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Published on: June 26, 2018
Differential molecular signatures in response to CD19-CAR T cell therapy compared with conventional pharmacotherapy
Panagiotis Garantziotis1, Lorenzo Beretta2, Julius Lindblom3
1Department of Internal Medicine 3-Rheumatology and Immunology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany; Deutsches Zentrum für Immuntherapie (DZI), FAU Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany.
Objectives:
Early trials of CD19-chimeric antigen receptor (CAR) T cell therapy in systemic lupus erythematosus (SLE) show promise, but the molecular mechanisms underlying its disease-modifying effects remain unclear. We aimed to compare biological profiles and alterations following CD19-CAR T cell versus standard pharmacotherapy in SLE.
Methods:
Pseudo-bulk gene expression derived from single-cell RNA sequencing of peripheral blood mononuclear cells from 7 SLE patients before and after CD19-CAR T cell therapy was compared with whole-blood transcriptome data from 30 SLE patients in remission on standard pharmacotherapy and 31 SLE patients before and 6 months after treatment with rituximab, belimumab, or cyclophosphamide. Pathway analysis was conducted using Functional Analysis of Individual Microarray Expression and gene set enrichment analysis.
Results:
CD19-CAR T cell-induced remission was characterised by marked suppression of complement activation, type I interferon, DNA damage response (DDR), and cell death pathways compared with remission following conventional pharmacotherapy, alongside an upregulation of lipid metabolism pathways. Compared with rituximab and belimumab, CD19-CAR T cell therapy induced greater downregulation of type I/II interferon, DDR, and chemokine pathways. Compared with cyclophosphamide, CD19-CAR T cell therapy induced greater suppression of interferon, mitochondrial, and mammalian target of rapamycin signalling pathways.
Conclusions:
CD19-CAR T cell therapy induces substantial suppression of key immunological pathways involved in SLE, including complement activation and type I interferon responses, accompanied by a metabolic reprogramming. Molecular profiles of remission after CD19-CAR T cell therapy differ from those induced by conventional SLE pharmacotherapy, suggesting more profound CD19-CAR T cell-induced biological alterations.
Insights
Chimeric antigen receptor (CAR) T cell therapy for systemic lupus erythematosus (SLE) significantly suppresses key immune pathways like complement and interferon responses. This novel therapy shows distinct molecular alterations compared to standard SLE treatments.
Area of Science:
- Immunology
- Genomics
- Systems Biology
Background:
- Systemic lupus erythematosus (SLE) is a complex autoimmune disease with unmet therapeutic needs.
- Chimeric antigen receptor (CAR) T cell therapy targeting CD19 shows early promise in SLE treatment.
- The precise molecular mechanisms of CD19-CAR T cell therapy in SLE remain largely undefined.
Purpose of the Study:
- To compare the biological profiles and molecular alterations induced by CD19-CAR T cell therapy versus standard pharmacotherapy in SLE patients.
- To elucidate the distinct pathways modulated by CD19-CAR T cell therapy in achieving remission.
Main Methods:
- Single-cell RNA sequencing and pseudo-bulk gene expression analysis of peripheral blood mononuclear cells from SLE patients before and after CD19-CAR T cell therapy.
- Comparison with whole-blood transcriptome data from SLE patients in remission on standard pharmacotherapy (rituximab, belimumab, cyclophosphamide) and those undergoing treatment.
- Pathway analysis utilizing Functional Analysis of Individual Microarray Expression and gene set enrichment analysis.
Main Results:
- CD19-CAR T cell therapy induced remission characterized by suppressed complement activation, type I interferon, DNA damage response (DDR), and cell death pathways.
- Lipid metabolism pathways were upregulated following CD19-CAR T cell therapy.
- Compared to conventional therapies, CD19-CAR T cell therapy demonstrated greater suppression of interferon, DDR, and chemokine pathways, alongside significant impact on mitochondrial and mTOR signaling.
Conclusions:
- CD19-CAR T cell therapy profoundly suppresses key immunological pathways (complement, type I interferon) and induces metabolic reprogramming in SLE.
- The molecular profile of remission achieved by CD19-CAR T cell therapy differs significantly from that of conventional SLE pharmacotherapies.
- These findings suggest CD19-CAR T cell therapy induces more substantial biological alterations in SLE pathogenesis.
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