Researchers have developed a liquid gel that solidifies when injected into a solid tumor, is visible on a CT scan, and can slow-release cancer-fighting treatments. Using the gel in combination with immunotherapy improved survival in mice and affected distant, untreated tumors, suggesting it has potential as a therapy for metastatic cancers.
Injecting anti-cancer drugs directly into tumors – intratumoral therapy – is a promising way of treating solid cancers. However, clinical trials have highlighted some drawbacks. One is that most immunotherapies are composed of small molecules prone to dissipating quickly from the tumor site after injection. Another is visualizing the treatment in situ to confirm its on-target delivery.
Now, researchers from Mass General Brigham, in collaboration with the Koch Institute for Integrative Cancer Research, have developed a gel delivery system that overcomes these challenges.
“This gel tackles the two problems with existing attempts at intratumoral cancer immunotherapy: making the therapy visible and practical so that interventional radiologists can confirm delivery and making sure the drug actually stays in the region of interest,” said Avik Som, lead author of the study.
The researchers set out to create a gel that was multifunctional: it had to be injectable at room temperature and solidify at the tumor site; it had to contain an imaging agent so the therapy could be visualized using CT imaging; and it had to be able to deliver cancer treatment. In this case, the treatment was imiquimod, an FDA-approved immune-stimulating drug.
They settled on a co-polymer composed of biocompatible poly(lactic-co-glycolic acid) (PLGA) and polyethylene glycol (PEG) in a triblock structure. The triblock structure enabled two critical features that enabled the controlled release of imiquimod: first, it self-assembled into micellar nanoparticles that encapsulated the drug, increasing its solubility by about 2,000-fold and allowing a larger dose to be delivered; second, around body temperature, this micellar structure formed a viscous gel. Next, the researchers added iopamidol, a contrast agent, to enable the visualization of the intratumoral injection under CT. They named their gel drug delivery system ‘Imigel’.
Using mouse models of colon and breast cancer that are usually resistant to immunotherapy, the researchers administered the animals with a single intratumoral injection, a combination of Imigel and checkpoint inhibitor (CPI) therapy. Each mouse had two tumors of the same type, but only one was treated, allowing the researchers to test whether the gel stimulated both local and systemic immunity.
At 90 days after treatment, the combination treatment improved survival in both cancer models. For the colon cancer model, 46% of mice survived; in the breast cancer model, 20% survived. The treatment produced an all-or-nothing response. Mice that responded to it showed complete regression of the treated tumor and the distantly located tumor, while non-responders showed no regression at either site.
“When we inject this gel into a tumor, we’re able to teach the immune system to recognize the cancer and trigger it to attack not only the site where the gel was injected, but also other areas in the body where the same cancer may be hiding,” Som said.
The so-called ‘abscopal effect’, where a local therapy induces a therapeutic effect in distant metastases, presumably secondary to immune activation, is rarely seen in cancer treatment, particularly in cancers that are resistant to CPI therapy. The fact that the combination treatment used in the current study affected distant, untreated tumors has the potential to impact therapies for metastatic cancers.
The researchers will continue testing their gel technology for safety and plan to test its efficacy with drugs other than imiquimod.
“This is an early proof-of-concept, but we’re all actively working together to try and get these technologies to patients,” said Eric Wehrenberg-Klee, one of the study’s co-authors. “There’s quite a bit of benefit to be gained by being able to treat patients with a single injection, and we think this technology has the potential to help with cancers that are currently challenging to treat.”
The study was published in the journal Advanced Healthcare Materials.
Source: Mass General Brigham
