Volume 25, Issue 1, Pages (January 2017)

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Volume 25, Issue 1, Pages 285-295 (January 2017) Phase 1 Results of ZUMA-1: A Multicenter Study of KTE-C19 Anti-CD19 CAR T Cell Therapy in Refractory Aggressive Lymphoma  Frederick L. Locke, Sattva S. Neelapu, Nancy L. Bartlett, Tanya Siddiqi, Julio C. Chavez, Chitra M. Hosing, Armin Ghobadi, Lihua E. Budde, Adrian Bot, John M. Rossi, Yizhou Jiang, Allen X. Xue, Meg Elias, Jeff Aycock, Jeff Wiezorek, William Y. Go  Molecular Therapy  Volume 25, Issue 1, Pages 285-295 (January 2017) DOI: 10.1016/j.ymthe.2016.10.020 Copyright © 2017 The Authors Terms and Conditions

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. Molecular Therapy 2017 25, 285-295DOI: (10.1016/j.ymthe.2016.10.020) Copyright © 2017 The Authors Terms and Conditions

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. Molecular Therapy 2017 25, 285-295DOI: (10.1016/j.ymthe.2016.10.020) Copyright © 2017 The Authors Terms and Conditions

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. Molecular Therapy 2017 25, 285-295DOI: (10.1016/j.ymthe.2016.10.020) Copyright © 2017 The Authors Terms and Conditions