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Antigen-independent activation enhances the efficacy of 4-1BB-costimulated CD22 CAR T cells
- 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.
- Subjects :
- 0301 basic medicine
Adult
Male
medicine.medical_treatment
Sialic Acid Binding Ig-like Lectin 2
T-Lymphocytes
Antigens, CD19
Immunotherapy, Adoptive
General Biochemistry, Genetics and Molecular Biology
CD19
Immunological synapse
03 medical and health sciences
Mice
Tumor Necrosis Factor Receptor Superfamily, Member 9
0302 clinical medicine
Antigen
CD28 Antigens
Medicine
Animals
Humans
Receptor
Child
Cells, Cultured
B-Lymphocytes
Receptors, Chimeric Antigen
biology
business.industry
CD22
CD28
General Medicine
Immunotherapy
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Xenograft Model Antitumor Assays
Chimeric antigen receptor
030104 developmental biology
4-1BB Ligand
030220 oncology & carcinogenesis
Child, Preschool
Cancer research
biology.protein
Female
business
Subjects
Details
- ISSN :
- 1546170X
- Volume :
- 27
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Nature medicine
- Accession number :
- edsair.doi.dedup.....4851c530b559bbb2da81508213f14de9