The swift release of a clinical hold on Juno Therapeutics Inc.'s ROCKET trial notwithstanding, why and how high-dose fludarabine contributed to fatal neurotoxicity remains an unanswered - and important - question for the CAR T field.
FDA appears to agree with the company that the addition of fludarabine to the conditioning regimen used in ROCKET was the culprit in the deaths of three patients with acute lymphoblastic leukemia (ALL) who received JCAR015. And Juno has hypothesized that fludarabine and JCAR015 may have acted synergistically to unleash a rapid expansion of T cells in the CNS.
The company doesn't yet know why.
One theory proposed by Dario Campana, a professor of pediatrics at the National University of Singapore and an investigator in multiple chimeric antigen receptor (CAR) T therapy trials, is that the therapy's co-stimulatory domain and fludarabine had too great an effect together.
JCAR015 consists of autologous T cells expressing the 19-28z CAR, which is specific to CD19. Like other CAR T therapies, JCAR015 is given after a chemotherapy conditioning regimen that eliminates existing T cells and makes room for the CAR T cells to expand and proliferate.
The CAR construct of JCAR015 uses the CD28 co-stimulatory domain. The CD28 co-stimulatory domain is believed to boost initial T