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Immune Profiling: A New Opportunity for Drug Development


The immune system is involved in almost every disease, at one level or another. Special cells, proteins, tissues, and organs that defend people against germs and other perceived invaders are its sum. Doctors and researchers conduct an array of tests to characterize a person’s immune health, including looking at the amount of different types of T cells, which can help detect major problems, such as HIV. And tools to manipulate the immune system are a mainstay of modern medicine: immunizations to protect against infectious diseases, immunosuppression medications for organ transplant recipients, and treating cancers with immunotherapies. Collectively, assessing a snapshot of a person’s unique state of immune health is called immune profiling, which can entail identifying immune-cell-associated genes and proteins, as well as the cell types themselves.

“The immune system is a sensory organ as much as it is an organ that’s protecting us,” noted John Wherry, PhD, chair of Pharmacology, in a video marking the opening of the new Allen Institute for Immunology, a research organization for advancing the fundamental understanding of human immunology. “It’s seeing everything that’s going on in your body all the time. An immune cell that’s circulating in your blood in your left hand may end up in your heart in an hour, and the next day it may be in your brain surveying for something that’s wrong.”

At Penn, a cadre of immunologists, oncologists, infectious disease specialists, and others are thinking about the immune system in a new and exciting way based on its integral and ubiquitous ties to human health. In addition to the great strides made in cancer immunotherapy in the last decade, they are beginning to amass intriguing data on a key role for the immune system in therapies in gastroenterology, neurology, vaccines in vulnerable populations, cardiovascular disease, as well as obesity and metabolic disease.

“We’re looking at the immune system as a new opportunity to develop drugs. If we can understand it, we can turn it in the patient’s favor to treat these many, many diseases,” said Wherry, who is also director of the Penn Institute of Immunology.

Fields of Opportunity

There is an intimate connection between the human gut, inflammation, and the immune system. Two autoimmune conditions of the gut, Crohn’s disease and ulcerative colitis, collectively called inflammatory bowel disease (IBD), are one of next frontiers for immune profiling. IBD happens when a person’s immune system attacks their own healthy digestive tract, causing chronic inflammation and a host of painful symptoms. Some treatments help IBD, but they don’t work for everyone and can cause severe side effects.

Wherry’s lab has started a five-year project funded by the Allen Institute to better understand how patients’ immune systems change when IBD treatment is keeping their disease in check compared to patients who do not benefit from the medications. “Understanding the molecular details of immune cells and why IBD treatments work or don’t work will help us develop better, more targeted treatments for more people.”

Immune cells in the brain and central nervous system (CNS) are just starting to be appreciated for their role in neurodegenerative diseases. The programmed cell death 1 (PD-1) receptor protein, which is well-known in cancer immunotherapies, has also been associated with reducing pathology in some animal models of Alzheimer’s disease.

“Immune cells in the CNS, including macrophages, have been implicated in Alzheimer's, Parkinson’s and ALS,” Wherry said. “In fact, a PD-1 blockade has even been proposed for treating Alzheimer’s.” Virginia Lee, PhD, director of the Center for Neurodegenerative Disease Research, is looking into the possibility of using monoclonal antibodies to target plaque proteins and has described how microglia, the first and primary immune response cells in the brain and spinal cord, are essential for dealing with TDP-43-associated neuron death.

Vaccines are one of the most well-known and oldest ways that medicine harnesses the immune system to help people stay healthy. The level of antibodies in the blood indicates how well a vaccine is working, and the relatively rare circulating T follicular helper cells, cTfh for short, are key to antibody strength. Ramin Herati, MD, an instructor of Infectious Diseases, and Wherry track cTfh cells using a unique molecular bar code specific to viral strains used in the annual flu vaccine. Tracing antibody production in 12 healthy subjects, aged 20 to 45 for three years revealed that the number of cTfh cells sharply increased seven days after a subject received a flu shot. This ability to track cTfh responses in the blood laid the groundwork for the development of new approaches to tackling diseases like the flu, but also HIV and other infections in which inducing potent vaccine reactions has been a challenge.

The team is now looking at elderly populations in which vaccines are not as effective to see what role cTfh cells might play. “We have found, as others have previously noted, that the elderly have higher baseline inflammation,” Wherry said. “We now think this elevated inflammation alters the function of cTfh and the way they contribute to effective antibody responses following vaccination.” These studies are not yet in clinical trials, but Wherry envisions that treatments to decrease chronic inflammation before vaccination could happen in the future.

Immune profiling can also provide insights into the timing of drug delivery. Building on previous research showing the effect of anti-PD-1 therapy can be seen in melanoma patients’ blood as early as three weeks after treatment, a team led by Alexander C. Huang, MD, an instructor of Hematology-Oncology, gave patients a single dose before surgery, then looked for anti-tumor activity in the removed tumor three weeks later.” They found more tumor infiltrating white blood cells among patients with longer recurrence-free survival. Eight of 27 patients with late-stage melanoma given one dose of anti-PD-1 therapy before surgery had a complete or near-complete response that was detected at the time of surgery. These findings indicate that immunotherapy can act extremely rapidly in a subset of patients and help identify patients who benefit quickly compared to those who may be candidates for more aggressive forms of combination immunotherapies.

Together, these seemingly disparate efforts may point to a new frontier of medicine. “If we do this right, we will change how we practice medicine,” Wherry said. “We will turn immunology into a clinical discipline.”

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