Ran Reshef: Building Better Cell Therapies

When Ran Reshef was training to be an oncologist, a promising new type of cancer therapy was just starting to move from the lab to the clinic. “During my fellowship, immunotherapy started becoming a major success, and now it is one of the biggest breakthroughs of the decade,” says Reshef, who is now the director of the Cell Therapy Program at Columbia and a member of the Herbert Irving Comprehensive Cancer Center.  

For decades, “immunotherapy,” or using a patient’s own immune cells to attack and eliminate cancer, largely referred to bone marrow transplantation, which treats many types of blood disorders. Typically, the procedure eliminates a patient’s own blood-producing stem cells with high doses of radiation or chemotherapy, then replaces them by transplanting bone marrow from a healthy, immunologically similar donor. While often highly effective, it’s also risky. One of the biggest dangers is graft-versus-host disease, in which transplanted immune cells attack the recipient’s own tissues. 

As a result, bone marrow transplants have long been restricted to use in young, healthy patients, who have with the highest chance of being able to survive this complication. “The focus of my lab has been understanding why graft-versus-host disease happens specifically in the GI tract and other visceral organs, and then identify ways to stop it,” says Reshef. One major hint was that immune cells don’t travel randomly around the body. Instead, receptors on the surfaces of the cells cause them to go to specific tissues. 

By blocking a receptor called CCR5, Reshef’s team was able to stop the cells from entering visceral organs and prevent graft-versus-host disease. “We were the first ones to bring this from mouse models to human clinical trials,” says Reshef. Those trials yielded promising results but showed that blocking more than a single receptor may work better, a strategy that the Reshef lab continues to pursue. 

Creating a toolkit to redirect immune cells

In the meantime, Reshef is trying to apply the same principles to new forms of cell therapy. One especially promising technique, chimeric antigen receptor (CAR) T cell therapy, takes some of a patient’s own cells, genetically modifies them to better identify cancer cells, then transplants them back into the patient. Though this strategy often works well, major limitations still exist. “One of the limitations is poor trafficking of immune cells into tumor sites. Tumors have deception or decoy mechanisms, either creating certain chemicals that prevent immune cells from working, or certain proteins that would draw in regulatory cells, which would dampen the anti-tumor response,” says Reshef. 

To address that, his lab is building a toolkit to redirect the immune cell trafficking system, which uses dozens of different receptors and signals to direct cells around the body. “We’re trying to understand the deception mechanisms tumors use, how they are different from tumor to tumor, and how could we manipulate them,” says Reshef. 

One approach the lab is exploring is a “self-driving” CAR T cell. Rather than block a specific trafficking receptor, as with preventing graft-versus-host disease, the investigators are designing receptors that can be added to the genetically modified cells to send them straight into a tumor. The team is also deploying a suite of cutting-edge molecular techniques, such as single cell sequencing and spatial transcriptomics, to build a deeper understanding of cell targeting signals. “We can put a tissue on a slide, and instead of just plainly looking at it under the microscope, we can get the full gene expression profile and assign it to individual spots on the slide, and understand the interactions or the localization of cells,” Reshef explains. 

An in-house cell therapy facility for early phase trials

In addition to the work in his lab, Reshef runs the cell therapy program at Columbia, supervising the care of patients receiving CAR T cells and other cellular therapies. With colleague Pawel Muranski, MD, who directs Columbia’s cell manufacturing facility, the team is working on building an in-house cell and gene therapy manufacturing facility to the FDA’s stringent Good Manufacturing Practice (cGMP) standards. The idea is to help move promising therapies from the lab into early clinical trials, a risky process that’s long fallen into a gap between what academic researchers can afford to do and what pharmaceutical companies are willing to gamble on. 

“The way to move from lab experiments and mouse models into humans is to design a very careful manufacturing process that must be well validated. The manufacturing is very heavily regulated, and we need to be compliant with all regulations to ensure patient safety,” says Reshef.  

The onsite multimillion-dollar cGMP facility will allow Columbia researchers like Reshef to take their lab discoveries into early phase trials more nimbly, without the need for external involvement, working to get potential lifesaving treatments into the hands of patients much faster. 

 “Any investigator at Columbia who’s interested in building a new type of cell therapy for any disease will be able to use it, and we’re hoping to have that up and running by the end of the year,” says Reshef.