Route of 41BB/41BBL Costimulation Determines Effector Function of B7-H3-CAR.CD28ζ T Cells

Molecular Therapy: Oncolytics

Emmanuel Okeke¹  Phuong Nguyen¹  Dalia Haydar¹  Stephen Gottschalk¹  Christopher DeRenzo¹  Giedre Krenciute¹  Jennifer Moore¹  Carla O’Reilly¹  James Papizan²  Shondra Pruett-Miller²  Julie Justice³  Michael Clay³  Sheng Zhou⁴  Robert Throm⁵ 

[1] Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA;Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA;Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA;Experimental Cellular Therapeutics Laboratory, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA;Vector Development and Production Laboratory, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA;

关键词: Chimeric antigen receptor;    CAR;    T cell;    solid tumor;    pediatric;    B7-H3;   

DOI  :  

来源: DOAJ

【 摘 要 】

B7-H3 is actively being explored as an immunotherapy target for pediatric patients with solid tumors using monoclonal antibodies or T cells expressing chimeric antigen receptors (CARs). B7-H3-CARs containing a 41BB costimulatory domain are currently favored by several groups based on preclinical studies. In this study, we initially performed a detailed analysis of T cells expressing B7-H3-CARs with different hinge/transmembrane (CD8α versus CD28) and CD28 or 41BB costimulatory domains (CD8α/CD28, CD8α/41BB, CD28/CD28, CD28/41BB). Only subtle differences in effector function were observed between CAR T cell populations in vitro. However, CD8α/CD28-CAR T cells consistently outperformed other CAR T cell populations in three animal models, resulting in a significant survival advantage. We next explored whether adding 41BB signaling to CD8α/CD28-CAR T cells would further enhance effector function. Surprisingly, incorporating 41BB signaling into the CAR endodomain had detrimental effects, while expressing 41BBL on the surface of CD8α/CD28-CAR T cells enhanced their ability to kill tumor cells in repeat stimulation assays. Furthermore, 41BBL expression enhanced CD8α/CD28-CAR T cell expansion in vivo and improved antitumor activity in one of four evaluated models. Thus, our study highlights the intricate interplay between CAR hinge/transmembrane and costimulatory domains. Based on our study, we selected CD8α/CD28-CAR T cells expressing 41BBL for early phase clinical testing.

【 授权许可】

Unknown