By Wynne Parry
What if, with a little assistance, the body already possessed the means to overcome many of the diseases that afflict humanity?
Whether protecting against internal or external threats or becoming the source of the problem by acting up, the immune system plays a role in many, if not most medical conditions. The concept of manipulating it has a long history. More than two centuries ago, the first vaccine accomplished this by preparing the immune system to fight smallpox.
Scientific understanding of the immune system has grown immensely since then; however, this insight hasn’t always translated to proper recognition of its role until recently. Advancements in immunotherapy—a field dedicated to manipulating the immune system—have exploded especially over the last decade, empowered by basic biological discoveries.
“We have a huge diversity of ways the immune system can function. If we understand how to trigger it correctly, we have an amazing toolkit already prebuilt for us in the body,” said E. John Wherry, PhD, the Richard and Barbara Schiffrin President's Distinguished Professor, chair of Systems Pharmacology and Translational Therapeutics, and director of Penn’s Institute for Immunology and Immune Health and Colton Center for Autoimmunity.
Cancer therapy, where patients’ severe disease make the use of novel experimental treatments ethically permissible, has led the way. However, researchers worldwide are continuing to devise new, more precise ways to fight infection and to intervene in the malfunctions that cause autoimmune diseases, among other uses of immunotherapies—and Penn Medicine is among those at the forefront, seeking to build on an institutional legacy of leadership in the field.
How a Focus on the Immune System is Transforming Cancer Care
About 25 years ago, many doubted the importance of the immune system’s interaction with cancer, according to Robert Vonderheide, MD, DPhil, director of the Abramson Cancer Center at the University of Pennsylvania. “I was advised as a young faculty member by colleagues elsewhere not to study immunotherapy because it wasn’t going anywhere,” he said. “But Penn embraced this concept, the main reason I wanted to start my lab here.”
Since he established his laboratory in 2001, attitudes everywhere have shifted. “A very common phone call I'll get now as cancer center director is from another institution saying ‘We'd like to establish or extend an immunotherapy unit. What was your secret to success?’ And I say we started 20 years ago,” he said.
The sea change began with the discoveries of specific mechanisms involved in the immune system’s response to cancer. Researchers then began seeking to disrupt, or augment, those processes, leading to two seminal developments, according to Vonderheide.
The first, lab-grown immune proteins known as monoclonal antibodies, attack molecular targets in tumor cells and within the immune system. The earliest monoclonal antibodies, such as Herceptin, bound cancer cells and led to cell death directly. Then came second-generation monoclonal antibodies, designed to bind immune cells, and led to immune activation in a variety of ways. One of the most significant of these immunotherapy antibodies for cancer patients has been a treatment that latches onto proteins on T cells, specifically a protein called PD-1, that inhibits the immune cells’ tumor-fighting capacity. By interfering with PD-1, the antibodies remove the “brake pedal” on the T cells so they are able to destroy the cancer.
Carl June, MD
Carl June, MD, and a team of colleagues at Penn Medicine pioneered the subsequent breakthrough in cancer immunotherapy: a cell-based therapy known as CAR T. In CAR T, a patient’s T cells are altered to sport cancer-seeking receptors called chimeric antigen receptors, or CARs.
In the decade plus since a Penn Medicine team successfully treated three adult leukemia patients, the FDA has approved six CAR T therapies for leukemia, lymphoma, and multiple myeloma. Meanwhile, doctors have become more adept at managing the potentially dangerous immune reaction that can follow treatment. The results underscore the promise of this treatment that seemed such a distant and impossible horizon as Vonderheide was beginning his career. For substantial numbers of blood cancer patients, CAR T can eradicate signs of cancer. Some even see their malignancies remain at bay for such extended periods that researchers cautiously describe CAR T’s effects as “curative.”
The promise of more applications for immunotherapies has emerged. Efforts seek to, for example, adapt CAR T to fight solid tumors, revive war-weary T cells that have lost their ability to fight cancer, and—in a line of work Vonderheide finds most exciting—devise vaccines that use genetic material from cancer to prime the immune system to fight off these malignancies.
Immunotherapy Approaches for Autoimmunity, Infection, and More
While cancer treatments employ the most advanced arsenal of immunotherapies, patients with other disorders are also benefiting from this strategy. Monoclonal antibodies, for instance, are used to treat an assortment of disorders, from migraines to COVID-19 to inflammatory skin disease. Many of these therapies directly intervene in activity within the immune system.
Experimental studies, meanwhile, are exploring a host of cutting-edge applications. For HIV, researchers at Penn Medicine and elsewhere are looking to adapt CAR T so the modified immune cells can seek out and destroy virus-infected cells. Penn Medicine researchers are also investigating CAR T’s capacity to eliminate the immunological resistance that causes some people’s bodies to reject organ transplants. And clinical trials are now underway to test a version of CAR T adapted to treat certain autoimmune diseases.
CAR T is highly adaptable to more types of disease treatments in the future because all sorts of different artificial receptors could potentially be designed to enhance a variety of immune cells in a wide variety of ways. “At a high level, it’s a fairly simple concept,” said Vijay Bhoj, MD, PhD, a pathologist developing CAR T-inspired treatments for transplant resistance and an autoimmune disorder. “It’s very modular, like building with Legos.”
The diversity of these efforts—and the way this technology has diffused outward from its initial application in cancer—speaks to the collaborative culture nurtured at Penn Medicine, according to Vonderheide.
“We are an epicenter of this movement, and we’re not done yet,” he said.
An Age of Immunotherapies: Related Stories
The Immunotherapy Revolution for Autoimmune Diseases: With a deeper understanding of the immune system, there are growing possibilities to selectively turn down only the parts that malfunction—with hopes to someday cure these conditions.
Life, Gained: Walter Styer has cherished 11 years of life after being one of the earliest patients in a trial of the first CAR T cell therapy developed at Penn Medicine.
CAR T for Solid Tumors: Scientists are still learning how to help CAR T cells evade the body’s defenses so they can effectively treat cancers in the breast, brain, lungs, pancreas, and other organs.
Cancer Interception: Cancer vaccines are a form of immune therapy under investigation at Penn, part of a growing effort to intercept cancer before abnormal cells become malignant. (From the Spring 2023 issue of Penn Medicine magazine)
Energizing the Immune Army: A phenomenon known as “T cell exhaustion” has stymied some efforts to develop powerful immune-based therapies. E. John Wherry, PhD, describes how researchers are learning to manipulate this complex process.