New gel delivery system overcomes challenges of intratumoral cancer immunotherapy

Intratumoral therapy – where cancer drugs are injected directly into tumors – is a promising treatment option for solid cancers but has shown limited success in clinical trials due to the inability to deliver drugs precisely and because most immunotherapies are rapidly eliminated from the injection site. A team of researchers at Brigham, Mass., in collaboration with colleagues at the Koch Institute for Integrative Cancer Research, developed a gel delivery system that overcomes these challenges. The gel is injectable but hardens during delivery; A CT scan contains an imaging agent for visualization; and can hold high concentrations of drugs for slow, controlled release.

In a published research paper Advanced healthcare products, the team reported that using gel-delivered imiquimod (an immune stimulating drug) in combination with checkpoint inhibitor therapy induced tumor regression and increased survival in mouse models of colon and breast cancer that are normally resistant to checkpoint inhibitor therapy. The treatment also appeared to train the immune system to recognize and attack distant tumors that were not directly treated, suggesting it could be an adjunctive therapy for metastatic cancer.

This gel addresses two problems with existing efforts to develop intratumoral cancer immunotherapy: making the therapy visible and practical so that interventional radiologists can confirm delivery, and ensuring that the drug actually stays in the region of interest. When we inject this gel into a tumor, we are able to teach the immune system to recognize the cancer and have it attack not only the site where the gel was injected, but also other sites in the body where the same cancer may be present. is hidden.”

Avik Som, MD, PhD, Department of Radiology, Massachusetts General Hospital, Mass. General Brigham Health Care System, founding member

The research team, which is comprised of both engineers and medical professionals, first developed and optimized the gel-delivery system in the lab by altering the gel’s chemical structure. A key aspect of the gel’s design was that it should deliquesce at room temperature to be injectable but solidify at body temperature inside the tumor to create a drug-releasing depot, while maintaining drug encapsulation and delivery capabilities. , and carries adequate imaging agents.

After optimizing the gel in the lab, the team tested its ability to treat mouse models of colon and breast cancer that are typically resistant to immunotherapy. To do this, they used the gel to deliver imiquimod, an FDA-approved immune stimulating drug, in combination with checkpoint inhibitor therapy. Each mouse had two tumors of the same type, but the researchers only treated one per mouse, allowing them to test the gel’s ability to stimulate both local and systemic tumor immunity.

They showed that treatment with gel-delivered imiquimod in combination with checkpoint inhibitor therapy improved survival in both cancer models. Treatment results in an all-or-nothing response -; Mice that responded to treatment showed complete regression of both the treated tumor and a distant tumor (a model for metastasis), while non-responders showed no regression at either site. For the colon cancer model, 46% (6/13) survived when checkpoint inhibitor therapy was combined with gel-delivered imiquimod. For the breast cancer model, 20% (3/15) survived when treated with combination therapy.

“These two tumors are challenging to treat today, even though immunotherapies are changing how we think about treatment,” said co-corresponding author Giovanni Traverso, MB, PhD, MBBCH, founding member of the Department of Medicine at Brigham and Women’s Hospital. Mass. is an associate professor in the Department of General Brigham Health Care Systems and Mechanical Engineering at MIT. “The fact that we were able to induce responses in distant tumors in these colon and breast cancer models was a big win.”

Researchers are interested in transferring this technology to the clinic, but it must first undergo further testing for safety. They plan to test its effectiveness with a wider panel of drugs.

“This is an early proof of concept, but we are all actively working together to bring these technologies to patients,” said Eric Wehrenberg-Klee, MD, assistant radiologist in the Department of Radiology at Massachusetts General Hospital. First author of the study. “Being able to treat patients with a single injection has several advantages, and we think this technology has the potential to help cancers that are currently challenging to treat.”