An illustration of a human figure silhouette surrounded by shapes representing immune cells, and wearing a shield symbol on its front

The Immune Health future, today

Breaking the code of the immune system could provide a new fundamental way of understanding, treating, and preventing every type of disease. Penn Medicine is investing in key discoveries about immunity and immune system function, and building infrastructure, to make that bold idea a reality.

  • August 14, 2023

You can imagine the scene as an older gentleman lifts a thick, creamy envelope from his mailbox, seeing his own name written in richly scripted lettering. He beams with pride and gratitude at the sight of his granddaughter’s wedding invitation. Yet his next thought is a sober and serious one. Would he be taking his life in his hands by attending the ceremony?

This grandfather lives with primary progressive multiple sclerosis (MS), an autoimmune disorder that he controls with a medicine that depletes his body of the type of immune cells that make antibodies. So while he has completed his COVID-19 vaccine course, his immune system function isn’t very strong—and the invitation has arrived at a time when COVID-19 is still spreading rapidly.

“In the past, all we could do was [measure] the antibody response,” said Amit Bar-Or, MD, the Melissa and Paul Anderson President's Distinguished Professor in Neurology at the Perelman School of Medicine, and chief of the Multiple Sclerosis division. “If that person didn’t have a good antibody response, which is likely because of the treatment they’re on, we’d shrug our shoulders and say, ‘Maybe you shouldn’t go because we don't know if you’re protected.’”

Today, though, Bar-Or can take a deeper dive into his patients’ individual immune systems to give them far more nuanced recommendations. A clinical test for immune cells produced in response to the COVID-19 vaccine or to the SARS-CoV-2 virus itself—not just antibodies—was one of the first applied clinical initiatives of a major new Immune Health® project at Penn Medicine. Doctors were able to order this test and receive actionable answers through the Penn Medicine electronic health record for patients like the grandfather with MS.

“With a simple test and an algorithm we can have a very different discussion,” Bar-Or said. A test result showing low T cells, for instance, would tell Bar-Or his patient may get a meaningful jolt in immunity from a vaccine booster, while low antibody levels would suggest passive antibody therapy is more helpful. Or, the test might show his body is already well primed to protect him, making it reasonably safe to attend the wedding.

This COVID-19 immunity test is only the beginning.

The concepts behind the Immune Health future

Physicians and scientists at Penn Medicine are imagining a future where patients can get a precise picture of their immune systems’ activity to guide treatment decisions. They are working to bring the idea of Immune Health to life as a new area of medicine. In labs, in complex data models, and in the clinic, they are beginning to make sense of the depth and breadth of the immune system’s millions of as-yet-undeciphered signals to improve health and treat illnesses of all types.

Penn Medicine registered the trademark for the term “Immune Health” in recognition of the potential impact of this research area and its likelihood to draw non-academic partners as collaborators in its growth. Today, at the south end of Penn’s medical campus, seven stories of research space are being added atop an office building at 3600 Civic Center Boulevard, including three floors dedicated to Immune Health, autoimmunity, and immunology research.

The concept behind the whole project, said E. John Wherry, PhD, director of Penn Medicine’s Institute for Immunology and Immune Health (I3H), “is to listen to the immune system, to profile the immune system, and use those individual patient immune fingerprints to diagnose and treat diseases as diverse as immune-related diseases, cancer, cardiovascular disease, Alzheimer’s, and many others.”

The challenge is vast. Each person’s immune system is far more complex than antibodies and T cells alone. The immune system is made of multiple interwoven layers of complex defenders—from our skin and mucous membranes to microscopic memory B cells that never forget a childhood infection—meant to fortify our bodies from germs and disease. It is a sophisticated system that learns and adapts over our lifetimes in numerous ways, and it also falters and fails in some ways we understand and others that remain mysterious. And each person’s intricate internal battlefield is in some way unique.

The immune system is not just a set of defensive barricades, either. It’s also a potential source of deep insight about a person’s physiological functioning and responses to medical treatments.

“The immune system is sensing and keeping track of basically all tissues and all cells in our body all the time,” Wherry said. “It is surveying the body, trying to clean up any invaders and restore homeostasis by maintaining good health.”

“Our goal is to essentially break the code of the immune system,” said Jonathan Epstein, MD, executive vice dean of the Perelman School of Medicine and chief scientific officer at Penn Medicine. “By doing so, we believe we will be able to determine your state of health and your response to therapies in essentially every human disease.”

E. John Wherry and Allie Greenplate standing on an outdoor roof deck in a portrait
E. John Wherry, PhD, and Allie Greenplate, PhD, lead Penn Medicine's Institute for Immunology and Immune Health

Untangling millions of messages in the immune system

A man in a blue lab coat and safety goggles points a pen at a piece of lab equipment on a bench

Measuring and making sense of the immune system is a crucial step in Penn Medicine’s Immune Health platform.

An individual’s immune system—constantly adapting and responding to its environment—is sending millions of messages, such as a spiked fever during an infection. Most of these messages are still confounding to researchers. The challenge is to find ways to untangle those numerous signals in ways that broaden and deepen physicians’ understanding of patients’ health and response to disease.

Researchers across Penn Medicine, with the backing of I3H, are endeavoring to do so by tracking patients’ immune responses across the disease spectrum and, in some cases, partnering with informatics experts to use advanced artificial intelligence algorithms and machine-learning models to predict outcomes. Among the efforts: studying whether dietary interventions could enhance the efficiency of some cancer treatments, using immune signals to help determine MS treatments, and even testing a cancer prevention vaccine.

“The immune system operates very much like the nervous system in monitoring just about everything that goes on physiologically in our body,” Wherry said. “Unlike the nervous system, the immune system is mobile. Cells move around, survey different tissues, interpret their environment and then respond or, importantly, choose not to respond. In some ways, this cell movement is our opportunity. The blood system is the highway of the immune system, but also allows easy sampling, of at least a subset, of the cells in the immune system. If we know how to listen to the language of the immune system, we can use it to tell us about physiological changes that may not be obvious otherwise.”

Leading the way in cancer immunotherapy and COVID-19

A man wearing an Immune Health logo shirt stands at a window writing a flowchart equation with a dry erase marker

Penn Medicine arrived at this moment due to a combination of leadership in immune-based discoveries in cancer and recent advances using immune health insights to treat patients who were severely ill with COVID-19.

Much of Wherry’s own research for years had emphasized understanding patients’ immune responses to cancer and to cancer treatments that work by activating the immune system. Other Penn Medicine researchers—notably Carl June, MD, the Richard W. Vague Professor in Immunotherapy, along with many other collaborators—were pioneers of chimeric antigen receptor T cell (CAR T) cancer therapy, in which a patient’s own immune cells are reprogrammed to fight cancer cells. Once the first CAR T therapy was approved by the Food and Drug Administration in 2017, Robert H. Vonderheide, MD, DPhil, director of Penn Medicine’s Abramson Cancer Center and an immunotherapy researcher himself, said the Penn immunology community felt the moment had truly arrived to look for the clinical impacts they could have with the immune system beyond cancer.

“We realized there is this huge discrepancy between what we were measuring routinely in a tube of blood from a patient versus the billions of parameters that we can measure with the same tube of blood in a research lab 500 yards away,” Vonderheide said. “That was the start of immune health.”

The field truly began to explode at Penn three years later when COVID-19 struck. As doctors around the world were scrambling to find the best ways to treat severely ill patients, Wherry, who is also chair of Systems Pharmacology and Translational Therapeutics, thought his research approach for cancer patients could be applicable to combating the new virus. His study of cancer patients’ immune signals to predict their response to certain treatments accelerated care for patients who were racing the clock.

So when, early in the pandemic, critical care physicians were struggling to effectively treat hospitalized COVID-19 patients, Wherry jumped into action. Leveraging the work already being done on a smaller and slower scale in cancer, Wherry and Michael Betts, PhD, a Penn microbiologist studying immunology in human infection and diseases, established the COVID-19 Processing Unit to use patients’ individual immune responses to the virus to help inform their treatment. In the clinic, they partnered with Nuala Meyer, MD, MS, a critical care physician treating patients with COVID-19 in the intensive care unit. Meyer headed a laboratory with experience quickly enrolling critically ill patients into a clinical trial to study sepsis, and she was well versed in how immunology could fill in gaps in clinical knowledge.

For Wherry and others in Penn’s immunology community, the pandemic presented a once-in-a-lifetime opportunity to show how their work could extend far beyond cancer. “We’ve been saying for a number of years that the immune system matters, and that it should be a key to helping to diagnose [and treat] diseases,” he said. “If there was ever an opportunity to put our money where our mouth is and test whether what we’ve been saying is true, this is when we have to do it.”

The immune system’s all-stars

The immune system is made up of dozens of types of cells that surveil for threats, communicate with one another, and defend and protect the body in a variety of ways.

Studying immune system function in COVID-19

The team of more than two dozen highly trained researchers who made up the COVID-19 Processing Unit first processed peripheral blood and plasma samples from hospitalized patients with COVID-19 to extract immune cells. Then, they ran an assay called flow cytometry to measure the activation of the 30 or so immune cell types in the blood, more or less evenly divided into innate—or hardwired—cells, and adaptive cells, such as T cells and B cells (the cells that make antibodies). Because each immune cell type can exist in various forms of activation and anywhere throughout the body—for instance, a single B cell from the lungs of a person who recently received the COVID-19 vaccine might be very active, while a B cell from an unvaccinated person’s lymph nodes might be in a resting state—the team produced a data set of thousands of features of each patient’s immune system.

Immune Health fingerprints

The methods the Penn Medicine teams put in place to analyze individual patients’ blood and plasma samples for their immune cells’ activity and map those patterns into groupings had clear implications for patients beyond COVID-19, and even beyond cancer, where immune-based treatments are already most advanced. Once the pace of “emergency response science” slowed down, Wherry said the COVID-19 Processing Unit team saw potential in scaling up the systems they had built.

“The core infrastructure of immune health is disease agnostic,” he said. “The immune landscape analysis that we applied in COVID, we can apply to cancer, to autoimmunity or allergy. We get to look at all of those fingerprints across all patients.”

Researchers and clinicians see potential to better understand connections across conditions by creating large-scale immune landscape maps, like the one used to understand how different patients responded to COVID-19, by categorizing individual patients’ “immune fingerprints” into immune subgroups across diseases. For instance, Wherry said, the weakened immune system of a cancer patient is, in many ways, actually the inverse of the overactivated immune system of a person with an autoimmune disorder. “There’s this subgroup of cancer patients that didn’t respond to this immune-stimulating drug,” he said. “Well, there are some autoimmune patients who fall in that same category. Maybe the drugs that didn’t work in cancer will now work in autoimmunity.”

An illustration of six human silhouette shapes, each surrounded by clustered immune cells of a different color and each wearing a shield symbol on its chest

Creating tools for Immune Health research

Building new tools and adapting existing ones to the challenges of immune health are among the most crucial aspects of the work.

Penn Medicine patients have an important role to contribute to immune health research. Greenplate is hoping to make it easy for many patients to get involved by expanding on the model of the Penn Medicine BioBank, which already aggregates a wide range of clinical data from nearly a quarter of a million Penn patients along with tens of thousands of biological samples from those patients, for use in observational research. The Penn Medicine BioBank was established in 2012 but has grown rapidly in recent years since the option to consent to participate was built into the electronic patient portal for every Penn Medicine patient at every location, during the COVID-19 pandemic. Patients who opt into participating in the Penn Medicine BioBank have extra blood collected the next time they are scheduled for a blood draw in the course of their care, as well as any leftover tissue from biopsies saved for research. To date, about 44,000 of these patients have genomic data associated with their (anonymized) clinical histories, including diagnoses, visits, and clinical test results, available for researchers to study using the BioBank.

“I would love to see not only your genetic information, but your immune profile as part of your medical record,” Greenplate said.

Using Immune Health to guide medical treatment

A building under construction with several upper floors showing only the beams framing the new space
An office building on Penn’s campus is under construction, with an additional seven floors being added for research, including three floors dedicated to Immune Health, immunology, and autoimmunity research.

The ultimate goal of the work scientists and informaticists are doing in the lab is to untangle the thousands of immune signals into clear clinical messages. It’s only then that immune health data will be truly useful for doctors and patients.

Greenplate imagines “immune boards,” modeled on cancer’s tumor boards, that would bring together physicians and scientists to examine a patient’s immune health data and make decisions on how to move their care forward.

The I3H informatics team is also working to develop a streamlined Immune Health dashboard that can integrate with the electronic medical record. They have already created an Immune Health tab in Penn Medicine’s electronic health record that provides a home for test orders and test results like the COVID-19 immunity test. Their goal is to give clinicians easy access to immune health insights that offer meaningful guidance for patient care, as they work to identify and validate more of these measures.

“We don’t want to put those 100,000 features of your immune system in the electronic medical record,” Wherry said. “We want to find out which two or so features can tell whether you’re going to respond to a new MS drug better than one of the other drugs that could be used. That’s the actionable choice.”

In cancer—where immune health has a long history—some groundbreaking developments are perhaps close at hand. The field as a whole has made rapid advancements in recent years thanks to the explosion of immunotherapy research. Those developments, combined with mRNA and other gene therapy technology, bring the possibility of a cancer prevention vaccine within reach, Vonderheide said. One in the works at Penn is for individuals at high risk for breast cancer because of their genetic mutations. “There’s an active clinical trial using DNA to treat those individuals,” he said, “and boost their immune systems to intercept and prevent cancer.”

Vonderheide’s own research is showing the potential of treatments customized to an individual patient’s immune health. His team published a paper in Nature Medicine last year showing that certain patients with newly diagnosed metastatic pancreatic cancer responded extremely well to different combinations of chemotherapy and immunotherapy treatment. Depending on their immune health baseline, some patients responded well to combination A, while others found success with combination B.

Vonderheide’s team is following up on this finding with a forthcoming prospective study—selecting each trial participant’s treatment according to the predicted outcome. “That’s precision oncology,” he said. “We do that all the time, but mostly with the genetic sequence of the tumor.” This time, though, it’s entirely based on the patient’s immune system.

“This is really where the rubber meets the road,” he said. “We meet a patient and we say, ‘Based on your immune health, we think this therapy is best for you.’”

More from the Immune Health issue of Penn Medicine magazine

Follow us

Related Articles

Subscribe

Subscribe to Penn Medicine newsletters and publications for the latest developments.