FDA Puts Clinical Holds on "Off-the-Shelf" CAR-T Trials

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Following the death of a 78-year-old man being treated for blastic plasmacytoid dendritic cell neoplasm (BPDCN), the FDA placed clinical holds on 2 phase I trials investigating a gene-edited allogeneic CAR T-cell (UCART) therapy known as UCART123.

The man died after experiencing cytokine release syndrome (CRS). A 58-year-old woman being treated for acute myeloid leukemia (AML) also developed CRS. Although her condition resolved, a data safety monitoring board recommended lowering the dose of UCART123 cells and the FDA ordered the trials shut down. Both patients were the first to be treated in their respective trials.

UCART123 is being developed by Paris-based biopharmaceutical company Cellectis as a treatment for BPDCN and AML. Unlike Novartis’s autologous CAR-T therapy tisagenlecleucel (Kymriah), UCART’s process is allogeneic and, in theory, could treat any patient using T cells harvested from any donor.

The “off-the-shelf” allogenic process may be faster, easier to develop, and likely significantly less expensive than autologous CAR T-cell therapy—Novartis has set the price for a one-time treatment with tisagenlecleucel at $475,000.

Cellectis reported in a press release that it is working with the FDA in order to resume the trials with an amended protocol, including a reduced dose of UCART123 cells.

The male patient presented with relapsed/refractory BPDCN with 30% blasts in his bone marrow and cutaneous lesions. The female patient had 84% blasts in her bone marrow at baseline.

Both patients received 30 mg/m2 daily of fludarabine for 4 days and 1 g/m² daily of cyclophosphamide for 3 days as a preconditioning regimen. They then received 6.25 x 10⁵ UCART123 cells per kilogram, the first dose level explored in the protocol.

At day 5, the male patient experienced grade 2 CRS and grade 3 lung infection, which resolved following a dose of tocilizumab (Actemra), and administration of broad spectrum antibiotics. Three days later, the man developed a grade 5 CRS along with a grade 4 capillary leak syndrome. He was administered corticosteroids and tocilizumab, as well as intensive care unit support, but died on day 9.

In the case of the female patient, she developed an initial grade 2 CRS at day 8. By day 9, her CRS had worsened to grade 3 and she experienced a grade 4 capillary leak syndrome (CLS). Her CRS resolved by day 11 following treatment management in intensive care unit, and her CLS resolved at Day 12. Neither patient experienced GVHD.

Allogenic CAR-T cell therapy has shown promise in the past. In phase I results published in 2013, donor-derived CD19-28z-CAR-T cells were used to treat 4 patients with chronic lymphocytic leukemia (CLL) and 6 with lymphoma, including 2 with diffuse large B cell lymphoma (DLBCL) and 4 with mantle cell lymphoma (MCL). Researchers observed no GVHD, grade 1 acute GVHD, or mild global score chronic GVHD.

Within 1 month after CD19-CAR-T cell infusion, one CLL patient achieved complete remission (CR), 6 patients (1 with CLL, 2 with DLBCL, and 3 with MCL) had stable disease. One patient with MCL partial remission, and two patients with CLL showed disease progression.

In another study, 8 patients were treated with allogeneic CD19-28z-CAR-T cells for B cell malignancies, 4 with CLL and 4 with acute lymphoblast leukemia ALL). All had experienced disease relapse or were at high risk of disease relapse after allogeneic-hematopoietic stem cells transplantation.

CD19-CAR-T cells were administered using a dose escalation schedule of 1.5 × 10⁷/m², 4.5 × 10⁷/m², and 1.2 × 108/m². Researchers observed antitumor activity in 2 of 6 of the relapsed patients during the period of CD19-CAR-T cell persistence, whereas 2 patients who received cells while in remission remained disease-free. Of these 2 patients, 1 remained in CR for more than 8 months and the other remained in CR for 8 weeks after CAR-T infusion.

Liu, Zhong JF, Zhang X, Zhang C. Allogeneic CD19-CAR-T cell infusion after allogeneic hematopoietic stem cell transplantation in B cell malignancies. J Hematol Oncol. 2017;10(1):35. doi: 10.1186/s13045-017-0405-3.