Some call it the “therapeutic pipeline.” Others refer to it as “bench to bedside.” Both phrases refer to the scientific process that delivers new therapies, new medicines, to people who are sick. In the pipeline metaphor, an idea rushes along, like water in a hose, from the minds of researchers into the lab, through testing and approvals to the pharmacy or treatment room. In the bench metaphor, progress is similarly linear, advancing from the scientist’s bench in the lab to the patient’s bedside. But neither image paints an accurate picture.

Imagine instead a large Rube Goldberg machine, with cogs and wheels and diversionary paths. Research isn’t a straight-line prospect.

ILLUSTRATION OF CAR-T IMMUNOTHERAPY AT WORK. Photo courtesy of Science Photo

Washington University oncologist John DiPersio, MD, PhD, a nationally known expert in the treatment of leukemia and lymphoma, serves as deputy director of Siteman Cancer Center and director of the Washington University Center for Gene & Cellular Immunotherapy (CGCI). With more than three decades of experience as a physician-scientist, DiPersio has played an instrumental role in developing new therapies to treat blood cancers. Yet DiPersio, reflecting on his professional journey, notes that the work is never done. “It’s a constant iterative process of bench to bedside and back to bench again,” he says. His work with CAR-T immunotherapy is a clear example of what he’s talking about.

CAR-T immunotherapy isolates a person’s T cells—cells the immune system uses to find and destroy harmful invaders—and modifies them to home in on cancerous cells. Once modified, these cells are known as CAR-T cells: chimeric antigen receptor T cells. After modification, the CAR-T cells are returned to the body, where they find their malignant targets and, behaving as any T cell should, trigger a chain of reactions that destroys the targeted cell.

The genesis of CAR-T immunotherapy, now used to induce remissions in thousands of people each year with certain types of leukemia, lymphoma and multiple myeloma, began not at the bench but at the bedside. “Many years ago, physicians were asking a basic question: ‘Why doesn’t our immune system get rid of all the rogue cells that become cancerous?’” says Washington University oncologist Timothy Eberlein, MD, director of Siteman Cancer Center and surgeon-in-chief at Barnes-Jewish Hospital. “It turns out, the answer is complex. But from that initial question, John and other researchers like him eventually developed expertise using CAR-T cells.”

JOHN DIPERSIO, MD, PHD, DEPUTY DIRECTOR OF SITEMAN CANCER CENTER AND DIRECTOR OF THE WASHINGTON UNIVERSITY CENTER FOR GENE & CELLULAR IMMUNOTHERAPY.
Photo by Gregg Goldman

Basic questions drive medical research. DiPersio, like many physician-scientists, says he enjoys working in his lab, “thinking about these big problems.” And for every paper published and trial approved, more questions arise, driving him and scientists around the world back to the lab in search of answers. “Understanding how the immune system recognizes cancer and responds to it are the basic science observations that we’re still working to better understand,” Eberlein notes.

Science at CGCI

The researchers and clinicians working at CGCI, where questions about cancer immunotherapy are posed and answers sought, embrace three main goals, says Armin Ghobadi, MD, Washington University oncologist at Siteman Cancer Center and clinical director of CGCI. “First, to develop novel gene and cellular therapies; second, to design and conduct innovative clinical trials of gene and cellular therapies in-house and in collaboration with leading pharmaceutical companies; and third, to provide FDA approved, standard-of-care gene and cellular therapies for our patients.” When the first CAR-T therapy was approved, Ghobadi says, “we were one of 16 centers worldwide that could offer it right away.”

The first scientists to consider the immune system’s role in cancer modulation began exploring the concept about 60 years ago, Ghobadi notes. In 1957, bone marrow, where many T cells live, was first successfully transplanted into a person with cancer. “After that, researchers began thinking about activating and harnessing the body’s immune response to fight cancer,” he says.

I COULDN’T HAVE SAID THIS 25 YEARS AGO, BUT I TRULY BELIEVE WE’RE ON THE CUSP OF MAKING CANCER A CHRONIC DISEASE INSTEAD OF A KILLER. THERE’S GREAT HOPE.

Like most types of clinical research, scientists’ first attempts in the lab to prove the concept of harnessing and using a patient’s own immune cells yielded mixed results. Yet what some might consider failures, researchers like DiPersio see as crucial forks in the road, exposing pathways that may not be worth traveling and revealing new routes that could lead to new insights. For almost 20 years, scientists worked to develop technologies that allowed them to do the delicate work of altering CAR molecules, thus improving the efficacy of CAR-T cells in fighting cancer. “In 2011, promising results showing complete remission in patients with cancer receiving CAR-T therapy were reported,” Ghobadi says. “And that created a strong wave of clinical trials using newer and more advanced cellular therapies for both blood cancers and solid tumors, with close to 1,400 clinical trials in progress worldwide in 2020.”

But is it safe?

In any clinical trial, quality control and patient safety are paramount. The process of obtaining the approvals to proceed varies according to the type of research being conducted, and it involves extensive internal and external reviews of existing data. Following review, the Food and Drug Administration (FDA) may approve a new therapy as an Investigational New Drug, a designation that opens the door to testing in humans. “The most important aspect is the safety of the patient,” Eberlein says of the shift from research in the lab to human trials. “You have to have enough information to show that the treatment you propose to test won’t cause harm. But, as in the case of CAR-T immunotherapy, you need to actually do those human trials in order to prove that the treatment is safe, and you really don’t know for sure until that point.”

TIMOTHY EBERLEIN, MD, DIRECTOR OF SITEMAN CANCER CENTER AND SURGEON-IN-CHIEF AT BARNES-JEWISH HOSPITAL.
Photo courtesy of Washington University School of Medicine

For instance, one of the participants involved in the early CAR-T trials produced cytokines, a type of protein that causes inflammation. The patient was immediately treated for the side effect, and the episode provided important information for ongoing testing and management of this possibility, known as cytokine release syndrome (CRS). “When a research project is approved for human trials, it begins at phase I, which is designed to prove safety. Phase II determines efficacy, and the final phase considers whether the new treatment is better than existing treatments,” Eberlein explains. “At Siteman Cancer Center, we have a clear commitment to advancing clinical trials through all these phases.” As one of 39 NCI (National Cancer Institute) comprehensive cancer centers in the nation, Siteman, per NCI, is “recognized for leadership in substantial transdisciplinary research that bridges all scientific areas as well as translating these discoveries into innovative clinical trials.”

For some people with cancer, participation in clinical trials offers hope when other treatment options are limited. Large academic medical centers, including Barnes-Jewish Hospital, offer access to such treatments for selected patients who may not respond to the standard of care. Many people with cancer also recognize that, by participating in a trial, they are helping move medicine forward so future generations may benefit. Eberlein notes that “cancer patients are among our most altruistic.”

When a study moves from looking at reactions in animal models to human trials, Eberlein says, the project expands to include a more diverse team of experts, from basic science researchers to specialized clinicians. That mixture of expertise, insight and collaboration is key to reaching accurate conclusions. Ghobadi notes that the first CAR-T patient trials at CGCI occurred in 2015, representing the culmination of years of basic science research in lab and animal models. Within two years, the FDA approved the new treatment technology, a remarkably rapid pace. “It happened quickly because we showed that CAR-T immunotherapy could be very effective against certain types of blood cancers,” he says.

ONCOLOGIST MIRIAM KIM, MD, (LEFT) AND RESEARCHER PARMESHWAR AMATYA (RIGHT) AT WORK IN THE LAB
Photos by Gregg Goldman

And although the pathway from bench to bedside takes twists and turns, the rapid approval of CAR-T is an example of the overall quickening pace of discovery as scientists build on previous research. “Cancer’s been with us for thousands of years, and yet the breakthroughs we’ve had in just the past few decades are remarkable,” Eberlein says. “The pace is accelerating as we make discoveries and learn from them.”

Partners outside the lab

The medical and pharmaceutical industries are crucial in the process of moving new ideas through the research process. Less than 10% of research grants submitted to the National Institutes of Health are funded, and the cost of research and human trials is so great that other funding sources must be located. “In many cases, medical researchers collaborate with others outside their fields; we interact with all kinds of people, companies and institutions. And at the same time, we continue writing scientific papers and grant proposals to attract government and private funding,” DiPersio says.

Often, that funding comes through a licensing agreement with a pharmaceutical company for the potential new technology. The pharmaceutical company then provides the resources needed to begin human trials. Philanthropic support is also an important funding source. Eberlein acknowledges the work of The Foundation for Barnes-Jewish Hospital and the Siteman Advancement Office, which provide ongoing support for research.

More answers = new questions

While thousands of people are now benefiting from CAR-T immunotherapy, DiPersio has questions he’s keen to answer. “The translation from lab to clinic in this particular field has rapidly outpaced our understanding of how these cells function,” he says. “So far, they work for a limited number of diseases; how can we get them to work in other types of cancers?”

And so the research process moves on, taking surprising routes and moving in new directions. At CGCI, new clinical trials are underway or poised to begin that researchers hope will help bring CAR-T immunotherapy to the treatment of solid tumors, will decrease potential side effects and will create faster and more efficient ways to make CAR-T cells, thereby increasing availability for people who need them.

After working more than 40 years as a physician-scientist, Eberlein says his enthusiasm for his work remains palpable. “We’re privileged to live in this era,” he says. “I get to witness miracles almost every day. The pace of discovery is accelerating. I couldn’t have said this 25 years ago, but I truly believe we’re on the cusp of making cancer a chronic disease instead of a killer. There’s great hope.”