Development of a tumor-activated IL12 prodrug to treat solid tumors

Project Summary/Abstract: 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.