LAUSR

Immune checkpoint inhibitors (ICIs), such as nivolumab and ipilimumab, not only elicit antitumor responses in a wide range of human cancers but also cause severe immune-related adverse events (irAEs), including death. A largely unmet medical need is to treat irAEs without abrogating the immunotherapeutic effect of ICIs. Although abatacept has been used to treat irAEs, it risks neutralizing the anti–cytotoxic T lymphocyte–associated protein 4 (CTLA-4) monoclonal antibodies administered for cancer therapy, thereby reducing the efficacy of anti–CTLA-4 immunotherapy. To avoid this caveat, we compared wild-type abatacept and mutants of CTLA-4–Ig for their binding to clinically approved anti–CTLA-4 antibodies and for their effect on both irAEs and immunotherapy conferred by anti–CTLA-4 and anti–PD-1 antibodies. Here, we report that whereas abatacept neutralized the therapeutic effect of anti–CTLA-4 antibodies, the mutants that bound to B7-1 and B7-2, but not to clinical anti-CTLA-4 antibodies, including clinically used belatacept, abrogated irAEs without affecting cancer immunotherapy. Our data demonstrate that anti–CTLA-4–induced irAEs can be corrected by provision of soluble CTLA-4 variants and that the clinically available belatacept may emerge as a broadly applicable drug to abrogate irAEs while preserving the therapeutic efficacy of CTLA-4–targeting ICIs. Description CTLA-4–Ig mutants that bind to B7-1/B7-2 but not anti–CTLA-4 antibodies ameliorate irAEs without compromising antitumor activity of immunotherapy. Inhibiting irAEs Immune checkpoint inhibitors targeting CTLA-4 and PD-1/PD-L1 have revolutionized cancer therapy, but treatment can result in development of severe, and sometimes fatal, immune-related adverse events (irAEs). Previous strategies to combat anti–CTLA-4 irAEs have come at the expense of treatment efficacy, because the CTLA-4–Igs used to inhibit irAEs also bound to therapeutic anti–CTLA-4 antibodies. To address this, Liu et al. identified mutant versions of the CTLA-4 molecule that bound to CTLA-4’s targets, B7-1 and B7-2, but did not bind to CTLA-4–targeting antibodies. Two candidates, including the clinically available CTLA-4–Ig, belatacept, were shown to reduce irAEs without compromising antitumor efficacy of anti–CTLA-4 treatment. These results suggest that belatacept and similar molecules could be incorporated into immunotherapy regimens as a means of controlling irAEs. —CM