticles laden with mRNA and DNA sequences, the immune system could be trained to target and eliminate solid tumors. The award will also support graduate students and postdoctoral fellows in his lab over the next five years.

The project aligns with Mitchell’s larger research goals and the current explosion of interest in therapies that use mRNA, thanks to the technological breakthroughs that enabled the development of COVID-19 vaccines.

“The development of the COVID vaccine using mRNA has opened doors for other cell therapies,” says Mitchell. “The high-priority area of research that we are focusing on is oncological therapies, and there are multiple applications for mRNA engineering in the fight against cancer.”

A new wave of remarkably effective cancer treatments incorporates chimeric antigen receptor T-cell (CAR-T) therapy. There, a patient’s T-cells, a type of white blood cell that fights infections, are genetically engineered to identify, target and kill individual cancer cells that accumulate in the circulatory system.

However, despite CART-T therapy’s success in treating certain blood cancers, the approach is not effective against cancers that form solid tumors. Because T-cells are not able to penetrate tumors’ fibrous barriers, Mitchell and his colleagues have turned to another part of the immune system for help.

Read the full story in Penn Engineering Today.

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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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Bioengineering Student Savan Patel Receives the 2022 C. William Hall Scholarship

Savan Patel

Savan Patel, a junior studying Bioengineering and Finance in the Jerome Fisher Management and Technology dual degree program, was selected as the recipient of the 2022 C. William Hall Scholarship from the Society for Biomaterials. The C. William Hall Scholarship is named in honor of the Society for Biomaterials’ first president and is awarded annually “to a junior or senior undergraduate pursuing a bachelor’s degree in bioengineering or a related discipline focusing on biomaterials.” As this year’s recipient, Savan will receive complimentary membership to the Society and will have expenses paid to the Society’s annual meeting being held April 27-30, 2022 in Baltimore, Maryland.

Savan is currently a member of the lab of Michael J. Mitchell, Skirkanich Assistant Professor of Innovation in Bioengineering. Savan’s research interests lie in the interface of drug delivery and immunoengineering with a particular focus on T cell delivery. His current project involves the use of modified cholesterol molecules to improve the delivery of nucleic acids (i.e., mRNA) to cell populations using lipid nanoparticles.

Lipid nanoparticles (LNPs) are a clinically proven delivery platform for nucleic acid therapeutics. One drawback of these particles is their high cellular recycling rate. Savan and the members of the Mitchell lab are working to reduce this recycling by leveraging cellular processes and incorporating modified molecules into our lipid nanoparticle formulations. The focus of Savan’s project is on modifying cholesterol, a molecule that is important to both our LNP formulations and cell membranes. The goal is to generate a more potent delivery platform to improve current therapeutics.

Following graduation, Savan intends to pursue a Ph.D. in Bioengineering.

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Jenny Jiang on T Cell Diversity and Cancer Immunotherapy

by Melissa Pappas

Jenny Jiang, Ph.D.

Our body’s natural line of defense against infection and disease, as well as cancer, is our immune system equipped with T cells, a type of white blood cell that determines how we react to foreign substances, or antigens, in the body. While we have an arsenal of T cells to protect us from these various infections, some people lack certain T cells or simply do not have enough to fight off infections, such as the flu or HIV, or defend against the body’s own mutated cancer cells.

Understanding the diversity of T cells and which antigens they target can provide insight into developing personalized immunotherapy to help those patients with weak spots or gaps in their T cell community. Jenny Jiang, Peter and Geri Skirkanich Associate Professor of Innovation in Bioengineering, is characterizing this diversity.

Jiang recently received a Cancer Research Institute’s (CRI) Lloyd J. Old STAR grant to support her research on this topic. The CRI STAR grant identifies mid-career “Scientists TAking Risks” in innovative cancer immunotherapy research areas, providing freedom and flexibility to pursue high-risk, high-reward research with financial support of $1.25 Million over the course of five years.

Jiang spoke with CRI science writer Arthur Brodsky about her research and how the STAR grant will support it.

“In our studies of healthy individuals, who have some natural immune protection against commonly encountered viruses like the flu, we noticed that not everyone has T cells that cover all the possible antigens,” says Jiang. “There are differences in the number and types of flu-targeting T cells that each individual has. For some “exotic” antigens, like those of HIV for example, although the general population doesn’t actually have exposure to them, they should still have a very low level of minimum T cells that can offer some protection from possible future infection. So that part of our T cell arsenal acts as a safety net. But some individuals may completely lack those T cells. In those cases, as you can imagine, those people will have a hard time overcoming a future infection.”

Jiang describes how this is similar to how our bodies prevent cancerous tumor growth.

Read the full story in Penn Engineering Today.

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Jenny Jiang Receives Immunotherapy Grant from Cancer Research Institute

Jenny Jiang, Ph.D.

Jenny Jiang, the Peter & Geri Skirkanich Associate Professor of Innovation in the department of Bioengineering, has received a Lloyd J. Old STAR Program grant from the Cancer Research Institute (CRI), which is a major supporter of cancer immunotherapy research and clinical trials with the goal of curing all types of cancer.

The CRI Lloyd J. Old Scientists Taking Risks (STAR) Program “provides long-term funding to mid-career scientists, giving them the freedom and flexibility to pursue high-risk, high-reward research at the forefront of discovery and innovation in cancer immunotherapy.” This prestigious grant was give to six awardees this year, chosen from a pool of hundreds of applicants, and recognizes “future leaders in the field of cancer immunotherapy [who are expected to] carry out transformational research.”

The Old STAR Program Grant comes with $1.25 million in funding over 5 years to support the awardees’ cancer immunology research.

Jiang, who recently joined Penn Bioengineering, is a pioneer in developing tools in genomics, biophysics, immunology, and informatics and applying them to study systems immunology and immune engineering in human diseases. She was also inducted into the American Institute for Medical and Biological Engineering (AIMBE) College of Fellows in March 2021 for her outstanding contributions to the field of systems immunology and immunoengineering and devotion to the success of women in engineering. 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.

“The STAR Award from CRI allows my lab to answer some of the fundamental questions in T cell biology, such as is the T cell repertoire complete to cover all possible cancer antigens, as well as to improve the efficacy of T cell based cancer immunotherapies,” says Jiang.