Engineering efficacy and safety into T cells for cancer immunotherapy

The International Agency for Research on Cancer (IARC) has estimated that in 2020 there were 19.3 million new cancer cases and 10 million cancer-related deaths worldwide. While surgery, chemotherapy, and radiation have been the standard treatments for cancer in the past decades, in recent years, cancer immunotherapy paved the way for more effective and targeted therapies. In this context, adoptive cell therapy (ACT), an emerging form of cancer immunotherapy that involves the transfer of either allogeneic or autologous tumor-specific T cells into patients, has demonstrated encouraging clinical efficacy both in liquid and in solid tumors. However, safety remains an important concern for ACT and, to date, no universal T-cell activity control strategy has been developed for TCR- and CAR-engineered T cells. Here, we propose to re-program the ZAP70 kinase in order to obtain mutants that are able to maintain their canonical biological function, but become reversibly inhibited by Erlotinib, an FDA-approved kinase inhibitor, which instead does not inhibit or affect the wild-type kinase. We have shown that the insertion of these mutations do not impair the biological functionality of ZAP70, while endowing a higher affinity for the inhibitors than for the wild-type. This method allows the modulation of T-cell activity via an essential kinase and thus, represents a novel method for a universally applicable ACT safety strategy. Therefore, we believe that this approach could represent a crucial progression in the improvement of the clinical efficacy of adoptive T-cell therapies.