Researchers in Seattle are reporting success with an experimental therapy that modifies T cells to express a CD19-specific chimeric antigen receptor (CAR) to treat B-cell malignancies.
Researchers in Seattle are reporting success with an experimental therapy that modifies T cells to express a CD19-specific chimeric antigen receptor (CAR) to treat B-cell malignancies. In the past, identification of the factors that determine toxicity and efficacy of these T cells has been challenging. However, in a new study published in The Journal of Clinical Investigation, 27 out of 29 patients with B-cell acute lymphoblastic leukemia who had been resistant to multiple other forms of therapy went into remission after their T cells were genetically engineered to fight their cancers.
The trial was designed to evaluate the safety of administering the engineered cells and to lay the groundwork for future improvements. The patients in this study had previously received a median of three prior intensive chemotherapy regimens and 11 patients had relapsed at a median of 7 months (range: 1 to 28) after prior allogeneic hematopoietic cell transplantation. The median age of the patients was 40 years (range: 20 to 73). The investigators evaluated CD19 CAR T cells that were manufactured from defined CD4-positive (+) and CD8-positive (+) T-cell subsets. The treatment was administered in a defined CD4+:CD8+composition to adults with B-cell acute lymphoblastic leukemia after lymphodepletion chemotherapy.
The treatment was found to be remarkably potent, as 27 of 29 patients (93%) achieved bone marrow (BM) remission, which was determined by flow cytometry. In addition, the researchers were able to establish that high CAR T-cell doses and tumor burden increase the risks of serious side effects and neurotoxicity. In this study, risk-stratified CAR T-cell dosing based on BM disease burden actually decreased toxicity.
“Patients who come onto the trial have really limited options for treatment. They have refractory, acute leukemia. So, the fact that we’re getting so many into remission is giving these people a way forward,” said study investigator Cameron Turtle, MD, PhD, who is with the Fred Hutchinson Cancer Research Center in Seattle, in a news release. “It sounds fantastic to say that we get over 90% remissions, but there’s so much more work to do make sure they’re durable remissions, to work out who’s going to benefit the most, and extend this work to other diseases.”
Dr. Turtle and his team report that positive findings have also been demonstrated in clinical trials of CD19 CAR T-cell therapy in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL).
Until now, this approach has been associated with cytokine release syndrome (CRS). It is characterized by hyperpyrexia, hypotension, capillary leak, neurotoxicity, and in some cases fatal. However, previous studies have included a wide variation in CAR T-cell doses and differences in the phenotypic composition of T cells isolated from patients for genetic modification and infusion.