As Baylor College of Medicine’s Max Mamonkin, PhD, noted in a presentation, patients with conditions such as T-cell lymphoma and T-cell acute lymphoblastic leukemia (ALL) have limited treatment options and grim prognoses. “This is an area with huge unmet need,” he said. “They don’t have options that patients with B-cell malignancies have, like [CAR T-cell therapy] and bispecifics.”
One big challenge is that CAR-targeted antigens in T-cell blood cancers are shared by both normal and malignant T-cells, he said. That poses a risk during therapy that the engineered cells will target each other with “disastrous consequences.”
Research by his team and others have shown that gene editing can help the cells to stop engaging in “fratricide,” Dr. Mamonkin said.
The problem is “it’s much easier to do gene editing on the bench and much harder to translate it into the clinic,” especially in light of limitations posed by the Food and Drug administration, he said. “We started to think about alternative methods to get this approach to the clinic.”
One strategy is to use pharmacologic inhibition via the Bruton’s tyrosine kinase inhibitors ibrutinib and dasatinib to mute the tendency of CAR T toward self-destruction. When tested in mice, “the unedited cells not just persisted, they expanded with sustained anti-leukemic activity and significantly prolonged their lives even more than the knock-out [gene-edited] cells.”
The research has now moved to human subjects. In 2021, researchers at Texas Children’s Hospital and Houston Methodist Hospital launched a clinical trial to test CD7 CAR T-cell therapy with CD28 in 21 patients with CD7-positive T-cell lymphoma. The initial part of the transplant-enabling CRIMSON-NE study is expected to be completed by mid-2024, and patients will be followed for 15 years.
Early results show that CD7 CAR T-cells have persisted in the blood of patients over weeks and months, Dr. Mamonkin said. In eight patients, “we’re seeing good evidence of activity,” with two patients reaching complete remissions.
The findings suggest that CD7 can be targeted in T-cell malignancies, he said. What about CD5? A similar study known as MAGENTA is testing CD5 CAR T-cell therapy with CD28 in T-cell leukemia and lymphoma in 42 patients. The phase 1 trial began in 2017. It’s expected to be completed by 2024 and to track patients for 15 years.
Results so far have been positive with complete remission achieved in three of nine patients with T-cell lymphoma; two remained in remission for more than 4 years.
Results in T-cell ALL improved after researchers adjusted the manufacturing of the cells. As for durability in these patients, “we try to bridge them to transplantation as soon as possible.”
As for side effects overall, there wasn’t much immune effector cell-associated neurotoxicity syndrome, and the CD7 approach seems to be more inflammatory, he said.
The presentation didn’t address the potential cost of the therapies. CAR T-cell therapy can cost between $500,000 and $1 million. Medicare covers it, but Medicaid may not depending on the state, and insurers may refuse to pay for it.
Dr. Mamonkin disclosed ties with Allogene, Amgen, Fate, Galapagos, March Bio, and NKILT.