Phase 1 Results of ZUMA-1: A Multicenter Study of KTE-C19 Anti-CD19 CAR T Cell Therapy in Refractory Aggressive Lymphoma

Abstract

Outcomes for patients with refractory diffuse large B cell lymphoma (DLBCL) are poor. In the multicenter ZUMA-1 phase 1 study, we evaluated KTE-C19, an autologous CD3ζ/CD28-based chimeric antigen receptor (CAR) T cell therapy, in patients with refractory DLBCL. Patients received low-dose conditioning chemotherapy with concurrent cyclophosphamide (500 mg/m²) and fludarabine (30 mg/m²) for 3 days followed by KTE-C19 at a target dose of 2 × 10⁶ CAR T cells/kg. The incidence of dose-limiting toxicity (DLT) was the primary endpoint. Seven patients were treated with KTE-C19 and one patient experienced a DLT of grade 4 cytokine release syndrome (CRS) and neurotoxicity. Grade ≥3 CRS and neurotoxicity were observed in 14% (n = 1/7) and 57% (n = 4/7) of patients, respectively. All other KTE-C19-related grade ≥3 events resolved within 1 month. The overall response rate was 71% (n = 5/7) and complete response (CR) rate was 57% (n = 4/7). Three patients have ongoing CR (all at 12+ months). CAR T cells demonstrated peak expansion within 2 weeks and continued to be detectable at 12+ months in patients with ongoing CR. This regimen of KTE-C19 was safe for further study in phase 2 and induced durable remissions in patients with refractory DLBCL.

Keywords: CAR T; CD19; KTE-C19; diffuse large B cell lymphoma; refractory NHL.

Figure 1

Clinical Efficacy after KTE-C19 Infusion (A) Duration of response and survival post-infusion with KTE-C19. (B) CR at 30 days post KTE-C19 infusion in patient 5. Representative PET-CT scans at baseline and 30 days post KTE-C19 infusion in a patient with DLBCL relapsing after prior therapy with R-CHOP, R-ICE, and ASCT with Rituximab-gemcitabine-busulfan-melphalan+azacitidine-vorinostat.

Figure 2

Apheresis and Product Phenotype as Determined by Flow Cytometry Using CD45RA and CCR7 Cell Surface Markers N, naive; CM, central memory; EM, effector memory; Eff, effector. The bars and boxes show the minimum, maximum, median, and interquartile range.

Figure 3

Kinetics of Peripheral Blood CAR T Cells and Serum Biomarkers (A) PCR data demonstrates exponential expansion and persistence of CD19 CAR T cells in blood. Expansion occurs rapidly with peak levels achieved within the first 7–14 days post-KTE-C19 infusion (note: patient 7 was not tested). Persisting CD19 CAR T cells were detectable in six of six (100%) patients at week 4 and in four of five (80%) patients with samples available for testing at month 3. Three patients with ongoing CR had detectable CAR T cells at 12 months. Limit of detection of the qPCR assay is 0.001% or 1 × 10⁻⁵. (B) Analysis of patient serum reveals a biomarker profile composed of specific cytokines, chemokines, and effector proteins associated with KTE-C19 treatment. The expansion of CD19 CAR T cells (Figure 3A) was mirrored by induction and elevation of a range of cytokines that regulate proliferation, activation, and effector function. Induction of IL-15 occurs during conditioning chemotherapy and levels continue to rise post-infusion, promoting anti-CD19 CAR T cell expansion. CRP levels parallel CRS and generally resolve within the first 28 days. Granzyme B levels peak 3–7 days post-infusion, during peak anti-CD19 CAR T cell expansion, and provide evidence of effector function and tumor killing. (C) Heat map of serum biomarkers demonstrates sequential induction and gradual resolution within the first 2 weeks after KTE-C19 infusion of key cytokines, chemokines, and effector proteins. Patients 1–6 demonstrated similar baseline levels and post-infusion kinetics for induction of IL-15 (T cell proliferation), CRP (marker of inflammation), granzyme B (evidence of effector function), and IP-10 (chemokine that promotes CAR T cell homing). Early induction of IL-15, CRP, and IP-10 was observed 1–3 days post-infusion and effector function occurred around days 3–7 for these patients. In contrast, patient 7 demonstrated a dysregulated profile relative to the other six patients both at baseline (IL-15, CRP, and IP-10) and after KTE-C19 administration (all markers), indicative of an inflammatory state prior to KTE-C19.