Nat Biomed Eng: Step on the accelerator for the immune system, MIT develops IL-12+ alum therapy, which effectively kills tumors and has fewer side effects

Cancer , because of its intractability and complexity, is known as the " king of all diseases "
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Fighting cancer is like life and death on a racing track - killing cancer cells faster than they multiply

Cancer Cancer King of Diseases King of Diseases Immune System Immune System

Attacking tumors by stimulating the immune system is a promising cancer treatment
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Today, scientists are working on two complementary strategies to achieve this goal: "turning off the brakes" - unblocking the immune system from the tumor; and "stepping on the gas" - activating the immune system with immunostimulatory drugs

"Turn off the brakes" - release the tumor's inhibition of the immune system; "step on the gas" - activate the immune system with immunostimulatory drugs

On January 10, 2022, a research team from the Massachusetts Institute of Technology (MIT) published a research paper entitled: Intratumourally injected alum-tethered cytokines elicit potent and safer local and systemic anticancer immunity in Nature Biomedical Engineering, a sub-journal of Nature
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The study developed a new method to prime the immune system by combining the cytokine IL-12 with aluminum hydroxide (alum) and delivering it to tumors, activating tumor immunity while avoiding the use of immune-stimulating drugs throughout the body possible toxic reactions
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In a study in mice, the research team used this therapeutic strategy with an anti-PD-1 mAb to successfully activate the immune system and eliminate multiple types of tumors
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"IL-12 is just the beginning, and this therapeutic strategy may be applicable to any other immune-stimulating drug," said the study's corresponding author, Professor Darrell Irvine, associate director of the Koch Institute for Integrative Cancer Research at MIT
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At present, the research team has applied for a patent for the treatment technology and licensed it to a start-up company, which is expected to start clinical trials by the end of 2022
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Bioworld: We speculate that Strand Therapeutics may have licensed the technology, but it hasn't been announced, so we can't be sure
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step on the gas

Step on the gas Step on the gas

As tumors develop, they secrete molecules that disable nearby T cells and other immune cells, allowing the tumor to grow uncontrollably
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It's as if cancer cells put the "brake" on the immune system

Combining immune checkpoint inhibitors with drugs that stimulate the immune system may make cancer immunotherapy effective for more patients
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Cytokines are immune chemicals naturally produced by the body that activate the body's immune system

Professor Dane Wittrup, one of the corresponding authors of the study, said: "If patients are exposed to a large number of cytokines, their whole body will react, which will have very strong toxic side effects, so it is difficult to achieve the desired anti-tumor effect
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To avoid these side effects, the research team has been investigating ways to deliver cytokines in a more targeted manner
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In June 2019, the team published a paper in Science Translational Medicine in which they attached the cytokines IL-12 and IL-2 to collagen-binding proteins that bind to collagen that is abundantly expressed in tumors, thereby binding these cells to Factors are specifically delivered to tumor tissue

This therapeutic strategy worked well in mouse studies, but they hoped to find a way to make the cytokine bind more strongly to the tumor
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Now, in their latest study, they replaced the collagen-binding protein with aluminum hydroxide

Aluminum hydroxide, also known as alum, is often used as a vaccine adjuvant (a drug that helps boost the immune response) and is also a food additive, such as when fried dough sticks are added as a bulking agent, but because alum contains aluminum Excessive intake of ions will affect the body's absorption of iron, calcium and other ingredients, resulting in osteoporosis, anemia, and even affect the development of nerve cells
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Therefore, some nutrition experts propose to try to eat less food containing alum

However, it is such a notorious food additive that has become the key to the success of this latest study! Yash Agarwal, first author of the study? "One of the main advantages of alum is that the particles are micron-sized, so when you inject them into a human or mouse, they stay where you inject them for weeks, sometimes months
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Stronger tumor suppression, less toxic side effects

Stronger tumor inhibition, lower toxic side effects Stronger tumor inhibition, lower toxic side effects

To test the effectiveness of this treatment, the researchers injected mice with either IL-12 or IL-2 bound to alum particles and an immune checkpoint inhibitor, an anti-PD-1 mAb, every few days.

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In three mouse models of cancer, the researchers found that tumors were eliminated in 50 to 90 percent of the mice
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In a mouse model of breast cancer lung metastases, a single injection at the breast cancer site also cleared metastatic tumors
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Furthermore, IL-12-alum particles showed the ability to stimulate the immune system to fight tumors even without the combined use of anti-PD-1 mAbs
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IL-12-Alum particles promote systemic immunity in an orthotopic 4T1 breast cancer model

IL-12-Alum particles promote systemic immunity in an orthotopic 4T1 breast cancer model IL-12-Alum particles promote systemic immunity in an orthotopic 4T1 breast cancer model

Further research showed that IL-12 stimulates the production of another cytokine called interferon gamma, and the two molecules work together to activate T cells, dendritic cells and macrophages
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Not only that, but the therapy stimulates memory T cells to respond to tumor regeneration
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What's more, mice treated with IL-12-alum particles did not experience any of the side effects seen with systemic injection of IL-12
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IL-12-alum particles remain in tumor tissue with negligible systemic toxicity following administration

IL-12-alum particles remain in tumor tissue with negligible systemic toxicity after administration IL-12-alum particles remain in tumor tissue with negligible systemic toxicity after administration

Currently, the startup that has licensed the technology plans to test IL-12-alum particles on its own for the first time by the end of this year, and if the therapy proves to be safe, they hope to further test IL-12-alum particles with immune checkpoint inhibition The effect of combined use of agents
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In conclusion, this study develops an immunotherapy strategy that activates the immune system with minimal side effects by combining alum particles with the cytokine IL-12 and delivering them directly into tumor tissue, where the IL-12-alum particles are located at the tumor site.
Stay for a few weeks, reduce toxic side effects while stimulating the production of γ-interferon, and activate the immune system to initiate tumor immune responses
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IL-12-alum particles activate the immune system

IL-12-alum particles activate the immune system IL-12-alum particles activate the immune system

The combination of IL-12-alum particles and the immune checkpoint inhibitor anti-PD-1 monoclonal antibody has shown good therapeutic effects in a variety of mouse cancer models, and can treat metastatic tumors
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Professor Darrell Irvine said: "This new method of attaching molecules to alum could also be used to deliver other types of immune-stimulating drugs
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This type of drug that involves 'tapping the gas' is largely unprecedented, and we hope this will provide Testing these drugs opens the way"

Original source:

Original source:

Agarwal, Y.
, Milling, LE, Chang, JYH et al.
Intratumourally injected alum-tethered cytokines elicit potent and safer local and systemic anticancer immunity .
Nat Biomed Eng (2022).
https://doi.
org/10.
1038/s41551- 021-00831-9.

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