UCSF

Many potential immunotherapies are hindered by poor efficacies and unacceptable toxicities, such as on-target, off-tumor toxicity. In contrast to constitutive CAR expression, inducing a T cell to only express a CAR in the presence of a second tumor antigen adds additional regulation over the cytotoxic response. The ability to tune the level and duration of an induced cell-based immunotherapeutic would also further improve on the safety of cell-based immunotherapies and provide a platform for robust tuning of an immunotherapeutic regimen. In pursuit of this goal, I have engineered a set of SyNthetic Intramembrane Proteolysis Receptors (SNIPRs), a series of Type I transmembrane proteins which, upon binding to their designated target, activate an orthogonal transcriptional program. Compared to current synthetic receptor designs, SNIPRs are smaller, more well-expressed, more sensitive, and more easily tunable in response to surface antigen and certain soluble antigens. I have demonstrated that SNIPRs, when expressed in human primary T-cells, can respond to tumor cells both in vitro and in vivo by outputting regulatable levels of a CAR or cytokine. I have also demonstrated in vivo that a SNIPR-CAR circuit can specifically clear a dual positive tumor and a SNIPR-superIL2 circuit can improve tumor clearance at lower T cell dosages. Together, these data demonstrate the potential for SNIPRs in the development of safer and more effective cell-based immunotherapeutics.