Researchers have engineered molecules called inhibitory chimeric antigen receptors that can help divert off-target responses, better protecting normal tissues from damage caused by some engineered T-cell therapies.

In all the excitement around T-cell therapies for cancer, one aspect often gets overlooked: Normal tissue can be damaged by treatment, leaving patients sicker than they were before.

In a proof-of-principle study published in December in Science Translational Medicine, researchers at Memorial Sloan-Kettering Cancer Center in New York, NY, propose a solution (Sci Transl Med 2013;5:215ra172). They have engineered molecules called inhibitory chimeric antigen receptors (iCAR) that can protect normal tissue from the off-target effects of T-cell therapy.

The T-cell therapies do exactly what they're designed to do—attack tumor cells that express specific antigens on their surface. Unfortunately, there are very few antigens on cancer cells that aren't also on the surface of normal cells, so T-cell therapies attack them, too.

To stop that attack, the Sloan-Kettering team designed the iCARs to turn off if they encounter a second antigen found on healthy cells that's downregulated or absent on tumor cells. To do this, they combined an antigen-recognition domain with signaling domains of CTLA-4 and PD-1. In this context, the checkpoint blockades downstream of these proteins are used for their natural purpose: to ensure that the immune system doesn't overreact to threats.

Because the checkpoint blockades respond only to an antigen found on normal tissue but not on the tumor, the iCARs can be turned on again if they meet a tumor cell.

“What's very exciting about the concept is that it's reversible, mimicking what the normal immune system does, but we've twisted it to make it selectively protective for what we want to protect,” says molecular pharmacologist Michel Sadelain, MD, PhD, who led the work.

“I think it's a wonderful idea,” says Stanley Riddell, MD, an immunologist at the Fred Hutchinson Cancer Research Center in Seattle, WA, who praised the Sloan-Kettering team for experimentally evaluating what others have only talked about. “And I think this does demonstrate in principle that this could work.”

The real challenge will come when the iCARs are tested in the clinic, where T cells will need to be carefully engineered to express both a chimeric antigen receptor and an iCAR in a way that maximizes antitumor activity and minimizes off-target killing. However, current mouse models are not really rigorous enough to adequately test the iCARs, notes Riddell, who is working to improve these models.

“The reason this paper is important is that it provides a new avenue to investigate,” Riddell explains. “As we proceed in identifying new receptors, we can think about how we can combine signaling modules to tune the response to be more selective against the tumor and less against normal tissues.”

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