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Antigen-independent activation enhances the efficacy of 4-1BB-costimulated CD22 CAR T cells

Authors :
Olga Shestova
Simon F. Lacey
Brian Granda
Jessica Perazzelli
Stephan A. Grupp
Pranali Ravikumar
Katherine D. Cummins
Liaomin Peng
Yong Gu Lee
Nathan Singh
Ting Liu
Marco Ruella
Mohamed Abdel-Mohsen
Noelle V. Frey
David M. Barrett
Florent Colomb
Saar Gill
Steven Highfill
Carl H. June
Janis K. Burkhardt
Raymone Pajarillo
Shannon L. Maude
Amy Shyu
Jennifer Brogdon
Boris Engels
Melissa Ramones
Mohammad Damra
Dongfang Liu
David A. Christian
Daron M. Standley
Andrew Price
Inkook Chun
Xueqing Maggie Lu
Regina M. Young
Linlin Zhao
Nathan H. Roy
Source :
Nature medicine. 27(5)
Publication Year :
2019

Abstract

While CD19-directed chimeric antigen receptor (CAR) T cells can induce remission in patients with B cell acute lymphoblastic leukemia (ALL), a large subset relapse with CD19- disease. Like CD19, CD22 is broadly expressed by B-lineage cells and thus serves as an alternative immunotherapy target in ALL. Here we present the composite outcomes of two pilot clinical trials ( NCT02588456 and NCT02650414 ) of T cells bearing a 4-1BB-based, CD22-targeting CAR in patients with relapsed or refractory ALL. The primary end point of these studies was to assess safety, and the secondary end point was antileukemic efficacy. We observed unexpectedly low response rates, prompting us to perform detailed interrogation of the responsible CAR biology. We found that shortening of the amino acid linker connecting the variable heavy and light chains of the CAR antigen-binding domain drove receptor homodimerization and antigen-independent signaling. In contrast to CD28-based CARs, autonomously signaling 4-1BB-based CARs demonstrated enhanced immune synapse formation, activation of pro-inflammatory genes and superior effector function. We validated this association between autonomous signaling and enhanced function in several CAR constructs and, on the basis of these observations, designed a new short-linker CD22 single-chain variable fragment for clinical evaluation. Our findings both suggest that tonic 4-1BB-based signaling is beneficial to CAR function and demonstrate the utility of bedside-to-bench-to-bedside translation in the design and implementation of CAR T cell therapies.

Details

ISSN :
1546170X
Volume :
27
Issue :
5
Database :
OpenAIRE
Journal :
Nature medicine
Accession number :
edsair.doi.dedup.....4851c530b559bbb2da81508213f14de9