Epigenetic Profiling and Response to CD19 Chimeric Antigen Receptor T-Cell Therapy in B-Cell Malignancies

García-Prieto, Carlos A.; Villanueva, Lorea; Bueno-Costa, Alberto; Dávalos, Verónica; González-Navarro, Europa Azucena; Juan, Manel; Urbano-Ispizúa, Álvaro; Delgado, Julio; Ortiz‐Maldonado, Valentín; Bufalo, Francesca Del; Locatelli, Franco; Quintarelli, Concetta; Sinibaldi, Matilde; Soler, Marta; Moura, Manuel Castro de; Ferrer, Gerardo; Urdinguio, Rocío G.; Fernández, Agustín F.; Fraga, Mario F.; Bar, Diana; Meir, Amilia; Itzhaki, Orit; Besser, Michal J.; Avigdor, Abraham; Jacoby, Elad; Esteller, Manel

doi:10.1093/jnci/djab194

Cited by 40 publications

(30 citation statements)

References 40 publications

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“…At the molecular level, in addition to cell surface markers, some studies have identified indicators of response associated with CAR-T cell gene expression, CAR integration site, and its epigenetic regulation. Recently, our group described a DNA methylation signature in CAR-T cells that we named EPICART ( 79 ). EPICART, like a previously described gene expression signature ( 77 ), associates good outcome with a signature enriched in naïve-like or early memory cell populations, thus reinforcing the importance of the presence of these subsets at preinfusion to determine overall response.…”

Section: Biomarkers In Actmentioning

confidence: 99%

Biological and Molecular Factors Predicting Response to Adoptive Cell Therapies in Cancer

Ferrer

Álvarez-Errico

Esteller

2022

JNCI: Journal of the National Cancer Institute

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Adoptive cell therapy (ACT) constitutes a major breakthrough in cancer management that has expanded in the past years due to impressive results showing durable and even curative responses for some patients with hematological malignancies. ACT leverages antigen specificity and cytotoxic mechanisms of the immune system, particularly relying on the patient´s T lymphocytes to target and eliminate malignant cells. This personalized therapeutic approach exemplifies the success of the joint effort of basic, translational and clinical researchers that has turned the patient´s immune system into a great ally in the search for a cancer cure. Adoptive cell therapies are constantly improving to reach a maximum beneficial clinical response. Despite being very promising therapeutic options for certain types of cancers, mainly melanoma and hematological malignancies, these individualized treatments still present several shortcomings including elevated costs, technical challenges, management of adverse side effects and a limited population of responder patients. Thus, it is crucial to discover and develop reliable and robust biomarkers to specifically and sensitively pinpoint the patients that will benefit the most from ACT, as well as those that are at higher risk of developing potentially serious toxicities. Although unique readouts of infused cell therapy success have not yet been identified, certain characteristics from the adoptive cells, the tumor and/or the tumor microenvironment have been recognized to predict patients' outcome upon ACT. Here, we comment on the importance of biomarkers to predict ACT chances of success to maximize efficacy of treatments and increase patients' survival.

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Section: Biomarkers In Actmentioning

confidence: 99%

Biological and Molecular Factors Predicting Response to Adoptive Cell Therapies in Cancer

Ferrer

Álvarez-Errico

Esteller

2022

JNCI: Journal of the National Cancer Institute

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“…A limitation of our work includes the relatively small number of diagnostic CSF specimens of inherently very small volumes and/or paucity of available cell number as well as the small number of patients. Our findings however emphasize the need for further systematic in-depth studies, using next generation single-cell RNA sequencing (scRNASeq), proteomics, and/or epigenetic analysis, 40,41 to reveal the precise transcriptional signature underlying the treatment-refractory state of individual T-cell clones. Possible mechanisms may include an acquired steroid-resistance due to altered JAK-STAT-pathway signaling, 42,43 upregulation of the glucocorticoid-induced TNF receptor family-related protein (GITR) expression, 44 and/or a previously observed chemo-resistance of certain central memory/memory stem T-cell subsets.…”

Section: Discussionmentioning

confidence: 91%

Molecular monitoring of T-cell kinetics and migration in severe neurotoxicity after real-world CD19-specific chimeric antigen receptor T cell therapy

Berger¹,

Akyüz²,

Geffken³

et al. 2022

haematol

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CD19-specific chimeric antigen receptor (CD19-CAR)-T cell therapies mediate durable responses in late-stage B-cell malignancies, but can be complicated by a potentially severe immune effector cell-associated neurotoxicity syndrome (ICANS). Despite broad efforts, the precise mechanisms of ICANS are not entirely known, and resistance to current ICANSdirected therapies (especially corticosteroids) has been observed. Recent data suggest that inflammatory cytokines and/or targeting of cerebral CD19-expressing pericytes can disrupt the blood-brain barrier and facilitate influx of immune cells, including CAR-T cells. However, specific tools for CD19-CAR-T cell analysis within often minute samples of cerebrospinal fluid (CSF) are not broadly available. Here, we applied our recently developed digital-PCR assays to monitor CD19-CAR-T cell kinetics in CSF and blood in real-world patients with neurotoxicity. Consistently, we observed a CAR-T cell enrichment within CSF in ICANS patients with further progressive accumulation despite intense corticosteroid-containing immuno-chemotherapies in a subset of patients with prolonged and therapy-resistant grade 3-4 neurotoxicity. We used next-generation T-cell receptor-β sequencing to assess the repertoire of treatment-refractory cells. Longitudinal analysis revealed a profound skewing of the T-cell receptor repertoire, which at least partly reflected selective expansion of infused Tcell clones. Interestingly, a major fraction of eventually dominating hyperexpanded T-cell clones were of non-CAR-T cell derivation. These findings hint to a role of therapy-refractory T-cell clones in severe ICANS development and prompt future systematic research to determine if CAR-T cells may serve as ‘door openers’ and to further characterize both CARpositive and non-CAR-T cells to interrogate the transcriptional signature of these possibly pathologic T cells.

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“…The T-cell methylation profiles of 157 patients with B-cell malignancies, including ALL and NHL, were downloaded from the GEO database under the accession number GSE179414 ( 22 ). The dataset comprised 77 ALL and 37 NHL cases, who were treated with CART19 cells.…”

Section: Methodsmentioning

confidence: 99%

Identification of methylation signatures associated with CAR T cell in B-cell acute lymphoblastic leukemia and non-hodgkin’s lymphoma

Song

Huang²,

Chen³

et al. 2022

Front. Oncol.

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CD19-targeted CAR T cell immunotherapy has exceptional efficacy for the treatment of B-cell malignancies. B-cell acute lymphocytic leukemia and non-Hodgkin’s lymphoma are two common B-cell malignancies with high recurrence rate and are refractory to cure. Although CAR T-cell immunotherapy overcomes the limitations of conventional treatments for such malignancies, failure of treatment and tumor recurrence remain common. In this study, we searched for important methylation signatures to differentiate CAR-transduced and untransduced T cells from patients with acute lymphoblastic leukemia and non-Hodgkin’s lymphoma. First, we used three feature ranking methods, namely, Monte Carlo feature selection, light gradient boosting machine, and least absolute shrinkage and selection operator, to rank all methylation features in order of their importance. Then, the incremental feature selection method was adopted to construct efficient classifiers and filter the optimal feature subsets. Some important methylated genes, namely, SERPINB6, ANK1, PDCD5, DAPK2, and DNAJB6, were identified. Furthermore, the classification rules for distinguishing different classes were established, which can precisely describe the role of methylation features in the classification. Overall, we applied advanced machine learning approaches to the high-throughput data, investigating the mechanism of CAR T cells to establish the theoretical foundation for modifying CAR T cells.

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Epigenetic Profiling and Response to CD19 Chimeric Antigen Receptor T-Cell Therapy in B-Cell Malignancies

Cited by 40 publications

References 40 publications

Biological and Molecular Factors Predicting Response to Adoptive Cell Therapies in Cancer

Biological and Molecular Factors Predicting Response to Adoptive Cell Therapies in Cancer

Molecular monitoring of T-cell kinetics and migration in severe neurotoxicity after real-world CD19-specific chimeric antigen receptor T cell therapy

Identification of methylation signatures associated with CAR T cell in B-cell acute lymphoblastic leukemia and non-hodgkin’s lymphoma

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