Companies Continue to Face Challenges With Developing CAR-T Treatment

Cellectis, a clinical-stage biotechnology company, was asked by the FDA to place a clinical hold on 2 phase 1 trials evaluating its allogeneic chimeric antigen receptor-T (CAR-T) cell treatments following the report of a fatality in the first patient treated in one of the studies.

The company has initiated 2 phase 1 studies using gene-edited allogeneic CAR-T cells (UCART123), which are being tested in acute myeloid leukemia (AML) and in blastic plasmacytoid dendritic cell neoplasm (BPDCN). The first patient treated in the BPDCN trial, who had received 1 prior line of treatment, was administered a preconditioning regimen of 30 mg/m² fludarabine daily for 4 days and 1 g/m² cyclophosphamide daily for 3 days.

Soon after (5 days) the first infusion of the modified UCART123 cells was administered, the patient experienced grade 2 cytokine release syndrome (CRS) and a grade 3 lung infection, which were treated with tociluzumab and broad-spectrum antibiotics. Three days after, the patient came down with grade 5 CRS and grade 4 capillary leak syndrome (CLS). Immediate standard-of-care treatment proved insufficient and the patient died the next day.

A patient in the AML study who was treated with the same preconditioning regimen and was administered the same dose of UCART123 experienced similar adverse events: an initial grade 2 CRS that worsened to grade 3, but resolved following management in the intensive care unit—as did her grade 4 CLS.

In the summer of 2016, Juno Therapeutics was directed by the FDA to dissolve the phase 2 evaluation of JCAR015 in patients with relapsed/refractory B cell acute lymphoblastic leukemia (ALL) following 3 patient deaths due to cerebral edema. The company initially proposed changing its preconditioning regimen and eliminating fludarabine from the protocol. However, in early 2017, the company announced that it had terminated the trial following additional deaths.

For Cellectis, its Data Safety Monitoring Board has proposed lowering the dose of cell infusion as well as restricting the dose of the chemotherapy, cyclophosphamide, that the patients receive as preconditioning treatment.

Although Novartis received unanimous support from the FDA’s Oncologic Drugs Advisory Committee, and subsequent FDA approval, for tisagenlecleucel (Kymriah) in pediatric and young adult patients with B-cell ALL, the Cellectis and Juno experiences point to the need for caution with this treatment modality.