Immediately, the research team stopped giving participants the highest dose level, and those participants with the most tumors received the lowest doses. This helped.
Turtle and colleagues were also able to identify biomarkers in the participants’ blood after infusion, which were linked with the development of the severe toxicities. These biomarkers will hopefully allow them to create tests that could prevent such toxicities from occurring, or head them off before they become too severe.
However, for Kristin Kleinhofer, diagnosed with leukemia in 2010, even the cytokine release syndrome, which brought her high fevers and low blood pressure for a week, was worth the aftermath: remission. She received her first infusion in November 2014.
Kleinhofer, who was only 36 at the time of diagnosis, had already enrolled in one clinical trial for an experimental chemotherapy at Stanford that did not work. In the meantime her doctors suggested she pursue a bone marrow transplant, if they could find a match. A bone marrow transplant is a radical option, as a patient’s cancerous blood and immune system must first be completely destroyed by chemotherapy and radiation, and then healthy donor cells are implanted. However, Kleinhofer’s donor match fell through and they couldn’t find another.
“You really don’t know how strong you are until something happens to you,” Kleinhofer said. “No matter what, no matter where the journey led, I was going to go out fighting. I thought I would do everything I could, even if my life ended short.”
Having heard of CAR T-cell therapies during her journey through her cancer, she and her mother vigorously researched such clinical trials. When she was admitted to the Fred Hutchinson trial, her spirits rose.
“The trial gave me the hope that I could proceed to get into remission so I could get a [bone marrow] transplant,” Kleinhofer said. “Which is now my next hope, that [my transplant] can give me the gift of more time until things are more figured out in the immunotherapy world.”
Follow up and further research will be necessary to determine if transplant is indeed the next step for patients who have received a CAR T-cell infusion.
“No one really knows the answer to that question,” Maloney said. “I think in some cases, CAR T cells will be enough to control the disease. But we don’t have enough confidence in that yet.”
Genetic test may prevent recurrence
Aside from great disease progress, their research also turned up what may be a better way of determining a patient’s prognosis after treatment. In order to assess if any cancer cells were left behind after receiving the therapy, the researchers analyzed samples of patients’ bone marrow using a genetic test called IGH deep sequencing. This essentially turns genetic markers into a bar code that allows researchers to keep track of the cancer cells as they make their way through the body.
Turtle and his colleagues sequenced twelve of the patients. Of that twelve, seven did not have any malignant genetic copies of the cancer cells. Those seven were disease free at the six and a half month mark after CAR T-cell infusion.
When they compared the IGH deep sequencing to the CT scan method of checking for tumors, they found that patients without malignant gene sequences in the bone marrow after CAR T-cell therapy was more likely to remain in remission. This suggests the deep sequencing test is a better predictor than a CT scan for assessing progression of the cancer. They believe this is the first study to suggest that link.
The trial is by no means over. The immunotherapy team at Fred Hutchinson continues to seek eligible patients with CLL, acute lymphoblastic leukemia and non-Hodgkin lymphoma for CD19 CAR T-cell trials. The patients must be able to attend Seattle Cancer Care Alliance.