“Living Drug” Created by Columbia Immunologists May Save Transplanted Organs
Inside a freezer in Columbia’s cell therapy lab, nearly a billion customized cells packed in a container no bigger than a yogurt cup may be the last chance to save the kidney of Pawel Muranski’s patient.
The kidney was transplanted only a few months ago. But because the patient’s immune system is suppressed to keep it from attacking the organ, a virus in the patient has reactivated and sparked a dangerous infection.
No antiviral therapies exist to fight the virus causing the infection. And taking the patient off immunosuppressants will almost definitely lead to loss of the transplanted organ.
The only option now is an experimental cell therapy—a “living drug” developed by Muranski and his colleagues at Columbia’s Cellular Immunotherapy Laboratory—that sets loose an army of T cells inside the patient to recognize and kill the virus.
Muranski, director of cellular immunotherapy at Columbia University Vagelos College of Physicians and Surgeons, saw the need for such cells when he worked at the NIH, where some of the original immunotherapy strategies were developed. About 40,000 organ transplants and 20,000 bone marrow transplants take place every year in the United States, but up to 20% of patients will get infections that threaten the success of the transplant.
At the NIH, Muranski was part of a team that developed a way to produce large numbers of virus-specific T cells that are trained to identify and eliminate the patient’s virus but leave other parts of the body alone.
The viruses that threaten transplant patients are usually not a big deal for most people. By adulthood, most people have been infected with the viruses, which remain in the body in a dormant state. In people whose immune systems are suppressed, however, the viruses can wake up and run rampant.
“The idea behind our cell therapy is that we can take T cells from a healthy donor, select the ones that recognize the virus, and multiply those in the lab so we create a population of immune cells that we can give to the patient to control the infection,” Muranski says.
The immune cells need a degree of matching to work well, so the cells are obtained from first-degree relatives of the patients.
In trials Muranski ran at the NIH, such cells proved to be safe and, in some patients, beat back the infection. But creating the cells took several weeks, too long when trying to fight a virulent infection.
Faster production line
The virus-specific T cell therapy now being tested in transplant patients is similar in concept to earlier experimental therapies but is being produced much more rapidly.
What previously took more than a month and huge vats of cell culture can now be done in two weeks inside bioreactors smaller than a cup of coffee.
As of late October, three patients had received the cell therapy without any adverse reactions. The patients are part of a phase 1 clinical trial that is testing the therapy’s safety.
Once the phase 1 safety study is completed, the therapy’s effect will be rigorously tested in a phase 2 trial, when multiple doses of cells may be used to increase the odds of effectiveness. Meanwhile, new and improved methods to create anti-viral immune cells will be developed in the laboratory and introduced for testing in additional phase 1 trials.
Next target: cancer
Using T cells to target viral infections is relatively straightforward because our immune system is naturally poised to control viruses.
But Muranski’s biggest goal is to develop new types of T cell therapies to attack cancer. In recent years, CAR T cells (cell removed from the patient and genetically engineered to recognize cancer cells) have been developed for blood cancers and approved by the FDA. But these T-cell therapies have not had much success with solid cancers.
Solid cancers represent difficult targets for the immune system, and CAR T cells are largely limited to recognizing cancer’s surface molecules, while many cancer-associated antigens reside inside the tumor cells.
Muranski thinks naturally occurring T cells might be a better bet. He focuses on a type of T cell called CD4+ T helper cells that are master orchestrators of the entire immune system.
“T helper cells allow us to target cancer antigens that are not just on the surface of the cells, but also inside the cells,” he says. This is how normal T cells in the body typically recognize infected cells or cancer cells.
“Emerging data suggest that T helper cells can be really very powerful, and I think the majority of cancers can be targeted with T helper cells rather than with CAR T cells.”
Developing cell therapies of the future at Columbia
Other in-house cell therapies can be created at Columbia now that the facility, one of the few housed at an academic medical center, has been opened.
Muranski hopes to make cell-based immunotherapy more accessible to patients from diverse ethnic backgrounds. “Furthermore, by manufacturing CAR-T cells and other cancer and virus specific cells on site at Columbia,” he says, “we might significantly reduce the cost of some of these life-saving but very expensive treatments.”
Columbia has very active immunology and immunotherapy programs and new therapies are under development for treatment of cancer and transplant patients.
“Many immunotherapies originate at academic institutions and then they are developed further by industry,” says Muranski, who arrived at Columbia in 2017 to build the facility from scratch. “With academic cell manufacturing, we can easily and rapidly translate new ideas for therapies into early phase clinical trials and see if they are safe and effective.
“We’re not trying to replicate what industry is doing,” he adds. “The idea is to innovate and produce the next generation of cell therapies.”
Pawel Muranski, MD, is assistant professor of medicine and of pathology & cell biology at the Vagelos College of Physicians and Surgeons and a principal investigator at Columbia Center for Translational Immunology.
Rodica Ciubotariu, MD, PhD, is director of clinical operations at the Cellular Immunotherapy Laboratory and associate research scientist in the Department of Medicine.
Hei T. Chan, RN, is a research nurse and immune effector and cell therapy program lead at the Cellular Immunotherapy Laboratory.
Agata Jurewicz, MS, is a quality assurance specialist at the Cellular Immunotherapy Laboratory.
Jian B. Pan is a senior technician at the Cellular Immunotherapy Laboratory.