Researchers developed gel-mediated cancer drug delivery for solid tumors

Intratumoral therapy, in which cancer drugs are injected directly into tumors

The researchers at the Mass General Brigham developed the gel, which requires only a single injection, induced tumor regression and improved survival in preclinical models of immunotherapy-resistant colon and breast cancer.

A promising treatment option for solid cancers, intratumoral therapy involves injecting cancer drugs directly into tumors. However, due to its inability to deliver the drug precisely and the fact that most immunotherapies quickly wear off at the injection site, intratumoral therapy had limited success in clinical trials. Working with partners at the Koch Institute for Integrative Cancer Research, a group of Mass General Brigham researchers has created a gel delivery technique that gets around these problems. The gel can have a high concentration of medication for gradual, controlled release; it is injectable but hardens upon delivery and includes an imaging agent for visibility under a CT scan.

In a paper published in Advanced Healthcare Materials, the group finds that in mice models of colon and breast cancer, which are often resistant to checkpoint inhibitor therapy, the combination of checkpoint inhibitor therapy plus gel-delivered imiquimod, an immune-stimulating medication, produced tumor shrinkage and improved survival. Additionally, the treatment seemed to teach the immune system to identify and target distant tumors that escaped direct treatment, indicating that it may be a useful treatment for malignancies that metastasized.

This gel tackles the two problems with existing attempts at making 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. 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

Avik Som, MD, PhD, of the Department of Radiology at Massachusetts General Hospital

By adjusting the gel’s chemical composition, the study team—which included engineers and medical experts—first created and perfected the gel-delivery system in the lab. A crucial component of the gel’s design was its requirement to change from a liquid at room temperature to an injectable solid inside the tumor to form a drug-releasing depot, maintaining the gel’s ability to encapsulate and deliver drugs and carry an adequate amount of imaging agent.

The scientists investigated the gel’s potential to treat mice models of colon and breast cancer, which are often resistant to immunotherapy, after refining it in the lab. In order to do this, they combined checkpoint inhibitor treatment with imiquimod, an immune-stimulating medication authorized by the FDA, and administered it via gel. The researchers tested the gel’s capacity to activate both local and systemic immunity by treating only one of the two tumors of the same type per animal.

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They demonstrated that treating both cancer models with imiquimod given by gel in conjunction with checkpoint inhibitor treatment increased survival. The mice who reacted to the medication showed total regression of both the treated tumor and a distant tumor (a model for metastasis); the other animals showed no regression at any site. The treatment produced an all-or-nothing response. When gel-delivered imiquimod was paired with checkpoint inhibitor treatment, 46% (6/13) of the colon cancer model’s participants survived. 20% (3/15) of the breast cancer model’s patients survived treatment with the combination of medicines.

These two tumors remain challenging to treat today, even though immunotherapies are transforming how we think about treatment,” said co-corresponding author Giovanni Traverso. The fact that we were able to induce responses in distant tumors in these colon and breast cancer models was a big win.

Giovanni Traverso, MB, PhD, MBBCH, Department of Medicine at Brigham and Women’s Hospital

Although the researchers are motivated to get this technology into the clinic, further safety testing must be done on it before. They also intend to evaluate its effectiveness using a larger range of medications.

This is an early proof of concept, but we’re all actively working together to try and get these technologies to patients. 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.

Eric Wehrenberg-Klee, MD, assistant radiologist in the Department of Radiology at Massachusetts General Hospital and one of the study’s first authors

Journal reference: Som, A., Rosenboom, G., Wehrenberg-Klee, E., Chandler, A., Ndakwah, G., Chen, E., Morimoto, J., Kim, J., Mustafa, A. R., Marcos-Vidal, A., Fintelmann, F. J., Basu, A., Langer, R., Traverso, G., & Mahmood, U. Percutaneous Intratumoral Immunoadjuvant Gel Increases The Abscopal Effect of Cryoablation for Checkpoint Inhibitor Resistant Cancer. Advanced Healthcare Materials, 2301848.

Source: Mass General Brigham’s Newsroom

Report: Achuth B S

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