An inducible signal 1 booster overcomes limited access to antigen for solid tumor cell therapy

Antigen (signal 1) is the ignition and fuel for T cell responses. Chimeric antigen receptors (CARs) co-opt T cell receptor (TCR) signaling domains (e.g., ITAM elements) to redirect T cell responses to specific antigens. Most efforts to enhance potency have added elements intended to preserve antigen dependence while boosting sensitivity, persistence, etc. However, solid tumors pose unique challenges compared to blood cancers. For example, access to tumor tissues that express target antigen is highly restricted by the blood vessel walls and, with limiting antigen, it is unclear how antigen-dependent boosters can be brought into action. Here, we describe a simple circuit that addresses this problem by mimicking an antigen stimulus with a small molecule to boost signaling downstream of the CAR. These signal 1 boosters are variants of the previously identified MyD88-CD40 fusion protein but mitigate the excessive antigen sensitization of this molecule. We identified a booster that, when expressed with CAR or Tmod, produces small-molecule-inducible T cell expansion and activation while maintaining a favorable safety profile in a surrogate normal-tissue mouse model.