"Intratumourally injected alum-tethered cytokines elicit potent and safer local and systemic anticancer immunity", published by a team of researchers from the Massachusetts Institute of Technology (MIT) in Nature Biomedical Engineering on January 10, 2022.
Attacking tumors by stimulating the immune system is a promising approach to cancer treatment. Today, scientists are working on two complementary strategies to achieve this goal: relieving the tumor from suppressing the immune system, and activating the immune system through immune-stimulating drugs. While the former has already been marketed with immune checkpoint (https://www.creative-biolabs.com/immuno-oncology/immune-checkpoint-assay...) inhibitors, including anti-PD-1/PD-L1 monoclonal antibodies, the latter has no precedent for success.
The study developed a novel, immune system-initiating approach that combines and delivers the cytokine IL-12 with aluminum hydroxide to tumors, activating tumor immunity while avoiding the toxic reactions that can occur when immune-stimulating drugs are used systemically.
In a study on mice, the team used this treatment strategy with anti-PD-1 monoclonal antibodies to successfully activate the immune system and eliminate multiple types of tumors.
"IL-12 is just the beginning of a therapeutic strategy that might be applicable to any other immunostimulatory drug," according to Professor Darrell Irvine, corresponding author of this study and the Associate Director of the Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology.
Tumors produce chemicals that inhibit neighboring T cells and other immune cells, causing the tumor to grow out of control. The immune system appears to be "braked" by cancer cells. Immune checkpoint inhibitors can be used to activate the immune system, however they are only effective against some types of cancer, and many other cancers are resistant to them.
Combining immune checkpoint inhibitors with immune system stimulants could make cancer immunotherapy (https://www.creative-biolabs.com/immuno-oncology/) more successful for a broader spectrum of patients. Cytokines are immunological molecules produced naturally by the body in order to stimulate the immune system. However, these drugs have too many adverse side effects in clinical trials, such as flu-like symptoms and even organ failure.
The team has been looking for ways to distribute cytokines in a more focused manner to avoid these unwanted effects. The team published a study in Science Translational Medicine in June 2019 in which they attached the cytokines IL-12 and IL-2 to collagen-binding proteins, which bind to collagen that is highly expressed in tumors, thereby specifically delivering these cytokines to tumor tissue.
In mice experiments, this therapeutic tactic worked well, but the researchers hoped to find a way to make the cytokines bind to tumors more tightly. In their most recent investigation, scientists used aluminum hydroxide to substitute the collagen-binding protein.
Aluminum hydroxide, also known as alum, is commonly used as a vaccine adjuvant and as a food additive, such as alum as a bulking agent when frying doughnuts. However, because alum contains aluminum ions, excessive consumption can affect the body's absorption of iron, calcium, and other nutrients, leading to osteoporosis, anemia, and even affecting nerve cell development. Yet, it was such a notorious food additive that was the key to the success of this latest study! Dr. Yash Agarwal, the study's first author, said, "one of the key advantages of alum is that the particles are micron-sized, so when you inject them into people or mice, they stay where you inject them for weeks, sometimes for months."
The researchers injected mice with either IL-12 or IL-2 linked to alum pellets and gave them immune checkpoint inhibitors with anti-PD-1 monoclonal antibodies every few days to test the effectiveness of this treatment.
Researchers discovered that tumors were eradicated in 50% to 90% in three types of cancer mice models. A single injection at the site of the breast cancer eradicated metastatic tumors in a mouse model of lung metastases from breast cancer. Furthermore, even without the use of anti-PD-1 monoclonal antibodies, IL-12-alum particles were able to stimulate the immune system to combat malignancies.
Further research revealed that IL-12 stimulates the synthesis of gamma-interferon, a cytokine that works in tandem with IL-12 to activate T cells, dendritic cells, and macrophages. Furthermore, this approach activates memory T-cells, causing them to respond to tumor regeneration. More critically, mice given IL-12-alum pellets did not develop any of the adverse effects associated with systemic IL-12 injections.
In conclusion, this study developed an immunotherapeutic strategy that activates the immune system with few side effects by combining alum particles with the cytokine IL-12 and then delivering them directly to tumor tissue. The IL-12-alum particles will stay at the tumor site for several weeks, reducing toxic side effects while stimulating the production of gamma-interferon and activating the immune system, thereby initiating the tumor immune response.
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