Intratumoral IL12 mRNA Therapy Reverses Cancer Immunotherapy Resistance

This study explored whether the mRNA encoding the cytokine, interleukin-12 (IL12) could activate anti-tumor immune responses in immunotherapy resistant tumors. Immune checkpoint inhibitor (ICI) based immunotherapy is highly effective and is now used to treat virtually all types of cancers. ICis work by helping the immune system recognize and kill cancer cells. Unfortunately, many patients develop resistance to ICI, and their tumors become unresponsive. Here the researchers aimed to determine if tumor localized IL12 introduction could induce anti-tumor immunity and overcome immunotherapy resistance.

Effectiveness of ICI immunotherapy in many cancer patients is limited due to development of resistance. Finding ways to overcome this resistance is crucial for improving outcomes in such patients. The IL12 cytokine potently activates the immune system and is toxic when administered intravenously. This study is significant as it examines a novel strategy of directly administering IL12 coding mRNA into the tumor resulting in production of IL12 within the tumor environment to activate anti- tumor immune responses. If successful, this approach could offer new hope for patients with immunotherapy resistant cancers.

The researchers used mouse models of melanoma and colorectal cancer that were either responsive or resistant to ICIs. They injected IL12 m RNA into these tumors and observed the effects of the standalone treatment or upon combination with a commonly used ICI drug (anti-PD-L1 antibody). To quantify treatment responses, they monitored: tumor growth, immune cell infiltration, activation of immune cells, and overall survival of the mice.

The IL12 mRNA treatment alone led to cures in at least 60% of mice with any type (ICI-sensitive or resistant) of tumor. The treatment increased the presence of immune cells that attack cancer cells and reduced the number of regulatory cells that suppress immune responses. The treatment resulted in activation of several immune pathways at once, significantly enhancing the killing of cancer cells resulting in durable cures.

The findings suggest that IL12 mRNA therapy could be a promising treatment checkpoint inhibitor resistant cancer. By boosting immune responses directly within the tumor, this approach avoids toxicity, helps overcome resistance and may improve the effectiveness of other existing cancer therapies.

The researchers recommend additional studies to better understand the mechanisms of IL12 mRNA in activation of the local immune environment. They also suggest clinical trials to evaluate the safety and effectiveness of this approach in humans, particularly in combination with other cancer therapies. These steps are crucial to translate these promising findings for patients with immunotherapy resistance who have run out of options.

This research was supported by a sponsored research agreement from AstraZeneca. Yale University also provided significant funding and support for this research.