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).

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.

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.

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.

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.