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Targeting metastatic breast cancer with CAR T-cell immunotherapy

$4M ‘Breakthrough’ award funds collaborative research aimed at destroying dormant disseminated tumor cells
Tumor killing T cells in action
Tumor killing by T cells: The left panels show CAR T cells (yellow) converging on a breast tumor lesion growing in a bone marrow organotypic co-culture (red). Colored lines in the right panel show the tracks of individual T cells as they attack the tumor. Tracks were generated from time-lapse microscopy images and analyzed using Imaris 3D advanced image analysis software. Experiments such as this allow investigators to develop cancer immunotherapies. Courtesy of Drs. Erica Goddard and Cyrus Ghajar

A team of researchers from Fred Hutchinson Cancer Research Center and its partner institutions, University of Washington and Seattle Cancer Care Alliance, just received a coveted Department of Defense Breast Cancer Research Program Breakthrough award.

The four-year, $4 million award, led by principal investigators Drs. Cyrus Ghajar and Stanley Riddell of Fred Hutch, will launch an innovative investigation aimed at preventing late-onset, metastatic breast cancer. The team is developing an immunotherapy strategy utilizing immune cells called T cells that are armed with tumor-targeting chimeric antigen receptors, or CARs.

Their ambitious goal: to eliminate both the seeds of metastasis and the need for chemotherapy in breast cancer patients.

“This award involves a lot of great people at Fred Hutch and the UW,” said Ghajar, a translational researcher who in 2015 won a Department of Defense Era of Hope award. “We’re going to leverage some remarkable advances in multiple fields — synthetic protein design, T-cell engineering and tumor cell biology — that our team has made together over the last two years.”


Ghajar and Riddell, who is an immunotherapy researcher and SCCA oncologist, will work with Dr. David Baker, director of UW’s Institute for Protein Design; Hutch clinical researcher Dr. Amanda Paulovich; Hutch immunologist Dr. Mark Headley; Hutch biostatistician Dr. Ted Gooley and translational researchers Drs. Shivani Srivastava, Erica Goddard and Candice Grzelak of the Hutch.

“We’re also very lucky to work with two wonderful breast cancer patient advocates, Teri Pollastro and Rebecca Seago-Coyle,” Ghajar said.

Targeting the drivers of late-onset metastasis

Ghajar’s research, along with that of his postdoctoral researchers Goddard and Grzelak, focuses on disseminated tumor cells, or DTCs, the tumor cells that can lie dormant in breast cancer patients for years or decades after treatment for early stage disease before emerging as metastasis.

DTCs spread early, sometimes even before tumors are formed, and they commonly hide out in a dormant state within the bone marrow. When these DTCs “wake up” years later (not all do), they spread throughout the body, sowing tumors in metastatic breast cancer patients’ brain, bones, lungs, liver or other sites. Metastatic, or stage 4 disease, is treatable but not curable. It’s what kills most breast cancer patients.

In previous research, Ghajar found that signals from tiny blood vessels in the bone marrow shield dormant DTCs from chemotherapy drugs. These dormant breast cancer cells are also able to hide from the body’s immune system by decreasing their production of HLA proteins, which are necessary to alert the immune system of danger.

No proteins. No natural immune response.

“Traditional means to enhance immune function that rely on T cells that are already present in the body, such as vaccines and checkpoint inhibitors, may be ineffective because DTCs are invisible to them,” Ghajar said.

What does this mean?

“It suggests we need to target DTCs based on something else that’s on their surface,” Ghajar said. The team’s ongoing work, identifying molecules on the surface of DTCs derived from human patients, will help inform this targeting. 

A composite photo of Drs. Stanley Riddell and Cyrus Ghajar
Drs. Stanley Riddell and Cyrus Ghajar Photos by Robert Hood / Fred Hutch News Service

Harnessing scientific advances to stop metastatic seeds

For years, Riddell’s lab has been designing specialized receptors, CARs, that redirect T cells to destroy tumors.

“This approach has been very successful in leukemia and lymphoma that grows in bone marrow and lymph nodes but has not achieved the same success in metastatic solid tumors,” he said. “This is due both to a lack of molecules that can be targeted and to challenges in eliminating large solid tumors.”

Using new advances in protein design developed in the Baker Lab at UW, the researchers believe it is possible to engineer unique, customizable CARs that will be highly specific for DTCs and can direct T cells to kill them.

“Targeting dormant DTCs, especially those in sites like the bone marrow that are readily accessible to T cells, is an exciting application of CAR T cells and will help determine how new advances in synthetic protein design can be applied to patient therapy,” Riddell said.

 

“We’re hoping to not only save lives but eliminate that dreaded feeling of ‘looking over your shoulder’ many breast cancer survivors experience after treatment. We’re also testing, in parallel, how CAR T cells will do against metastatic lesions.”

— Dr. Cyrus Ghajar

Once in place and active, these CAR T cells would continue to patrol the body for sites that harbor DTCs and destroy them, preferably without causing any kind of toxicity elsewhere.

If successful, Ghajar said it will be the first therapy to eradicate DTCs, and within five to seven years, it could result in the development and clinical application of a first-in-class immunotherapy to prevent metastasis.

“In a perfect world, we would have a therapy that eliminates the seeds of metastasis without affecting any other normal tissue,” he said. “If such a therapy could be realized, one could envision it eventually becoming standard of care, essentially eliminating the need for chemotherapy.

That would be a true breakthrough. And that’s what we’re trying to achieve here.”

Another boon: if successful, their work would eliminate the fear of recurrence many survivors have to live with every day.

“We’re hoping to not only save lives but eliminate that dreaded feeling of ‘looking over your shoulder’ many breast cancer survivors experience after treatment,” he said. “We’re also testing, in parallel, how CAR T cells will do against metastatic lesions.”

Also of note, this pattern of late recurrence as a result of “awakened” DTCs may not be limited to breast cancer.

“Conceptually, it does apply to other cancers,” Ghajar said. “Dormancy phases are thought to be relevant for melanoma, multiple myeloma, prostate cancer and others, like osteosarcomas. There’s even evidence of single DTCs that evade immunity in rapidly metastatic cancers like pancreas cancer.”

Diane Mapes is a staff writer at Fred Hutchinson Cancer Research Center. She has written extensively about health issues for NBC News, TODAY, CNN, MSN, Seattle Magazine and other publications. A breast cancer survivor, she blogs at doublewhammied.com and tweets @double_whammied. Email her at dmapes@fredhutch.org.

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Last Modified, November 08, 2019