Immune action at a distance

For most metastatic cancer types, there are no reliably effective treatments. Therapies may slow the growth of tumors, but they will not eradicate them. Occasionally, however, treating a tumor in one location will cause untreated tumors elsewhere in the body to shrink or even regress completely — a dramatic but exceedingly rare phenomenon known as the abscopal effect.

Cancer researchers have sought methods to induce the abscopal effect by design. The abscopal effect is thought to arise when dead or damaged tumor cells release antigens that teach some types of immune cells to recognize and attack other and even distant cancer cells. Essentially, the treated tumor behaves like a personalized cancer vaccine that incites the immune system to attack metastasized tumors. The advent of cancer immunoadjuvants, which enhance and sustain the activity of tumor-targeting immune cells, has been a key to unlocking the abscopal effect, at least in the laboratory setting. 

In the clinic, success has proven more elusive. Since immunotherapies can lead to serious toxicities if administered through the bloodstream, they must be delivered directly to the tumor — often by injection. It is difficult for clinicians to target injections precisely to the tumor and impossible to confirm delivery. Once injected, immunostimulatory drugs quickly leak out of the tumor before they have had a chance to take full effect.

MIT researchers, together with colleagues from Mass General Brigham, have developed a polymer gel delivery system that could help translate the promise of the abscopal effect into the clinic. The gel, visible with a CT scanner or ultrasound, solidifies after injection, where it remains in the tumor to release drugs at a controlled rate.

In a study published in Advanced Healthcare Materials, the team delivered the immune-stimulating drug imiquimod in combination with checkpoint blockade therapy to dual-tumor mouse models of colon and breast cancer, which showed improved survival as well as tumor regression in both treated and untreated tumors.

“The field has been seeking the ‘holy grail’ of the abscopal effect for the past 15 years,” says Giovanni Traverso, a senior author of the study, Karl Van Tassel Career Development Professor in the Department of Mechanical Engineering, and a member of the Koch Institute for Integrative Cancer Research at MIT. “Now, with drug-delivery materials better adapted for the clinic, it could be within reach.”

Traverso’s co-senior author is Umar Mahmood, director of the Center for Precision Imaging and chief of the Division of Nuclear Medicine and Molecular Imaging at Massachusetts General Hospital (MGH). Avik Som, interventional and diagnostic radiology resident at MGH; Jan-Georg Rosenboom, senior postdoc in the Langer and Traverso labs at the Koch Institute; and  Eric Wehrenberg-Klee, director of the Center for Image-Guided Cancer Therapy and assistant professor at Harvard Medical School, are co-lead authors. Robert Langer, David H. Koch Institute Professor, is also an author of the study.

Defining the problem

At MGH, clinicians saw that of 18 patients that were treated with an intratumoral injection of immunotherapy either just before or after undergoing a procedure known as cryoablation, one patient with metastatic melanoma showed a sustained abscopal effect. In cryoablation, a tumor is injected with freezing gas and then thawed out, with the hope of inducing a system-wide immune response to tumors.

The observation pointed to a promising avenue for achieving the abscopal effect for more patients, but a new tool was needed to address some of the realities of intratumoral injections in the clinic. In addition to the difficulties of delivering intratumoral injections for the clinician, these treatments are costly and infeasible for patients. Because tumors do not retain immunotherapies for long, patients require repeat injections — with sedation — over several days. The clinicians looked across the river to their MIT colleagues for help.

 “My clinical colleagues came to us with this very interesting problem, so we thought, how can we address this from our own chemical engineering perspective?” says Rosenboom.

The interdisciplinary team determined that the injected material would need to be liquid at room temperature during injection, and then solidify once inside the tumor to prevent leakage. For optimal drug delivery, the gel would need to carry a high concentration of drug in a small volume and then release its payload in a controlled fashion over several days. The team planned to add an iodinated and clinically approved contrast agent to make it visible with a CT scan to help clinicians confirm they have successfully injected the material. To help smooth the path of the platform to the clinic, the gel should be known to be safe and biocompatible and the immunotherapy it transports to have proven effectiveness.

“As a radiologist, I can see tumors under CT or ultrasound, but I can't see the drugs they are asking me to inject!” says Som. “That's why we designed a formulation for a promising immunoadjuvant that could be image guided by both modalities. This platform should hopefully realize the immense promise of personalized cancer vaccines.”

Adds Wehrenberg-Klee, “When developing new intratumoral immunotherapies, being able to confirm delivery into tumor is a critical variable. Intratumoral immunotherapy relies on the assumption that you are delivering therapy to tumor, but our clinical experience suggests this may not always be true. If we can see what we’ve injected, we can eliminate that concern.”

“As engineers, we needed to solve the problem of how to tune a polymer formulation to achieve injectability, solidification at body temperature, prolonged drug release, and visibility — all at the same time, all while these properties affect one another,” says Rosenboom. “That took us about four years to figure out.”

A solution gels

After investigating several polymers, the researchers found that a three-part polymer called PLGA-PEG-PLGA would help them balance the several competing features required of their platform. The polymer is thermosensitive. With slight changes to its molecular weight (size), it can be adjusted to be liquid at room temperature during injection and more viscous in the warmer environment of the tumor.

The polymer is also amphiphilic, with a PEG block that is attracted to water and two PLGA blocks that repel water, so that it forms a nanoparticle around the hydrophobic drug. Its amphiphilic properties allow its drug-release behaviors to be precisely tuned: the more hydrophobic the PLGA block, the slower the release. The formulation allowed a slowed drug release over four to five days, which was a timeframe previously reported to be effective when injected daily.

A similar version of the polymer has already been studied in clinical trials for delivering a type of chemotherapy, paclitaxel. However, in this scenario, the gel would transport imiquimod, an immunotherapy already approved by the Food and Drug Administration (FDA) that is commonly used topically to treat basal cell carcinoma.

Once the gel had been tailored to meet their requirements, the team tested it in mouse models of colon and breast cancer that are usually resistant to immunotherapy. In combination with a type of immunotherapy called checkpoint blockade therapy, they used the platform to deliver imiquimod. Each mouse had two tumors of the same type, but only one tumor was treated. If both tumors regressed, then the researchers could confirm their platform could induce a system-wide immune response to tumors — the abscopal effect.

Overall, the combination of checkpoint blockade therapy and intratumorally delivered imiquimod resulted in improved survival in both colon and breast cancer models. The treatment resulted in an all-or-nothing response, with complete regression of both the treated and untreated tumors in the mice that did respond to therapy. For nonresponders, there was no regression in either tumor. The researchers also tested the combination therapy of gel-delivered imiquimod and checkpoint blockade therapy with and without cryoablation of the treated tumor and found that the two approaches gave similar results.

Because the platform is made from safe materials to deliver an already-approved drug, the team expects that the path to FDA approval will be significantly shorter than for completely novel platforms and therapies. The team is also working with industry partners to adapt the platform for treating other tumor types and to deliver other therapies.

This study was funded in part by a Philips RSNA Research Award, a Schlaeger Research Fellowship, a postdoctoral fellowship from the Ludwig Center at the Koch Institute, and grants from Boston Scientific, the MIT Deshpande Center for Technological Innovation, and the National Cancer Institute.

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