Small-molecule remote control allows communication with cell therapies

Print 06 October 2015
Anette Breindl / BioWorld

Researchers have developed a small-molecule "on" switch for chimeric antigen receptor (CAR) T cells that allowed them, in preclinical models, to control the cells' activity after transplantation.

The approach could be used to improve the safety of the cells, which can lead to near-miraculous remissions but also regularly send the patients receiving them into intensive care due to cytokine storm or tumor lysis syndrome.

CAR T cells, which are engineered to seek out and destroy tumor cells, are a hot area of tumor immunotherapy. Companies in the fray range from big players like Novartis AG to smaller players like Juno Therapeutics Inc., Kite Pharma Inc. and Autolus Ltd.

For all the excitement around CAR T cells, though, no one would deny that they have serious side effects.

The problem with those side effects, and with the side effects of cell-based therapies more generally, is that once the cells are infused, they literally take on a life of their own.

That is, in fact, part of what makes them so appealing.

"These cells have a lot of autonomous behavior, which is why we want to use them," Wendell Lim toldBioWorld Today. "But we also want to be able to control those behaviors."

Lim is professor and chair of the department of cellular and molecular pharmacology at the University of California at San Francisco. He and James Onuffer are co-corresponding authors of the paper reporting the work, which was published in the Sept. 24, 2015, advance online issue of Science.

So far, control does not exist once the engineered cells have been infused into patients.

"When we put CAR T cells into a patient, we really don't have a way to communicate with them," Lim said.

There have been attempts to bring CAR T cells under control via so-called suicide switches that turn them off. But if those suicide switches need to be used, it amounts to totaling a Maserati – a transplant that cost $100,000 is irreversibly destroyed, and now you've got no way to get where you're going.

In their work, Lim, Onuffer and their colleagues took the opposite approach.

The CAR T-cell system has two components – a recognition domain that binds to CD19, thus targeting B cells, and a domain that activates intracellular pathways that tell the cell what to do.

Those domains are usually "preassembled," Onuffer told BioWorld Today.

What the team has done is to have those two domains separated as the default state, allowing them to come together only in the presence of an activating molecule, a rapamycin analogue. The authors showed that in the absence of the activating molecule, their CAR T cells still bound to CD19. But they did not kill their target cells unless the activating molecule was present.

Furthermore, activation was not an all-or-none phenomenon. Higher doses of activating molecule led to stronger CAR T-cell activation, showing that the approach could be used to titrate the activity of the cells.

Lim described it as "reconfiguring the CAR T-cell structure so that we essentially add in a throttle."

One open question is to what extent the cytokine storm and tumor lysis syndrome contribute to CAR T cells' therapeutic efficacy.

Lim said that there is "no clear answer," about the extent to which such side effects are necessary, though Onuffer acknowledged they are "part and parcel of the desired effect."

Lim said that even if cytokine release and tumor lysis syndromes are necessary to a degree, "it's better for physicians to have the ability to find that threshold" where therapeutic and side effects are in balance – a balance that is likely to be different for individual patients.

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