Anti-cancer cell-laden gel keeps tumors under control after surgery in mice
A new biodegradable gel filled with a cocktail of immune system-boosting cytokines and anti-cancer cells prevented the growth of persistent cancer cells in mice after surgical removal of the tumors.
Three weeks after surgery, the tumors of the mice treated with the specialized gel were approximately 60 times smaller than those of the untreated mice.
Proof of concept experiments show that these gels could help fight cancer at a critical time: when a tumor has been removed but malignant cells continue to hide after surgery, ready to grow back. While more research is needed to develop a treatment for cancer in humans, these preclinical findings offer a promising new way to deploy the immune system to wipe out cancer cells after surgery.
Quanyin Hu, who recently joined the faculty of the University of Wisconsin – Madison School of Pharmacy, led the research. He completed the work with colleagues from the University of California at Los Angeles, University of North Carolina, Chapel Hill, and Zhejiang University, including teams from Zhen Gu and Gianpietro Dotti. The research was published April 26 in the journal Nature Biomedical Engineering.
The technique relies on the concentration of the efforts of T cells, which are part of the immune system capable of destroying tumor cells. The researchers genetically reprogrammed the cells to target specific cancer markers, concentrated the cells in the biodegradable gel, and supported them with T cell stimulating cytokines and anti-tumor antibodies.
The Food and Drug Administration has approved three T-cell therapies for lymphoma and leukemia, two types of blood cancer. Known as CAR T-cell therapies, these treatments reprogram a patient’s own T cells to recognize cancer-specific markers, which are characteristics unique to cancer cells. Reinfused into the patient’s bloodstream, these CAR-T cells detect and destroy cancer cells much better than before.
But CAR T cell therapies don’t work as well for solid tumors, such as melanoma or breast cancer, because they’re harder to reach through the bloodstream. And although many tumors can be removed surgically, it is very difficult to remove every last malignant cell, so additional chemotherapy or radiation therapy is often used to remove persistent cancer. This cleansing treatment saves lives, but can cause serious side effects, so creative new ways to clean surgically removed tumors could be a boon to patients.
“This is why we want to develop these new technologies to facilitate the effectiveness of the treatment of CAR T cells against solid tumors,” says Hu.
To improve the system, Hu and his team made three main changes. First, they added IL-15, an immune boosting signal known as a cytokine that promotes the growth and vigor of T cells.
Second, they added platelets, grains of cells that coagulate the blood, which they bind to anti-tumor antibodies. Hu says the biggest limitation of CAR T cell therapy for solid tumors is some kind of switch that tumors use to hide from T cells. These antibodies block that switch, reactivating T cells in the area.
In the third step, the researchers loaded the reprogrammed T cells, IL-15-loaded nanoparticles, and antibody-decorated platelets into a gel made of biocompatible materials. The gel provides a good environment to support the T cells so that they can be applied during surgery to remove a tumor and then slowly release into the surgical site. The body ends up breaking down the gel.
In a mouse model of human melanoma, researchers removed the majority of a melanoma tumor during surgery, then applied the gel or salt water treatment. Within three weeks, the tumors of the mice given salt water only grew much larger, while the tumors of the mice given the gel hardly grew at all.
The beneficial effect of the gel has even spread to tumors in other parts of the body. In another experiment, the mice harbored two melanomas, one on each side of the body. The researchers removed only one and treated the site with the gel. But the modified T cells traveled from the gel to the other tumor, slowing its growth as well.
“This experiment mimics how tumors can metastasize from one part of the body to another. And we’ve seen that our topical treatment strategy can also induce systemic efficacy, ”says Hu.
While the results are promising, there are many other steps in trying to develop the gel system into a treatment for humans, including further animal studies. The Hu lab also wants to better understand how the body’s natural platelets affect the modified platelets in the gel. And they’re looking to study how well the gel works for other cancers, including inoperable tumors.
“I think we are on the right track for clinical translation, but first we need to learn more,” says Hu.
This work was funded in part by National Institutes of Health grant 1R01CA234343-01A1.