Abstract 960: Defined cell composition and precise control over JCAR017 dose enables identification of relationships between chimeric antigen receptor T cell product attributes, pharmacokinetics, and clinical endpoints in NHL
Authors: Larson Ryan P. , Lower Rachel , DeVries Todd , Jiang Yue , Hause Ronald J. , Getto Rich , Christin Brian , Yee Nathan K. , Bowen Michael A. , Weber Clinton , Li Daniel , Albertson Tina , Sutherland Claire , Ramsborg Christopher G. 
Published: August 2018

Abstract
JCAR017 is a CD19-directed 41BB chimeric antigen receptor (CAR) T cell product administered in a defined composition at a precise dose of CD8 and CD4 CAR T cells. JCAR017 manufacturing employs process controls that enable precise independent control of the infused dose of CD8 and CD4 cells. Preliminary safety data from JCAR017 administered in relapsed/refractory B cell non-Hodgkin lymphoma (NHL) demonstrated lower rates of cytokine release syndrome (CRS) and neurotoxicity (NT) compared to those reported for other CD19-directed CAR T cell therapies with heterogeneity in total infused dose and CD8 and CD4 composition. Multiple patient factors and blood biomarkers have been identified that correlate with JCAR017 CAR T cell in vivo expansion, antitumor activity, and toxicity (Heipel M et al. and Siddiqi T et al. ASH 2017). However, little is known regarding the contribution of CAR T cell product differentiation state to pharmacokinetics (PK), clinical outcome, or toxicity. Product characterization is executed on JCAR017 to define the CAR T cell memory phenotype composition and antigen-specific function. Product attributes were assessed for relationships with clinical response, safety, and PK through univariate, multivariate, and machine learning-based analyses. JCAR017 memory T cell composition demonstrated strong relationships with cytokine production profile observed following in vitro CD19 stimulation of the CAR T cell drug product. Specifically, products with elevated frequencies of CCR7+ central memory T cells exhibited increased production of IL-2 (Spearman ρ=0.55, P&lt;0.0001), whereas patient drug product with increased frequencies of effector differentiated T cells demonstrated increased production of IFNγ (ρ=0.51, P&lt;0.0001) and IL-13 (ρ=0.45, P&lt;0.0001). The correlations between CAR T cell drug product memory phenotype and function translated to positive correlations between central memory subset composition and peak in vivo CAR T cell expansion (ρ=0.42, P=0.002) and progression-free survival (Kaplan-Meier survival estimate, P=0.0164). In addition, an increased frequency of a central memory subpopulation in drug product demonstrated relationships with CRS (P=0.0069) and severe NT (P=0.0014) events. The phenotype to functional links described above offer insights as to how specific memory subpopulations contribute to the complex CAR T cell mechanism of action. CAR T cell products with increased CCR7+ central memory composition demonstrated increased peak CAR T cell expansion and persistence, suggesting less differentiated CAR T cells contribute to PK and progression-free survival. These findings can be used to further define the next generation of gene-engineered T cell products (e.g., a fixed dose of CCR7+CAR+) that will decrease the dose-to-dose variability.
Citation Format: Ryan P. Larson, Rachel Lower, Todd DeVries, Yue Jiang, Ronald J. Hause, Rich Getto, Brian Christin, Nathan K. Yee, Michael A. Bowen, Clinton Weber, Daniel Li, Tina Albertson, Claire Sutherland, Christopher G. Ramsborg. Defined cell composition and precise control over JCAR017 dose enables identification of relationships between chimeric antigen receptor T cell product attributes, pharmacokinetics, and clinical endpoints in NHL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 960.