Diffuse large B-cell Lymphoma is 30%-58% of all NHL with an incidence of 3.8/100,000 in Europe (Tilly et al, Ann Oncol 2015). Therapy with CD28/CD3&zgr; anti-CD19 CAR T cells led to durable remissions in patients with relapsed/refractory B cell malignancies at the NCI (Kochenderfer, J Clin Oncol 2015). KTE-C19 utilizes the same CAR construct as the NCI trial but centrally manufactured in a streamlined 6- to 8-day process. We present updated ZUMA-1 phase 1 study data.
Patients received KTE-C19 at a target dose of 2 × 106 anti-CD19 CAR T cells/kg after cyclophosphamide (500 mg/m2/day) and fludarabine (30 mg/m2/day) conditioning chemotherapy (Locke, ASH 2015). The primary objective was KTE-C19 safety. Secondary objectives included overall response rate (ORR), duration of response, and levels of blood CAR T cells and serum cytokines. Inclusion criteria were ECOG 0-1 and chemotherapy-refractory disease defined as progressive disease (PD) or stable disease as best response to last line of therapy, or PD ≤ 12 months after autologous stem cell transplant (ASCT).
As of April 16, 2016, seven patients received KTE-C19. One patient had a dose-limiting toxicity (DLT) of grade 4 encephalopathy and cytokine release syndrome (CRS), and grade 5 intracranial hemorrhage unrelated to KTE-C19. Except for the patient with DLT, all grade ≥3 KTE-C19 related toxicity resolved. ORR was 71% (57% complete response [CR]). Three patients with PD within 6 months of ASCT have ongoing CR at 6-9+ months. CAR T cells peaked within two weeks and were detectable 1-6+ months post infusion. Updated results as of September 2016 including up to 1 year of follow up will be presented.
Ongoing CRs have been observed at 9+ months after a single KTE-C19 dose in patients with refractory aggressive NHL. CRS and neurotoxicity were self-limiting and generally reversible. The central manufacturing process and KTE-C19 regimen were deemed safe and feasible for further study. The ZUMA-1 phase 2 study (NCT02348216) is ongoing.
Clinical trial identification
Legal entity responsible for the study
F.L. Locke: Scientific advisory board for Kite Pharma. S.S. Neelapu: Research funding from Kite Pharma. N.L. Bartlett: Consultancy for Gilead. T. Siddiqi: Speaker's bureau for Pharmacyclics, Janssen, and Seattle Genetics. A. Cashen: Speaker's bureau for Seattle Genetics, Gilead, Novartis, and Spectrum. M. Sherman, J.M. Rossi, L. Navale, Y. Jiang, J. Aycock, M. Elias, J. Wiezorek, W.Y. Go: Employment with Kite Pharma. All other authors have declared no conflicts of interest.