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

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

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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.

Original languageEnglish
Pages (from-to)842-850
Number of pages9
JournalNature medicine
Volume27
Issue number5
DOIs
StatePublished - May 2021

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