Making Cytokine Cancer Therapy Safer with a “Safety Lock”

Affiliation: College of Medicine/Post Baccalaureate Medicine

Our laboratory has long been dedicated to cancer therapy and the development of new anticancer drugs. Traditionally, many of the anticancer drugs we developed were designed to directly attack cancer cells. However, growing evidence suggests that the tumor microenvironment (TME) surrounding a tumor also plays a critical role in determining treatment outcomes. When the TME becomes immunosuppressive, existing therapies may not work effectively, allowing cancer cells to evade treatment. Therefore, finding ways to improve the TME and restore local immune activity has become an important strategy for enhancing the effectiveness of cancer treatment.

Cytokines, which are important signaling molecules that regulate immune responses, have demonstrated strong anticancer activity. One notable example is interleukin-12 (IL-12). However, the clinical translation of cytokine-based therapies has been significantly limited by systemic toxicity and their short circulation half-life in the body. To achieve safer and more effective treatment, it is therefore essential to prolong the circulation time of cytokines while enabling them to become selectively activated within tumors.

To address these challenges, our team developed a masking system based on the principle of Protease-unlock and steric-hindrance (PUSH). This system recruits serum albumin (Alb) to form a masking domain that physically blocks the receptor-binding site of IL-12. We expect the PUSH masking system to use Alb to effectively extend the half-life of IL-12 in the body while reducing its toxicity toward tissues outside the tumor. In addition, the high recovery of active Pro-IL-12 is expected to produce potent antitumor effects, thereby enhancing the clinical potential of cytokine-based cancer therapies.

  In the future, combining this approach with immune checkpoint inhibitors may further improve tumor responses and overall treatment efficacy, potentially offering more effective and safer therapeutic options for cancer patients.

Figure 1. Functional evaluation of the pro-cytokine protein.

Figure 2. Purification of the pro-cytokine therapeutic protein is currently underway.