Turning the tides on metastatic cancer

With many cancer treatment approaches including surgery, external beam radiation, and ablation, it is necessary to know exactly where the tumors are located before treating them.

However, patients with metastatic disease commonly have tumors or tumor cells that are not yet large enough to identify or target with such approaches. In addition, most cancers have evolved traits that enable them to evade the patient’s immune system, which could otherwise be very effective at warding off disease.

New developments in theranostics could help give oncologists a powerful and precise weapon to turn the tides.

What is theranostics?

Theranostics is a combination of the words therapeautic and diagnostics and involves using tumor-selective molecules to deliver a radioactive element to tumors throughout a patient’s body. This radioactive element can then be used to image the patient’s tumors and/or to deliver radiation treatment to all of these tumors.

Theranostics has been getting a lot of attention in recent years and has been called a key component in the future of cancer treatments. Based on recent successes with combining targeted radionuclide therapy (TRT) and immunotherapy, Dr. Jamey Weichert, Professor of Radiology, and Dr. Zach Morris, Associate Professor of Human Oncology, see UW in a unique position to become a leading theranostic treatment destination.

“We have tremendous facilities and an amazingly talented collaborative team here,” Weichert said.

Weichert and Morris are co-principal investigators on two large multi-investigator National Cancer Institute grants to pursue additional studies and testing of UW’s promising theranostics approach. The path to these grants started about eight years ago, when Morris said he and Dr. Paul Sondel, the Reed and Carolee Walker Professor of Pediatric Oncology, had been working together to study tumor immunology treatments.

Their research initially combined external beam radiation treatment with immunotherapy injections at the tumor site to stimulate immune system response to cancer cells. This approach worked well when mice were harboring a single tumor and only microscopic other tumor sites, but Morris said a persistent challenge was that the treatment was minimally effective when additional large tumors were present.

“Those distant tumors have their own established tumor microenvironment that can be suppressive of an anti-tumor immune response,” Morris said, noting that cancer can only take hold in the body if it avoids or suppresses immune detection.

Team approach

That led Morris and Sondel to reach out to Weichert, who exploits known biochemical differences between normal and cancer cells to develop theranostic molecules that target tumors. By attaching a radioactive isotope to a new molecule, NM600, developed by Weichert and Dr. Reinier Hernandez, Assistant Professor in the Department of Medical Physics, researchers could image all tumors throughout the body of mice.

In addition to providing tumor location, this imaging data allows the use of quantitative dosimetry to determine what amount of a therapeutic radioactive isotope would need to be injected in order to deliver a given dose of radiation to a mouse’s or patient’s tumors.

Using such a tool, Morris and Sondel worked with Weichert and Hernandez to study whether they could use theranostics to deliver radiation to all tumor sites in order to overcome immunosuppressive mechanisms that otherwise limited the efficacy of immunotherapy treatments.

They found that the combination of a theranostic and immunotherapy was successful in completely eliminating cancer in about 70 percent of mice studied. In fact, the use of low radiation doses tailored to those tumors also spurred lasting T-cell immune memory that continued to kill cancer cells injected months later.

"To our knowledge, no one else had been able to do that yet with a theranostic,” Weichert said of the immune response triggered in their studies.

Weichert and Morris said the process has been successful across a wide range of cancer types, and it has been shown to work on immunologically “cold” tumors that weren’t responding to other immunotherapy treatments.

“By far it’s the most promising thing I’ve seen in cancer treatment,” Weichert said. “I’m excited to come to work every day.”

Path forward

While the results so far are extremely encouraging, Morris cautioned it will likely still require a few years to test and determine whether this approach can be effectively implemented in patients.

He said it’s important to take a thoughtful approach when trying to translate this research to clinical trials, leveraging understanding from preclinical studies of the biologic processes at play. The careful design of clinical studies is critical, he says, because if initial human testing fails to meet expectations that could set back interest in this field.

“It needs to be done thoughtfully,” he said. “I think we can get there, but there will be challenges.”

A crucial piece of these treatments is ensuring the proper radiation dose that spurs but does not quench the anti-tumor immune response. Morris noted that personalized patient dosimetry will be critical to achieve this, and he credited much of his team’s success to the skills of the UW dosimetry group, led by Dr. Bryan Bednarz, Associate Professor of Medical Physics and Human Oncology, and Dr. Joe Grudzinski, a senior scientist in the Department of Medical Physics, who calculate those doses for their preclinical studies of theranostics.

Both Morris and Weichert said UW has assembled a uniquely strong team of experts to focus on this research, and they feel well-situated for the next steps in translating these results to humans.

“It’s an emerging field with tremendous potential for improving the way we treat patients with metastatic cancers,” Morris said.