Despite recent advances in cancer immunotherapy, solid tumors remain largely refractory to treatment due to disruption of immune homeostasis by the tumor microenvironment (TME). Within the TME, a combination of hypoxia, acidity, suppressive cells, and immune checkpoints leads to poor differentiation of type I effector cells, preventing the development of a robust immune response. IL12 is a naturally produced cytokine that can directly induce type I, cell-mediated immunity through the IL12R?1/IL12R?2 complex on innate lymphoid cells (ILCs) and T cells. IL12 has been remarkably successful against solid tumors in preclinical trials, but its clinical development has been impaired by lethal toxicity due to systemic immune overactivation. I have developed a novel IL12-based prodrug (proIL12) that displays no noticeable toxicity in vivo but maintains full antitumor efficacy. The kinetics and cellular mechanism of proIL12 must still be ascertained, but preliminary data suggests T cells play a critical role and IFN? is the main cytokine induced. Therefore, I hypothesize that proIL12 circulates in inert prodrug form until activated by tumor-specific enzymes, at which point it activates T cells directly through IL12 receptor and secondarily through IFN? production. To test my hypothesis, I will first validate proIL12?s drug profile by determining an optimal dosing schedule, monitoring tumor-specific activation, and measuring toxicity. Then, I will explore which specific cell subtypes among ILCs and T cells are necessary to reject tumors. Finally, I will independently assess the downstream role of IFN? in coordinating the proIL12 response. By systematically characterizing both physical and mechanistic properties of proIL12, I will not only prepare it for further clinical development but also inform future steps such as combination therapies or prognostic markers. As a whole, my study will produce a tolerable immunotherapeutic agent capable of reversing TME-induced immune disarray to eliminate solid tumors.
Solid tumors remain one of the leading causes of death in the United States because their complex microenvironment resists conventional treatment modalities. I have generated a novel IL12 prodrug that potently activates immune cells without adverse effects, allowing the administration of doses capable of eradicating solid tumors in mice. Through pharmacokinetic and mechanistic studies, I will ascertain exactly how this prodrug functions, bringing it one step closer to treating cancer in patients.
