Like deployed troops never told the war is over, modified immune cells dispatched to hunt and kill blood cancers continue their work long after the job is complete, leaving many patients in remission but chronically prone to serious infections.
It is one side effect of a promising immunotherapy that uses re-engineered cells, known as CAR T cells, to target malignant B cells in people with leukemia and lymphoma. After the cancer is gone, CAR T cells can keep finding and attacking healthy B cells that are needed to ward off invading bacteria and viruses.
Now, scientists at Fred Hutch, Seattle Children’s Research Institute, and the Technical University of Munich have demonstrated that activating a “kill switch” can turn off CAR T cells after doctors deem the cancer is defeated, allowing normal B cells to again flourish, according to a study published Monday in the Journal of Clinical Investigation.
The results involved mice but researchers predicted this approach could soon be tested in patients. That’s because the same tiny receptor or “tag” that scientists integrated into the tested CAR T cells to trigger their demise in the mice has already been built into CAR T cells being evaluated in ongoing clinical trials, said Dr. Dirk Busch, an infection immunology researcher at the Technical University of Munich in Germany and the paper’s senior author.
“Therefore, it would be possible to test the efficacy [of the approach] … very soon in patients,” Busch said.
It's still unclear when the approach would be available for patients.
“What we showed is that you can target this tag on the cell’s surface with an antibody, eliminate the CAR T cells and restore normal numbers of functioning B cells,” said co-author Dr. Stan Riddell an immunotherapy researcher and oncologist at Fred Hutchinson Cancer Research Center.
The promise of immunotherapy
CAR T-cell therapy represents some of brightest potential in cancer treatment research, fueling increasing hope for the premise that patients can tap their own immune systems to beat their cancers, a concept known as immunotherapy.
In September, Fred Hutch researchers, including Riddell, reported that many trial patients who had exhausted conventional treatments had their advanced non-Hodgkin lymphomas disappear completely after receiving CAR T cells following chemotherapy. In April, Hutch investigators reported that 93 percent of trial participants with B-cell acute lymphocytic leukemia, or ALL, went into complete remission after they were infused with CAR T cells — even though multiple other treatments had already failed them.
In each of those previous, Hutch-led studies, scientists extracted disease-fighting T cells from patients’ bloodstreams and sent them to a specialized lab at Fred Hutch to be re-engineered with a synthetic chimeric antigen receptor, or CAR. These CAR T cells target a marker called CD19, found on the surface of B cells, including leukemia cells and some types of lymphoma cells.
To date, more than 200 patients have been treated with CD19 CAR T cells in trials designed by researchers at Fred Hutch and Seattle Children’s Hospital, Riddell said. The longevity of these CAR T cells is one of their assets; unlike a medicine that must be administered every few days or weeks, these cells have the potential to live and multiply in the patient. But since their target, CD19, is present on both cancerous and noncancerous B cells, the CAR T cells knock out the healthy as well as the diseased versions of the immune cells. Months after their tumors were eradicated, some trial participants still struggle with B-cell deficiency.
Replenishing B cells
People whose bodies can’t make B cells for long periods can’t mount a natural defense to new infections. (B cells produce antibodies that take on invaders in the blood). Vaccines also don’t work for patients without B cells, Riddell said.
In patients with B-cell deficiency, doctors regularly monitor their levels of immunoglobulin, a family proteins used by the immune system to identify and wipe out pathogens like bacteria and viruses. If their levels are low, patients need to get monthly infusions of intravenous immunoglobulin, Riddell said.
“At some point, we may want to get their B cells back,” Riddell said. “The danger in doing that is that you want the (CAR T) cells around long enough to make sure the tumor is gone," and that’s the delicate dance many immune-compromised CAR T-cell recipients and their doctors may eventually have to face when the “kill switch” option enters the clinical trial phase.
In the study that Riddell and his colleagues at Fred Hutch and in Germany published Monday, the researchers gave mice CAR T cells that also carried a molecule called EGFRt (the eponymous capital letters stand for epidermal growth factor receptor; the little t means it’s a truncated, inert version). The marker was previously designed by Dr. Michael Jensen, a member of the Clinical Research Division at Fred Hutch, a researcher at Seattle Children’s Hospital, and a co-author on the paper.
The mice were later infused with an antibody called cetuximab — typically used to treat metastatic colon cancer, metastatic non-small cell lung cancer, and head and neck cancer — that targets the EGFRt. When the cetuximab bound to the EGFRt, the CAR T cells were eliminated, “resulting in complete and permanent recovery of normal functional B cells, without tumor relapse,” the authors wrote.
'Broader implications'
“Most importantly, we show that the selective elimination of (anti-CD19) CAR T cells can fully revert a chronic toxicity/side effect of this treatment, B-cell aplasia,” Busch said via email.
"That’s a step in the right direction for being able to regulate the survival of CAR T cells but also any cell therapy that might be used," Riddell said. "It has broader implications for tissue engineering or cell engineering in general — you might want to think about having a tag on the cells that you can target so you can eliminate them if something went wrong."
Riddell and Busch have been working together since 2008 to find cancer cures. Together, they operate a Clinical Cell Processing and Purification Focus Group at the Institute for Advanced Study at the Technical University of Munich. Their group works to develop clinical cell therapeutics to treat infections and certain cancers.
Collaborative research teams like theirs — which is this both international and longstanding — are a cornerstone of Vice President Joe Biden’s Cancer Moonshot, which seeks to break down scientific silos to speed creation of new cancer treatments. Riddell and Busch said they are working way ahead to make what is now a nascent, experimental treatment something effective and viable for patients in the long run.
“That’s exactly what we’re all about,” Riddell said.
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Bill Briggs was a former Fred Hutch News Service staff writer as well as a contributing writer for NBCNews.com and TODAY.com. As a staff writer for The Denver Post, he was part of the newspaper's team that earned the Pulitzer Prize for coverage of the Columbine High School massacre. He authored two books, including "The Third Miracle: An Ordinary Man, a Medical Mystery, and a Trial of Faith."
