15 results on '"Pau Puigdevall"'
Search Results
2. GenomicScores: seamless access to genomewide position-specific scores from R and Bioconductor.
- Author
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Pau Puigdevall and Robert Castelo
- Published
- 2018
- Full Text
- View/download PDF
3. Activation priming and cytokine polyfunctionality modulate the enhanced functionality of low-affinity CD19 CAR T cells
- Author
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Ilaria M. Michelozzi, Eduardo Gomez-Castaneda, Ruben V. C. Pohle, Ferran Cardoso Rodriguez, Jahangir Sufi, Pau Puigdevall Costa, Meera Subramaniyam, Efstratios Kirtsios, Ayad Eddaoudi, Si Wei Wu, Aleks Guvenel, Jonathan Fisher, Sara Ghorashian, Martin A. Pule, Christopher J. Tape, Sergi Castellano, Persis J. Amrolia, and Alice Giustacchini
- Subjects
Hematology - Abstract
We recently described a low-affinity second-generation CD19 chimeric antigen receptor (CAR) CAT that showed enhanced expansion, cytotoxicity, and antitumor efficacy compared with the high-affinity (FMC63-based) CAR used in tisagenlecleucel, in preclinical models. Furthermore, CAT demonstrated an excellent toxicity profile, enhanced in vivo expansion, and long-term persistence in a phase 1 clinical study. To understand the molecular mechanisms behind these properties of CAT CAR T cells, we performed a systematic in vitro characterization of the transcriptomic (RNA sequencing) and protein (cytometry by time of flight) changes occurring in T cells expressing low-affinity vs high-affinity CD19 CARs following stimulation with CD19-expressing cells. Our results show that CAT CAR T cells exhibit enhanced activation to CD19 stimulation and a distinct transcriptomic and protein profile, with increased activation and cytokine polyfunctionality compared with FMC63 CAR T cells. We demonstrate that the enhanced functionality of low-affinity CAT CAR T cells is a consequence of an antigen-dependent priming induced by residual CD19-expressing B cells present in the manufacture.
- Published
- 2022
4. Somatic mutations alter the differentiation outcomes of iPSC-derived neurons
- Author
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Pau Puigdevall, Julie Jerber, Petr Danecek, Sergi Castellano, and Helena Kilpinen
- Subjects
Genetics ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Article - Abstract
The use of induced pluripotent stem cells (iPSC) as models for development and human disease has enabled the study of otherwise inaccessible tissues. A remaining challenge in developing reliable models is our limited understanding of the factors driving irregular differentiation of iPSCs, particularly the impact of acquired somatic mutations. We leveraged data from a pooled dopaminergic neuron differentiation experiment of 238 iPSC lines profiled with single-cell RNA and whole-exome sequencing to study how somatic mutations affect differentiation outcomes. We found that deleterious somatic mutations in key developmental genes, notably the BCOR gene, are strongly associated with failure in dopaminergic neuron differentiation and a larger proliferation rate in culture. We further identified broad differences in cell type composition between incorrectly and successfully differentiating lines, as well as significant changes in gene expression contributing to the inhibition of neurogenesis. Our work calls for caution in interpreting differentiation-related phenotypes in disease-modeling experiments.
- Published
- 2023
5. Effects of somatic mutations on cellular differentiation in iPSC models of neurodevelopment
- Author
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Pau Puigdevall, Julie Jerber, Petr Danecek, Sergi Castellano, and Helena Kilpinen
- Abstract
The use of induced pluripotent stem cells (iPSC) as models for development and human disease has enabled the study of otherwise inaccessible tissues. A remaining challenge in developing reliable models is our limited understanding of the factors driving irregular in vitro differentiation of iPSCs, particularly the impact of acquired somatic mutations. We leveraged data from a pooled dopaminergic neuron differentiation experiment of 238 iPSC lines profiled with single-cell and whole-exome sequencing to study how somatic mutations affect differentiation outcomes. Differentiation was tracked at three time points corresponding to neural progenitors, early neurons and mature neurons. We found that deleterious somatic mutations in key developmental genes, notably the BCOR gene, are strongly associated with failure in dopaminergic neuron differentiation, with lines carrying such mutations also showing larger proliferation rate in culture. We further identified broad differences in cell type composition between failed and successfully differentiating lines, as well as significant changes in gene expression contributing to the inhibition of neurogenesis, a functional process also targeted by deleterious mutations in failed lines. Our work highlights the need to routinely measure the burden of deleterious mutations in iPSC lines and calls for caution in interpreting differentiation-related phenotypes in disease-modelling experiments.
- Published
- 2022
6. Genetic linkage analysis of a large family identifies FIGN as a candidate modulator of reduced penetrance in heritable pulmonary arterial hypertension
- Author
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Dan Geiger, Lucilla Piccari, Pau Puigdevall, Montserrat Milà, Irene Madrigal, Robert Castelo, Celia Badenas, Isabel Blanco, and Joan Albert Barberà
- Subjects
0301 basic medicine ,Genetics ,medicine.medical_specialty ,Mutation ,Haplotype ,Biology ,medicine.disease_cause ,Penetrance ,Human genetics ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030228 respiratory system ,Genetic linkage ,medicine ,Medical genetics ,Functional genomics ,Gene ,Genetics (clinical) - Abstract
BackgroundMapping the genetic component of molecular mechanisms responsible for the reduced penetrance (RP) of rare disorders constitutes one of the most challenging problems in human genetics. Heritable pulmonary arterial hypertension (PAH) is one such disorder characterised by rare mutations mostly occurring in the bone morphogenetic protein receptor type 2 (BMPR2) gene and a wide heterogeneity of penetrance modifier mechanisms. Here, we analyse 32 genotyped individuals from a large Iberian family of 65 members, including 22 carriers of the pathogenic BMPR2 mutation c.1472G>A (p.Arg491Gln), 8 of them diagnosed with PAH by right-heart catheterisation, leading to an RP rate of 36.4%.MethodsWe performed a linkage analysis on the genotyping data to search for genetic modifiers of penetrance. Using functional genomics data, we characterised the candidate region identified by linkage analysis. We also predicted the haplotype segregation within the family.ResultsWe identified a candidate chromosome region in 2q24.3, 38 Mb upstream from BMPR2, with significant linkage (LOD=4.09) under a PAH susceptibility model. This region contains common variants associated with vascular aetiology and shows functional evidence that the putative genetic modifier is located in the upstream distal promoter of the fidgetin (FIGN) gene.ConclusionOur results suggest that the genetic modifier acts through FIGN transcriptional regulation, whose expression variability would contribute to modulating heritable PAH. This finding may help to advance our understanding of RP in PAH across families sharing the p.Arg491Gln pathogenic mutation in BMPR2.
- Published
- 2019
7. The BIOMEPOC Project: Personalized Biomarkers and Clinical Profiles in Chronic Obstructive Pulmonary Disease
- Author
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Joaquim Gea, Sergi Pascual, Ady Castro-Acosta, Carmen Hernández-Carcereny, Robert Castelo, Eduardo Márquez-Martín, Concepción Montón, Alexandre Palou, Rosa Faner, Laura I. Furlong, Luis Seijo, Ferran Sanz, Montserrat Torà, Carles Vilaplana, Carme Casadevall, José Luis López-Campos, Eduard Monsó, Germán Peces-Barba, Borja G. Cosío, Alvar Agustí, Mireia Admetlló, Carlos Alvarez-Martínez, Esther Barreiro, Ferran Casals, Rocío Córdova, Marian García, José G. González-García, Eduardo Márquez, Miren Josune Ormaza, Pau Puigdevall, Luis Seijó, and Yolanda Torralba
- Subjects
medicine.medical_specialty ,COPD ,business.industry ,Sample processing ,medicine ,Pulmonary disease ,General Medicine ,Personalized medicine ,business ,Intensive care medicine ,medicine.disease ,Proteomics ,Omics - Abstract
Chronic obstructive pulmonary disease (COPD) is an entity with a heterogeneous presentation. For this reason, attempts have been made to characterize different phenotypes and endotypes to enable a more individualized approach. The aim of the Biomarkers in COPD (BIOMEPOC) project is to identify useful biomarkers in blood to improve the characterization of patients. Clinical data and blood samples from a group of patients and healthy controls will be analyzed. The project will consist of an exploration phase and a validation phase. Analytical parameters in blood will be determined using standard techniques and certain 'omics' (transcriptomics, proteomics, and metabolomics). The former will be hypothesis-driven, whereas the latter will be exploratory. Finally, a multilevel analysis will be conducted. Currently, 269 patients and 83 controls have been recruited, and sample processing is beginning. Our hope is to use the results to identify new biomarkers that, alone or combined, will allow a better characterization of patients.
- Published
- 2019
8. Enhanced functionality of low-affinity CD19 CAR T-cells is associated with activation priming and a polyfunctional cytokine phenotype
- Author
-
Ilaria M. Michelozzi, Eduardo Gomez Castaneda, Ruben V.C. Pohle, Ferran Cardoso Rodriguez, Jahangir Sufi, Pau Puigdevall Costa, Meera Subramaniyam, Efstratios Kirtsios, Ayad Eddaoudi, Si Wei Wu, Aleks Guvenel, Jonathan Fisher, Sara Ghorashian, Martin A. Pule, Christopher J. Tape, Sergi Castellano, Persis J. Amrolia, and Alice Giustacchini
- Subjects
biology ,Chemistry ,medicine.medical_treatment ,Priming (immunology) ,Stimulation ,CD19 ,In vitro ,Chimeric antigen receptor ,Cell biology ,Cytokine ,In vivo ,biology.protein ,medicine ,Cytotoxicity - Abstract
We recently described a low-affinity second-generation CD19 chimeric antigen receptor (CAR) CAT that showed enhanced expansion, cytotoxicity, and anti-tumour efficacy compared to the high-affinity (FMC63 based) CAR used in Tisagenlecleucel, in pre-clinical models. Furthermore, CAT demonstrated an excellent toxicity profile, enhanced in vivo expansion, and long-term persistence in a Phase I clinical study. To understand the molecular mechanisms behind these properties of CAT CAR T-cells, we performed a systematic in vitro characterization of the transcriptomic (RNA-seq) and protein (CyTOF) changes occurring in T-cells expressing low-affinity vs high-affinity CD19 CARs following stimulation with CD19-expressing cells. Our results show that CAT CAR T-cells exhibit enhanced activation to CD19 stimulation and a distinct transcriptomic and protein profile, with increased activation and cytokine polyfunctionality compared to FMC63 CAR T-cells. We demonstrate that the enhanced functionality of low-affinity CAT CAR T-cells is a consequence of an antigen-dependent priming induced by residual CD19-expressing B-cells present in the manufacture.
- Published
- 2020
9. The Enhanced Functionality of Low-Affinity CD19 CAR T Cells Is Associated with Activation Priming and Polyfunctional Cytokine Phenotype
- Author
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Ruben V.C. Pohle, Meera Subramaniyam, Sara Ghorashian, Jahangir Sufi, Martin Pule, Sergi Castellano, Ilaria M. Michelozzi, Persis Amrolia, Pau Puigdevall, Eduardo Gomez-Castaneda, Christopher J. Tape, Alice Giustacchini, Aleks Guvenel, Si Wei Wu, and Ferran Cardoso Rodriguez
- Subjects
biology ,Chemistry ,medicine.medical_treatment ,T cell ,CD3 ,Immunology ,Priming (immunology) ,Cell Biology ,Hematology ,Biochemistry ,Molecular biology ,Granzyme B ,Cytokine ,medicine.anatomical_structure ,Antigen ,medicine ,biology.protein ,Cytotoxic T cell ,IL-2 receptor - Abstract
We have recently described a low-affinity second-generation anti-CD19 Chimeric Antigen Receptor (CAR) (CAT), characterized by faster antigen dissociation rate which showed enhanced expansion, cytotoxicity and anti-tumour efficacy compared with the high affinity (FMC63 based) CAR used in Tisagenlecleucel in pre-clinical models. Furthermore, CAT CAR T cells showed an excellent toxicity profile, enhanced in vivo expansion and long-term persistence in a Phase I clinical study (Ghorashian et al Nature Med 2019). However the molecular mechanisms behind the improved properties of CAT CAR T cells remain unknown. Herein, we performed a systematic in vitro characterization of the transcriptomic (bulk RNA-seq) and protein (CyTOF) changes occurring in CAR T cells expressing a low-affinity (CAT) vs high affinity (FMC63) anti-CD19 CARs following stimulation with CD19 expressing targets. Untransduced (UT) controls and T cells lentivirally transduced to express CAT or FMC63 CD19 CARs were compared both at baseline and following stimulation with CD19+ Acute Lymphoblastic Leukaemia cell line NALM6. In Principal Component Analysis for both RNA-seq and protein results, we found that the major variance across conditions was explained by CD19-mediated CAR T activation. Strikingly, unstimulated CAT CAR T cells showed an intermediate degree of activation between UT T cells and antigen stimulated CAR T cells. Indeed, when comparing RNA-seq results of unstimulated CAT vs FMC63, we found enhanced expression (FDR To identify the mechanisms underlying the stronger basal activation of CAT CAR T cells, we analysed cytokine expression at the single cell level by mass cytometry. Interestingly, rather than an increment in the expression of individual cytokines, we found that the distinctive feature of CAT CAR T cells was a shift toward a cytokine polyfunctional phenotype, with a marked increase in the proportion of cells co-expressing 3 or more cytokines (17.50% CAT vs 7.33% FMC63) (Figure 1b). Of note, cytokine polyfunctionality (expression of more than 1 cytokine/cell) in pre-infusion CAR T cell products has been associated to improved clinical efficacy. The functional phenotype observed in CAT CAR T cells was linked to the preferential activation of the p38 MAPK phospo-signalling, which is activated downstream of TCR CD3ζ chain (present in the CARs) but is also central to cytokine-dependent T cell activation in memory T cells. Interestingly, cytokine polyfunctional CAT CAR T cells were enriched in the CD3+CD19+ trogocytic (trog+) population, found at higher proportion in CAT vs FMC63 at 24h post antigen stimulation. Although trogocytosis has been associated to CAR T cell fratricide killing, trog+ CAT CAR T cells displayed higher levels of proliferation (pRB), activation (CD25, NFAT1) and cytotoxic (Granzyme B, Perforin B) markers, pointing at a stimulatory role of trogocytosis over fratricide killing, potentially due to the low-affinity CAR T cells distinctive property of better discriminating between low (trog+ CAR T cells) and high (tumour cells) target expression levels. In conclusion, we described the molecular mechanisms underlying the low affinity CAT CAR T cells functional phenotype. Our results show that the potent and long-term anti-tumour responses observed with CAT may be sustained by the establishment of CAR T cells self-reinforcing circuits activated through polyfunctional cytokine crosstalk. This work may inform the future design of versatile CAR T cells, capable of balancing safety, efficacy and long-term persistence. Disclosures Ghorashian: Amgen: Honoraria; UCLB: Patents & Royalties; Novartis: Honoraria. Pule:Autolus: Current Employment, Other: owns stock in and receives royalties, Patents & Royalties; UCLB: Patents & Royalties; Mana Therapeutics: Other: entitled to share of revenue from patents filed by UCL.
- Published
- 2020
10. Enhanced functionality of low-affinity CD19 CAR T-cells is associated with activation priming and a polyfunctional cytokine phenotype
- Author
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Michelozzi, Ilaria M., primary, Castaneda, Eduardo Gomez, additional, Pohle, Ruben V.C., additional, Rodriguez, Ferran Cardoso, additional, Sufi, Jahangir, additional, Costa, Pau Puigdevall, additional, Subramaniyam, Meera, additional, Wu, Si Wei, additional, Guvenel, Aleks, additional, Ghorashian, Sara, additional, Pule, Martin A., additional, Tape, Christopher J., additional, Castellano, Sergi, additional, Amrolia, Persis J., additional, and Giustacchini, Alice, additional
- Published
- 2020
- Full Text
- View/download PDF
11. Transcriptomic footprint of COPD patients with well-defined frequent severe exacerbations
- Author
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Esther Barreiro, Pau Puigdevall, Carme Casadevall, Robert Castelo, Joaquim Gea Guiral, and Sergi Pascual
- Subjects
Transcriptome ,COPD ,Immune system ,business.industry ,Antimicrobial peptides ,Immunology ,Gene expression ,medicine ,medicine.disease ,business ,Gene ,Phenotype ,KIR2DS4 - Abstract
There is a specific COPD phenotype known as ‘frequent exacerbator’. Many of the exacerbations suffered by these patients are severe and require hospitalization (SFECOPD). In a previous study we analyzed the transcriptomic characteristics found in the blood of SFECOPD patients recruited in different hospitals. However, results were very heterogeneous. Our present AIM was to analyze the genetic expression profile in the blood of SFECOPD patients from a single center, where hospitalization requires strict objective criteria. Methods: 20 COPD patients (half of them with SFECOPD, >3 hospitalizations in the previous year) from a referral center were included, and blood samples were obtained and processed for the transcriptomic analysis. Results: SFECOPD showed changes in the expression (FDR 1500 genes, 60 of them showing a full change >50%. Those genes encoding transmembrane proteins TMEM176 A & B and KIR2DS4 (detection-destruction of ‘abnormal cells’, Δ -370%, -300% & +260%, respectively), cell adhesion molecule CEACAM6 (Δ+160%, increase in susceptibility to bacterial infections), as well as proteases CTSG & ELANE, defensines DEFA 3 & 4, and RNASE3 (Δ+130 to +140%, all of them with antibacterial activity) stood out among them. Moreover, GO analysis also revealed that pathways most significantly involved in changes were immune responses against bacteria and fungi (5 genes each; OR 89 and 67, respectively), and those mediated by antimicrobial peptides (6 genes, OR 48). Conclusion: Blood of SFECOPD exhibits a differentiated expression profile, which is mainly characterized by changes in genes related with the immune response against infections. Funded SAF2014-54371, Menarini, SEPAR 15 & 16
- Published
- 2019
12. Proyecto de biomarcadores y perfiles clínicos personalizados en la enfermedad pulmonar obstructiva crónica (proyecto BIOMEPOC)
- Author
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Joaquim Gea, Sergi Pascual, Ady Castro-Acosta, Carmen Hernández-Carcereny, Robert Castelo, Eduardo Márquez-Martín, Concepción Montón, Alexandre Palou, Rosa Faner, Laura I. Furlong, Luis Seijo, Ferran Sanz, Montserrat Torà, Carles Vilaplana, Carme Casadevall, José Luis López-Campos, Eduard Monsó, Germán Peces-Barba, Borja G. Cosío, Alvar Agustí, Mireia Admetlló, Carlos Alvarez-Martínez, Esther Barreiro, Ferran Casals, Rocío Córdova, Marian García, José G. González-García, Eduardo Márquez, Miren Josune Ormaza, Pau Puigdevall, Luis Seijó, and Yolanda Torralba
- Subjects
Pulmonary and Respiratory Medicine ,Biological markers ,business.industry ,Marcadores biológicos ,Análisis multinivel ,Endotypes ,Personalized medicine ,Multilevel analysis ,Endotipos ,Medicine ,COPD ,EPOC ,Medicina personalizada ,business ,Humanities - Abstract
[ES] La enfermedad pulmonar obstructiva crónica (EPOC) es una entidad de presentación heterogénea. Por ello, se han intentado perfilar diferentes fenotipos y endotipos, que permitirían un manejo más diferenciado. El objetivo del proyecto Biomarcadores en la EPOC (BIOMEPOC) es identificar biomarcadores sanguíneos útiles para tipificar mejor a los enfermos. Se analizarán datos clínicos y muestras sanguíneas en un grupo de pacientes y controles sanos. El proyecto constará de fases de prospección y de validación. Se realizarán determinaciones analíticas sanguíneas con técnicas convencionales y de diversas ciencias «ómicas» (transcriptómica, proteómica y metabolómica). Las primeras se realizarán orientadas por hipótesis, mientras que con las segundas se realizará una exploración sin dicho condicionante. Finalmente se realizará un análisis multinivel. En el momento actual se han reclutado 269 pacientes y 83 controles, y se está iniciando el procesamiento de muestras. Con los resultados obtenidos se espera identificar nuevos biomarcadores que, en solitario o combinados, permitan una mejor tipificación de los pacientes., [EN] Chronic obstructive pulmonary disease (COPD) is an entity with a heterogeneous presentation. For this reason, attempts have been made to characterize different phenotypes and endotypes to enable a more individualized approach. The aim of the Biomarkers in COPD (BIOMEPOC) project is to identify useful biomarkers in blood to improve the characterization of patients. Clinical data and blood samples from a group of patients and healthy controls will be analyzed. The project will consist of an exploration phase and a validation phase. Analytical parameters in blood will be determined using standard techniques and certain ‘omics’ (transcriptomics, proteomics, and metabolomics). The former will be hypothesis-driven, whereas the latter will be exploratory. Finally, a multilevel analysis will be conducted. Currently, 269 patients and 83 controls have been recruited, and sample processing is beginning. Our hope is to use the results to identify new biomarkers that, alone or combined, will allow a better characterization of patients.
- Published
- 2019
13. Genetic linkage analysis of a large family identifies
- Author
-
Pau, Puigdevall, Lucilla, Piccari, Isabel, Blanco, Joan Albert, Barberà, Dan, Geiger, Celia, Badenas, Montserrat, Milà, Robert, Castelo, and Irene, Madrigal
- Subjects
Heterozygote ,Genotype ,Genetic Linkage ,Hemodynamics ,Blood Pressure ,Penetrance ,Polymorphism, Single Nucleotide ,Linkage Disequilibrium ,Pedigree ,Phenotype ,Amino Acid Substitution ,Chromosomes, Human, Pair 2 ,Mutation ,ATPases Associated with Diverse Cellular Activities ,Humans ,Familial Primary Pulmonary Hypertension ,Family ,Genetic Predisposition to Disease ,Microtubule-Associated Proteins ,Alleles ,Genetic Association Studies ,Genome-Wide Association Study - Abstract
Mapping the genetic component of molecular mechanisms responsible for the reduced penetrance (RP) of rare disorders constitutes one of the most challenging problems in human genetics. Heritable pulmonary arterial hypertension (PAH) is one such disorder characterised by rare mutations mostly occurring in the bone morphogenetic protein receptor type 2 (We performed a linkage analysis on the genotyping data to search for genetic modifiers of penetrance. Using functional genomics data, we characterised the candidate region identified by linkage analysis. We also predicted the haplotype segregation within the family.We identified a candidate chromosome region in 2q24.3, 38 Mb upstream fromOur results suggest that the genetic modifier acts through
- Published
- 2018
14. GenomicScores: seamless access to genomewide position-specific scores from R and Bioconductor
- Author
-
Robert Castelo and Pau Puigdevall
- Subjects
0301 basic medicine ,Statistics and Probability ,Mutation ,Information retrieval ,Genome ,Computer science ,Genomics ,medicine.disease_cause ,Biochemistry ,Computer Science Applications ,Bioconductor ,03 medical and health sciences ,Computational Mathematics ,030104 developmental biology ,0302 clinical medicine ,Computational Theory and Mathematics ,medicine ,Molecular Biology ,030217 neurology & neurosurgery ,Software - Abstract
Summary Genomewide position-specific scores, such as those estimating conservation, constraint, fitness or mutation tolerance, are ubiquitous in current genome analyses. The diversity of sources and formats of these scores, as well as their size, increase the burden to use them. We present GenomicScores, a Bioconductor package that provides efficient storage and seamless access of genomewide position-specific scores from R, facilitating their use in genome analysis workflows. Availability and implementation GenomicScores is implemented in R and available at https://bioconductor.org/packages/GenomicScores under the open source ‘Artistic-2.0’ license. Supplementary information Supplementary data are available at Bioinformatics online.
- Published
- 2018
15. Activation priming and cytokine polyfunctionality modulate the enhanced functionality of low-affinity CD19 CAR T cells
- Author
-
Michelozzi, Ilaria M., Gomez-Castaneda, Eduardo, Pohle, Ruben V.C., Rodriguez, Ferran Cardoso, Sufi, Jahangir, Costa, Pau Puigdevall, Subramaniyam, Meera, Kirtsios, Efstratios, Eddaoudi, Ayad, Wu, Si Wei, Guvenel, Aleks, Fisher, Jonathan, Ghorashian, Sara, Pule, Martin A., Tape, Christopher J., Castellano, Sergi, Amrolia, Persis J., and Giustacchini, Alice
- Abstract
We recently described a low-affinity second-generation CD19 chimeric antigen receptor (CAR) CAT that showed enhanced expansion, cytotoxicity, and anti-tumour efficacy compared to the high-affinity (FMC63 based) CAR used in Tisagenlecleucel, in pre-clinical models. Furthermore, CAT demonstrated an excellent toxicity profile, enhanced in vivoexpansion, and long-term persistence in a Phase I clinical study. To understand the molecular mechanisms behind these properties of CAT CAR T-cells, we performed a systematic in vitrocharacterization of the transcriptomic (RNA-seq) and protein (CyTOF) changes occurring in T-cells expressing low-affinity vs high-affinity CD19 CARs following stimulation with CD19-expressing cells. Our results show that CAT CAR T-cells exhibit enhanced activation to CD19 stimulation and a distinct transcriptomic and protein profile, with increased activation and cytokine polyfunctionality compared to FMC63 CAR T-cells. We demonstrate that the enhanced functionality of low-affinity CAT CAR T-cells is a consequence of an antigen-dependent priming induced by residual CD19-expressing B-cells present in the manufacture.
- Published
- 2022
- Full Text
- View/download PDF
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