Gene-edited CD19 CAR-T cells with superior proliferation, persistence and serial-killing activity

There is no doubt that CAR-T therapy, using a patient’s own T-cells as a drug, has been very successful in extending the lives of those with blood cancers. However, it is also true that for the majority of patients, CAR-T therapy eventually fails, and the cancer returns.

We understand many of the reasons this occurs, with one being that our T-cells contain built-in restraints that limit how many times they can repeatedly kill tumor cells. This fail-safe system is an inherent part of our immune system, and in cancer treatment, this means that the CAR-T cells eventually self-destruct, and don’t remain in the body long enough to be effective if the cancer starts to come back.

Our lab has been investigating a way to modify our T cells so that they can bypass nature’s self-imposed limits. By using a technique called gene editing, we have found that when we alter a specific gene in T-cells, we can turn them into what we call ‘serial killers.’ Instead of self-destructing, these special T-cells can repeatedly kill leukemia cells, and the T cells continue to multiply while doing so. In effect, these T cells turn into an exponentially growing army that can muster an overwhelming response against cancer, and possibly even eliminate it.

We have tested these special T cells in test tubes and in mice, and we have made them using blood from several different human donors. Some have worked spectacularly well, but others have not. With this research proposal, we wish to learn how our modification improves CAR-T cells, and we will verify the safety of our therapy. Because our alterations allow the CAR-Ts make more copies of themselves, we must be extra careful that they don’t start growing out of control. Our goal is to find the best way to safely modify these CAR-Ts so that they will work for a majority of patients.

Also, we have already learned that these gene-edited CAR-Ts often develop into a special type of cell called a ‘memory’ subtype. The memory subtype is desirable, because it means that the cells can stay in the body longer and ‘remember’ the cancer, so that if it crops up again, they can muster a new army to attack it. In this proposal, we will be looking for ways to capitalize on this finding about the memory cells, hopefully making the T cells even more potent, long-lasting killers.

Finally, we will then test these CAR-T cells in mice which have leukemia or lymphoma. If we see that our special CAR-T cells lead to better outcomes than the current CAR-Ts which are FDA-approved, that will be a terrific impetus to then move to a clinical trial, where we can determine if our CAR-T cells will lead to improved outcomes for real patients.