immunotherapy – Page 3 – Penn Bioengineering Blog

August 4, 2022August 4, 2022

Deconstructing the Mechanics of Bone Marrow Disease

by Katherine Unger Baillie

Acollaborative team developed an alginate-based hydrogel system that mimics the viscoelasticity of the natural extracellular matrix in bone marrow. By tweaking the balance between elastic and viscous properties in these artificial ECMs, they could recapitulate the viscoelasticity of healthy and scarred fibrotic bone marrow, and study the effects on human monocytes placed into these artificial ECMs. (Image: Adam Graham/Harvard CNS/Wyss Institute at Harvard University)

Fibrosis is the thickening of various tissues caused by the deposition of fibrillar extracellular matrix (ECM) in tissues and organs as part of the body’s wound healing response to various forms of damage. When accompanied by chronic inflammation, fibrosis can go into overdrive and produce excess scar tissue that can no longer be degraded. This process causes many diseases in multiple organs, including lung fibrosis induced by smoking or asbestos, liver fibrosis induced by alcohol abuse, and heart fibrosis often following heart attacks. Fibrosis can also occur in the bone marrow, the spongy tissue inside some bones that houses blood-producing hematopoietic stem cells (HSCs) and can lead to scarring and the disruption of normal functions.

Chronic blood cancers known as “myeloproliferative neoplasms” (MPNs) are one example, in which patients can develop fibrotic bone marrow, or myelofibrosis, that disrupts the normal production of blood cells. Monocytes, a type of white blood cell belonging to the group of myeloid cells, are overproduced from HSCs in neoplasms and contribute to the inflammation in the bone marrow environment, or niche. However, how the fibrotic bone marrow niche itself impacts the function of monocytes and inflammation in the bone marrow was unknown.

Now, a collaborative team from Penn, Harvard, the Dana-Farber Cancer Institute (DFCI), and Brigham and Women’s Hospital has created a programmable hydrogel-based in vitro model mimicking healthy and fibrotic human bone marrow. Combining this system with mouse in vivo models of myelofibrosis, the researchers demonstrated that monocytes decide whether to enter a pro-inflammatory state and go on to differentiate into inflammatory dendritic cells based on specific mechanical properties of the bone marrow niche with its densely packed ECM molecules. Importantly, the team found a drug that could tone down these pathological mechanical effects on monocytes, reducing their numbers as well as the numbers of inflammatory myeloid cells in mice with myelofibrosis. The findings are published in Nature Materials.

“We found that stiff and more elastic slow-relaxing artificial ECMs induced immature monocytes to differentiate into monocytes with a pro-inflammatory program strongly resembling that of monocytes in myelofibrosis patients, and the monocytes to differentiate further into inflammatory dendritic cells,” says co-first author Kyle Vining, who recently joined Penn’s School of Dental Medicine and School of Engineering and Applied Science as an assistant professor of preventive and restorative sciences. “More viscous fast-relaxing artificial ECMs suppressed this myelofibrosis-like effect on monocytes. This opened up the possibility of a mechanical checkpoint that could be disrupted in myelofibrotic bone marrow and also may be at play in other fibrotic diseases.”

Vining worked on the study as a postdoctoral fellow at Harvard in the lab of David Mooney. “Our study shows that the differentiation state of monocytes, which are key players in the immune system, is highly regulated by mechanical changes in the ECM they encounter,” says Mooney, who co-led the study with DFCI researcher Kai Wucherpfennig. “Specifically, the ECM’s viscoelasticity has been a historically under-appreciated aspect of its mechanical properties that we find correlates strongly between our in vitro and the in vivo models and human disease. It turns out that myelofibrosis is a mechano-related disease that could be treated by interfering with the mechanical signaling in bone marrow cells.”

Continue reading at Penn Today.

June 23, 2022June 16, 2022

Penn Medicine and Children’s Hospital of Philadelphia Announce Partnership with Costa Rica for CAR T Cell Therapy

Carl June, MD, Professor in the Perelman School of Medicine and member of the Penn Bioengineering Graduate Group, was quoted in a recent press release announcing a new international partnership between Penn Medicine (PSOM), the Children’s Hospital of Pennsylvania (CHOP), and Costa Rica’s CCSS, or the Caja Costarricense de Seguro Social (Social Security Program), to develop CAR T research in Costa Rica. June is a world renowned cancer cell therapy pioneer whose research led to the initial development and FDA approval of CAR T cell therapy:

“‘At least 15,000 patients across the world have received CAR T cells, and dozens more clinical trials using this approach are in progress, for almost every major tumor type, but people in many parts of the globe still do not have access to treatment with these transformative therapies,’ said Carl H. June, MD, the Richard W. Vague Professor in Immunotherapy and director of the Center for Cellular Immunotherapies in Penn’s Perelman School of Medicine. “We are honored to work with our colleagues in Costa Rica in hopes of building a path for patients in underserved areas to have the opportunity to benefit from clinical research programs offering this personalized therapy.’”

Read the the announcement in Penn Medicine News.

May 20, 2022

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

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).

May 18, 2022

Exploring the History of CAR-T Cell Therapy

A new feature in Chemistry World explores the history of CAR (chimeric antigen receptor)-T cell therapy, a revolutionary type of therapeutic treatment for certain types of cancer. One of the pioneers of CAR-T cell therapy is Carl June, Richard W. Vague Professor in Immunotherapy in the Perelman School of Medicine and member of the Penn Bioengineering Graduate Group. His groundbreaking research opened the door for FDA approval of the CAR T therapy called Kymriah, which treats acute lymphoblastic leukemia (ALL), one of the most common childhood cancers.

Read “A decade of CAR-T cell therapy” in Chemistry World.

May 11, 2022

Bioengineering Graduate Jason Andrechak Wins Graduate Leadership Award

Jason Andrechak

Congratulations to recent Penn Bioengineering graduate Jason Andrechak on winning a Graduate Leadership Awards for 2022. Each year a select number of students across the university are recognized for their service and lasting contributions to graduate student life at Penn. Andrechak, one of only ten recipients in 2022, won a Dr. Andy Binns Award for Outstanding Service to Graduate and Professional Student Life. This award is presented to “graduate or professional students, upon their graduation from Penn, who have significantly impacted graduate and professional student life through service involvement in student life initiatives or organizations.” Andrechak won this award for his “service and leadership in advocating for equity and accessibility during the transition to virtual operations and following a period of leadership transition within the Graduate and Professional Student Assembly (GAPSA). ”

Andrechak completed his Ph.D. in Bioengineering in 2022, where he studied macrophage immunotherapy in solid tumors in the lab of Dennis E. Discher, Robert D. Bent Professor in Chemical and Biomolecular Engineering, Bioengineering, and Mechanical Engineering and Applied Mechanics. He was named a National Science Foundation Graduate Research Fellow in 2018. He has actively led the Graduate Association of Bioengineers (GABE) as Community Service & Outreach chair from 2017-2019 and as co-President from 2019-2022. He also served as the Director of Equity & Access for the Graduate & Professional Student Assembly (GAPSA) from 2020-2021, in addition to several other service and advisory roles at the department, school, and university levels.

Learn more about the Penn Graduate Leadership Awards and read the full list of recipients on the Grad Center at Penn website.

March 1, 2022

Decade-long Remission After CAR T Cell Therapy

Bill Ludwig, left, was the first patient to receive CAR T cells as part of clinical trials at Abramson Cancer Center. Carl June, right, has played a pioneering roll in the therapeutic use of CAR T cells. (Image: Penn Medicine)

Carl H. June, the Richard W. Vague Professor in Immunotherapy in Pathology and Laboratory Medicine at Penn Medicine, director of the Center for Cellular Immunotherapies and the Parker Institute for Cancer Immunotherapy, and member of the Penn Bioengineering Graduate Group at the University of Pennsylvania, has led a new analytical study published in Nature that explains the longest persistence of CAR T cell therapy recorded to date against chronic lymphocytic leukemia (CLL), and shows that the CAR T cells remained detectable at least a decade after infusion, with sustained remission in both patients. June’s pioneering work in gene therapy led to the FDA approval for the CAR T therapy (sold by Novartis as Kymriah) for treating leukemia and transforming the fight against cancer. His lab develops new forms of T cell based therapies.

Read the story in Penn Today

February 10, 2022

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, 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.

December 21, 2021December 20, 2021

Jenny Jiang on T Cell Diversity and Cancer Immunotherapy

by Melissa Pappas

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.

December 14, 2021December 20, 2021

Penn Bioengineering Celebrates Five Researchers on Highly Cited Researchers 2021 List

The Department of Bioengineering is proud to announce that five of our faculty have been named on the annual Highly Cited Researchers™ 2021 list from Clarivate:

Dani S. Bassett, J. Peter Skirkanich Professor in Bioengineering and in Electrical and Systems Engineering
Bassett runs the Complex Systems lab which tackles problems at the intersection of science, engineering, and medicine using systems-level approaches, exploring fields such as curiosity, dynamic networks in neuroscience, and psychiatric disease. They are a pioneer in the emerging field of network science which combines mathematics, physics, biology and systems engineering to better understand how the overall shape of connections between individual neurons influences cognitive traits.

Robert D. Bent Chair — Jason Burdick, Ph.D.

Jason A. Burdick, Robert D. Bent Professor in Bioengineering
Burdick runs the Polymeric Biomaterials Laboratory which develops polymer networks for fundamental and applied studies with biomedical applications with a specific emphasis on tissue regeneration and drug delivery. The specific targets of his research include: scaffolding for cartilage regeneration, controlling stem cell differentiation through material signals, electrospinning and 3D printing for scaffold fabrication, and injectable hydrogels for therapies after a heart attack.

César de la Fuente, Presidential Assistant Professor in Bioengineering and Chemical & Biomedical Engineering in Penn Engineering and in Microbiology and Psychiatry in the Perelman School of Medicine
De la Fuente runs the Machine Biology Group which combines the power of machines and biology to prevent, detect, and treat infectious diseases. He pioneered the development of the first antibiotic designed by a computer with efficacy in animals, designed algorithms for antibiotic discovery, and invented rapid low-cost diagnostics for COVID-19 and other infections.

Carl H. June, Richard W. Vague Professor in Immunotherapy in the Perelman School of Medicine and member of the Bioengineering Graduate Group
June is the Director for the Center for Cellular Immunotherapies and the Parker Institute for Cancer Therapy and runs the June Lab which develops new forms of T cell based therapies. June’s pioneering research in gene therapy led to the FDA approval for CAR T therapy for treating acute lymphoblastic leukemia (ALL), one of the most common childhood cancers.

Vivek Shenoy, Eduardo D. Glandt President’s Distinguished Professor in Bioengineering, Mechanical Engineering and Applied Mechanics (MEAM), and in Materials Science and Engineering (MSE)
Shenoy runs the Theoretical Mechanobiology and Materials Lab which develops theoretical concepts and numerical principles for understanding engineering and biological systems. His analytical methods and multiscale modeling techniques gain insight into a myriad of problems in materials science and biomechanics.

The highly anticipated annual list identifies researchers who demonstrated significant influence in their chosen field or fields through the publication of multiple highly cited papers during the last decade. Their names are drawn from the publications that rank in the top 1% by citations for field and publication year in the Web of Science™ citation index.

Bassett and Burdick were both on the Highly Cited Researchers list in 2019 and 2020.

The methodology that determines the “who’s who” of influential researchers draws on the data and analysis performed by bibliometric experts and data scientists at the Institute for Scientific Information™ at Clarivate. It also uses the tallies to identify the countries and research institutions where these scientific elite are based.

David Pendlebury, Senior Citation Analyst at the Institute for Scientific Information at Clarivate, said: “In the race for knowledge, it is human capital that is fundamental and this list identifies and celebrates exceptional individual researchers who are having a great impact on the research community as measured by the rate at which their work is being cited by others.”

The full 2021 Highly Cited Researchers list and executive summary can be found online here.

October 21, 2021

Carl June Highlighted for Success in Gene Therapy

Scientific American recently featured two gene therapies that were invented at Penn, including research from Carl June, MD, the Richard W. Vague Professor in Immunotherapy in Pathology and Laboratory Medicine, director of the Center for Cellular Immunotherapies, and member of the Penn Bioengineering Graduate Group, which led to the 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 “Four Success Stories in Gene Therapy” in Scientific American.