Researchers at the University of California-San Francisco have engineered a molecular “on switch” that allows tight control over the actions of immune cells known as T cells, according to new research published in Science Express.
T cells form part of the immune system, and increasingly, scientists are seeking ways to maximize their anticancer potential while minimizing the side effects.
Over the past 2 decades, cell therapy – a branch of cancer immunotherapy – has focused on refining cell-surface sensors known as chimeric antigen receptors, or CARs.
When CARs are inserted into T cells, they prompt the T cells to home in on particular proteins found primarily in tumors, where they launch a series of cancer-killing immune responses. These cells are called CAR T cells.
CAR T cells have been used successfully to treat various forms of chemotherapy-resistant leukemia.
To make CAR T cells, T cells must first be removed from the patient’s body. These are then genetically engineered to carry CARs that will attack the tumor. The newly created CAR T cells are then put back into the bloodstream.
Once inside the body, CAR T cells, like all T cells, release molecules called cytokines. These are signaling molecules, and some of them will call on other T cells to help fight the tumor.
However, the side effects can be severe. Some patients have spent time in intensive care after treatment, and some have not survived. One danger is that when CAR T cells enter the body through the bloodstream, they immediately pass through the heart and lungs, damaging them before the intended target is reached.
Senior author of the current study, Prof. Wendell Lim, PhD, professor and chair of the Department of Cellular and Molecular Pharmacology at the University of California-San Francisco (UCSF), says:
“T cells are really powerful beasts, and they can be lethal when they’re activated. We’ve needed a remote control system that retains the power of these engineered T cells, but allows us to communicate specifically with them and manage them while they’re in the body.”
He says that until now, after engineered T cells have been put into patients, “we just hope for the best.”
One suggestion for dealing with the drawbacks has been to give the cells “suicide switches,” causing them to die if side effects become too dangerous. Prof. Lim sees this as wasteful, as it means abandoning a complex and expensive treatment.
Prof. Lim calls it the first of a series of “control knobs” that will hopefully allow greater command over T cells inside the body.
- Leukemia is the most common cancer affecting children in the US
- The incidence is highest among children ages 1-4 years, at 8.8 per 100,000
- The fatality rate is highest among children ages 1-4 years, at 0.8 per 100,000.
The technique involves a drug that will act as a kind of “on/off” switch for T cells inside the body. This would enable CAR T cells to navigate toward and interact with cancer cells, but to refrain from launching an assault until instructed. At that moment, the drug would be administered. This drug would form a chemical bridge between components in the CAR T cells, switching the cells “on” and sending them into action against the cancer cells.
This mechanism could help to protect the body by delaying activation of the CAR T cells until, for example, the heart and lungs are less vulnerable to the “first pass” side effects.
Cells expressing a protein called CD19, which is found in cancer cells, were put in a laboratory dish. CAR T cells were added. The CAR T cells moved quickly toward the cells, attaching to them, but without attacking. As soon as the controller drug was added, however, the CAR T cells started killing off the CD19 expressing cells, one by one.
Next, leukemia cells were implanted into mice, and CAR T cells were added. Again, the CAR T cells only attacked the cancer cells after the controller drug was given.
The dosage mechanism could help prevent issues such as tumor lysis syndrome, where CAR T cells attack only the target cancer cells, but the body is overwhelmed by toxic substances released when many tumor cells die in rapid succession.
It could also prevent a life-threatening vicious cycle known as a “cytokine storm.” In a cytokine storm, released cytokines summon numerous T cells to the tumor, then these newly arrived T cells release their own cytokines, and so on.
By “dialing in” the level of immune response by using appropriate doses of the controller drug, doctors could manage these side effects precisely, to meet individual patients’ needs.
It is hoped that these two control capabilities could help to manage the side effects of CAR T therapy.
Prof. Lim stresses that the current work should be considered a “proof of principle,” a foundation for future development. The half-life of the current controller drug is too short to be practically useful, but this technique has brought a solution to the “near horizon.”
While CAR T cells have proven successful against leukemia, they are far less effective against solid tumors found in colon, breast and other cancers.
However, the new ability to control CAR T cell action could ultimately lead to development of more powerful versions of CAR T cells that could attack solid tumors, while still keeping side effects in check.
Members of Lim’s laboratory have been testing other techniques, such as using light to control CAR T activation and introducing multiple CARs into T cells to enable them to respond to the distinct characteristics of individual tumors.