Integrative Bulk and Single-Cell Profiling of Premanufacture T-cell Populations Reveals Factors Mediating Long-Term Persistence of CAR T-cell Therapy

Chen, Gregory M.; Chen, Changya; Das, Rajat K.; Gao, Peng; Chen, Chia‐Hui; Bandyopadhyay, Shovik; Ding, Yangyang; Uzun, Yasin; Yu, Wenbao; Zhu, Qin; Myers, Regina M.; Grupp, Stephan A.; Barrett, David M.; Tan, Kai

doi:10.1158/2159-8290.cd-20-1677

Cited by 127 publications

(118 citation statements)

References 53 publications

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“…166 Combined with bulk and single-cell ATAC sequencing, Chen et al found that IRF7 could affect CAR-T-cell persistence across T-cell subsets by regulating chronic IFN signaling, and that the TCF7 regulon is maintained in effector T cells among patients with long-term CAR-T-cell persistence. 167 The dynamic epigenetic changes in various cell types during the CRS process are also worthy of further study.…”

Section: Cutting-edge Technologies In Crs-related Studies Single-cell Technologiesmentioning

confidence: 99%

Signaling pathways in the regulation of cytokine release syndrome in human diseases and intervention therapy

Shao

Zhang

et al. 2021

Sig Transduct Target Ther

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Cytokine release syndrome (CRS) embodies a mixture of clinical manifestations, including elevated circulating cytokine levels, acute systemic inflammatory symptoms and secondary organ dysfunction, which was first described in the context of acute graft-versus-host disease after allogeneic hematopoietic stem-cell transplantation and was later observed in pandemics of influenza, SARS-CoV and COVID-19, immunotherapy of tumor, after chimeric antigen receptor T (CAR-T) therapy, and in monogenic disorders and autoimmune diseases. Particularly, severe CRS is a very significant and life-threatening complication, which is clinically characterized by persistent high fever, hyperinflammation, and severe organ dysfunction. However, CRS is a double-edged sword, which may be both helpful in controlling tumors/viruses/infections and harmful to the host. Although a high incidence and high levels of cytokines are features of CRS, the detailed kinetics and specific mechanisms of CRS in human diseases and intervention therapy remain unclear. In the present review, we have summarized the most recent advances related to the clinical features and management of CRS as well as cutting-edge technologies to elucidate the mechanisms of CRS. Considering that CRS is the major adverse event in human diseases and intervention therapy, our review delineates the characteristics, kinetics, signaling pathways, and potential mechanisms of CRS, which shows its clinical relevance for achieving both favorable efficacy and low toxicity.

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Section: Cutting-edge Technologies In Crs-related Studies Single-cell Technologiesmentioning

confidence: 99%

Signaling pathways in the regulation of cytokine release syndrome in human diseases and intervention therapy

Shao

Zhang

et al. 2021

Sig Transduct Target Ther

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“…Logo plots showing the relative abundance of conserved nucleotides for several known transcription factors revealed a highly significant association for transcription factors that are coupled to T cell effector and memory differentiation (Figure 1G). Most notably, some of these-including FOS:JUNB, STAT5, and TCF7-have established roles in regulating CAR T cell anti-tumor responses (Lynn et al, 2019;Zheng et al, 2021;Chen et al, 2021). Taken together, these data document the vast changes in DNA methylation that occur in CAR T cells post-infusion and show that these epigenetic events parallel the modifications that arise during endogenous T cell differentiation.…”

Section: Resultsmentioning

confidence: 60%

“…CD19-CAR T cells derived from the less-differentiated central memory T cell subset have been reported to exhibit greater proliferation, contributing to the enhanced survival in pre-clinical murine tumor models (Sommermeyer et al, 2016). In patients receiving CD19-CAR T cell therapy, the pre-manufactured T cell population with higher proportions of the less-differentiated T cell subsets (naive, Tscm and Tcm) was associated with CAR T cell persistence beyond 6 months (Chen et al, 2021). Furthermore, it has recently been shown that CD19-CAR T cell infusion products enriched for gene expression signatures indicative of T cell exhaustion have poor expansion after infusion into patients (Deng et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

CD19-CAR T cells undergo exhaustion DNA methylation programming in patients with acute lymphoblastic leukemia

et al. 2021

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“…Another study by Garfall and colleagues also highlighted that higher frequencies of CD8 + CD45RO - CD27 + cells in the leukapheresis product of patients with MM correlated with more proliferation and better CTT responses ( 40 ). Increased frequencies of T N ( 38 ), T CM ( 41 ) and/or T SCM cells ( 42 ) appear to correlate with improved engraftment and/or tumour control in adoptive cell transfer models, probably because they have functional advantages compared to more differentiated, less proliferative subsets. For example, T N cells have been shown to possess longer telomeres, more robust proliferative capacity and generate more functional cells ( 38 ).…”

Section: Lessons From Ctt Biologymentioning

confidence: 99%

T Cell Fitness and Autologous CAR T Cell Therapy in Haematologic Malignancy

et al. 2021

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A range of emerging therapeutic approaches for the treatment of cancer aim to induce or augment endogenous T cell responses. Chimeric antigen receptor (CAR) T cell therapy (CTT) is one such approach that utilises the patient’s own T cells, engineered ex vivo to target cell surface antigens, to eliminate haematological malignancies. Despite mediating high rates of responses in some clinical trials, this approach can be limited by dysfunctional T cells if they are present at high frequencies either in the starting material from the patient or the CAR T cell product. The fitness of an individual’s T cells, driven by age, chronic infection, disease burden and cancer treatment, is therefore likely to be a crucial limiting factor of CTT. Currently, T cell dysfunction and its impact on CTT is not specifically quantified when patients are considering the therapy. Here, we review our current understanding of T cell fitness for CTT, how fitness may be impacted by age, chronic infection, malignancy, and treatment. Finally, we explore options to specifically tailor clinical decision-making and the CTT protocol for patients with more extensive dysfunction to improve treatment efficacy. A greater understanding of T cell fitness throughout a patient’s treatment course could ultimately be used to identify patients likely to achieve favourable CTT outcomes and improve methods for T cell collection and CTT delivery.

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Integrative Bulk and Single-Cell Profiling of Premanufacture T-cell Populations Reveals Factors Mediating Long-Term Persistence of CAR T-cell Therapy

Cited by 127 publications

References 53 publications

Signaling pathways in the regulation of cytokine release syndrome in human diseases and intervention therapy

Signaling pathways in the regulation of cytokine release syndrome in human diseases and intervention therapy

CD19-CAR T cells undergo exhaustion DNA methylation programming in patients with acute lymphoblastic leukemia

T Cell Fitness and Autologous CAR T Cell Therapy in Haematologic Malignancy

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