Activation priming and cytokine polyfunctionality modulate the enhanced functionality of low-affinity CD19 CAR T cells

Michelozzi, Ilaria M.; Gómez-Castañeda, Eduardo; Pohle, Ruben V.C.; Rodriguez, Ferran Cardoso; Sufi, Jahangir; Puigdevall, Pau; Subramaniyam, Meera; Kirtsios, Efstratios; Eddaoudi, Ayad; Wu, Si Wei; Guvenel, Aleks; Fisher, Jonathan; Ghorashian, Sara; Pulé, Martin; Tape, Christopher J.; Castellano, Sergi; Amrolia, Persis; Giustacchini, Alice

doi:10.1182/bloodadvances.2022008490

Cited by 10 publications

(9 citation statements)

References 40 publications

(59 reference statements)

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“…Additionally, by suppressing fatty acid metabolism essential for memory T cells, GCs decreased memory CD8 + T cells with low TCR affinity due to their lower phosphorylation of GR [ 23 ]. Since a recent study showed enhanced functionality of low-affinity in comparison to high-affinity CAR T cells [ 24 ], investigating whether GCs select CAR T cells depending on the CAR affinity may be pertinent.…”

Section: Discussionmentioning

confidence: 99%

CAR T cells and T cells phenotype and function are impacted by glucocorticoid exposure with different magnitude

Poiret,

Vikberg,

Schoutrop

et al. 2024

J Transl Med

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Background Chimeric antigen receptor (CAR) T cell therapy is associated with high risk of adverse events. Glucocorticoids (GCs) are cornerstone in the management of high-grade cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Given the potentially deleterious effects of GCs on CAR T cells anti-tumor activity, increasing our understanding of GCs impact on CAR T cells is crucial. Methods Using several CAR T cells i.e., CD19, mesothelin (MSLN)-CD28 and MSLN-41BB CAR T cells (M28z and MBBz), we compared phenotypical, functional, changes and anti-tumor activity between i) transduced CD19 CAR T cells with untransduced T cells, ii) M28z with MBBz CAR T cells induced by Dexamethasone (Dx) or Methylprednisolone (MP) exposures. Results Higher levels of GC receptor were found in less differentiated CAR T cells. Overall, Dx and MP showed a similar impact on CAR T cells. Compared to untreated condition, GCs exposure increased the expression of PD-1 and TIM-3 and reduced the expression of LAG3 and function of T cells and CAR T cells. GC exposures induced more exhausted (LAG3 + PD1 + TIM3 +) and dysfunctional (CD107a-INFγ-TNF-IL2-) untransduced T cells in comparison to CD19 CAR T cells. GC exposure impaired more CD4 + than CD8 + CD19 CAR T cells. GC exposures increased more PD-1 expression associated with reduced proliferative capacity and function of M28z as compared to MBBz CAR T cells. CAR T cells anti-tumor activity was greatly affected by repeated GC exposure but partly recovered within 48h after GCs withdrawal. Conclusions In summary, GCs impacted phenotype and function of untransduced and CAR T cell with different magnitude. The nature of the CAR costimulatory domain influenced the magnitude of CAR T cell response to GCs.

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Section: Discussionmentioning

confidence: 99%

CAR T cells and T cells phenotype and function are impacted by glucocorticoid exposure with different magnitude

Poiret,

Vikberg,

Schoutrop

et al. 2024

J Transl Med

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show abstract

“…Additionally, by suppressing fatty acid metabolism essential for memory T cells, GCs decreased memory CD8+ T cells with low TCR affinity due to their lower phosphorylation of GR [22]. Since a recent study showed enhanced functionality of low-affinity in comparison to high-affinity CAR T cells [23], investigating whether GCs select CAR T cells depending on the CAR affinity may be pertinent.…”

Section: Discussionmentioning

confidence: 99%

CAR T cells and T cells phenotype and function are impacted by glucocorticoid exposure with different amplitude.

Poiret,

Vikberg,

Schoutrop

et al. 2023

Preprint

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Background. Chimeric antigen receptor (CAR) T cell therapy is associated with high risk of adverse events. Glucocorticoids (GCs) are cornerstone in the management of high-grade cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Given the potentially deleterious effects of GCs on CAR T cells anti-tumor activity, increasing our understanding of GCs impact on CAR T cells is crucial. Methods. Using several CAR T cells i.e., CD19, mesothelin (MSLN)-CD28 and MSLN-41BB CAR T cells (M28z and MBBz), we compared phenotypical, functional, changes and anti-tumor activity between i) transduced CD19 CAR T cells with untransduced T cells, ii) M28z with MBBz CAR T cells induced by Dexamethasone (Dx) or Methylprednisolone (MP) exposures. Results. Higher levels of GC receptor were found in less differentiated CAR T cells. Overall, Dx and MP showed a similar impact on CAR T cells. GC exposures induced more exhausted (LAG3+PD1+TIM3+) and dysfunctional (CD107a-INFγ-TNF-IL2-) untransduced T cells in comparison to CD19 CAR T cells. GC exposure impaired more CD4+ than CD8+ CD19 CAR T cells. GC exposures increased more PD-1 expression associated with reduced proliferative capacity and function of M28z as compared to MBBz CAR T cells. CAR T cells anti-tumor activity was greatly affected by repeated GC exposure but partly recovered within 48h after GCs withdrawal. Conclusions. In summary, GCs impacted phenotype and function of untransduced and CAR T cell with different amplitude. The nature of the CAR costimulatory domain influenced the amplitude of CAR T cell response to GCs.

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“…For instance, high affinity of the CAR to CD19 antigen may not improve efficacy but promote T-cell exhaustion instead. Michelozzi, et al., recently demonstrated that low-affinity CD19-CAR T had enhanced in vivo expansion, prolonged persistence, and better tolerability, than traditional high-affinity CD19-CAR T ( 6 ). CAR integration using non-retroviral methods, such as using adeno-associated virus or non-viral gene editing to transfer a CD19-CAR into the T-cell receptor alpha constant (TRAC) region, has demonstrated improved functionality compared to traditional retroviral transduction ( 7 ).…”

Section: B-cell Non-hodgkin Lymphomamentioning

confidence: 99%

Novel and multiple targets for chimeric antigen receptor-based therapies in lymphoma

Pang,

Ghosh

2024

Front. Oncol.

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Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 in B-cell non-Hodgkin lymphoma (NHL) validates the utility of CAR-based therapy for lymphomatous malignancies. Despite the success, treatment failure due to CD19 antigen loss, mutation, or down-regulation remains the main obstacle to cure. On-target, off-tumor effect of CD19-CAR T leads to side effects such as prolonged B-cell aplasia, limiting the application of therapy in indolent diseases such as chronic lymphocytic leukemia (CLL). Alternative CAR targets and multi-specific CAR are potential solutions to improving cellular therapy outcomes in B-NHL. For Hodgkin lymphoma and T-cell lymphoma, several cell surface antigens have been studied as CAR targets, some of which already showed promising results in clinical trials. Some antigens are expressed by different lymphomas and could be used for designing tumor-agnostic CAR. Here, we reviewed the antigens that have been studied for novel CAR-based therapies, as well as CARs designed to target two or more antigens in the treatment of lymphoma.

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Activation priming and cytokine polyfunctionality modulate the enhanced functionality of low-affinity CD19 CAR T cells

Cited by 10 publications

References 40 publications

CAR T cells and T cells phenotype and function are impacted by glucocorticoid exposure with different magnitude

CAR T cells and T cells phenotype and function are impacted by glucocorticoid exposure with different magnitude

CAR T cells and T cells phenotype and function are impacted by glucocorticoid exposure with different amplitude.

Novel and multiple targets for chimeric antigen receptor-based therapies in lymphoma

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