Treatment of aggressive T-cell lymphoma/leukemia with anti-CD4 CAR T cells

Feng, Jia; Xu, Hai-chan; Cinquina, Andrew; Wu, Zehua; Zhang, Wenli; Sun, Lihua; Chen, Qi; Liu, Tian; Song, Lixin; Pinz, Kevin G.; Wada, M.; Jiang, Xun; Hanes, William; Ma, Yupo; Zhang, Hongyu

doi:10.3389/fimmu.2022.997482

Cited by 13 publications

(3 citation statements)

References 53 publications

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“…Our data revealed that the high expression of CD4 increases the risk of relapse and death (Figure 3). Recently, preclinical studies and a Phase I clinical trial reported that CD4 CAR has cytotoxic effects against T cell malignancies, creating an opportunity to treat cases via the over-expression of this gene [62][63][64].…”

Section: Promising Therapeutic Target Genesmentioning

confidence: 99%

Transcriptome Analysis in Mexican Adults with Acute Lymphoblastic Leukemia

Cruz-Miranda,

Olarte-Carrillo,

Bárcenas-López

et al. 2024

IJMS

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Acute lymphoblastic leukemia (ALL) represents around 25% of adult acute leukemias. Despite the increasing improvement in the survival rate of ALL patients during the last decade, the heterogeneous clinical and molecular features of this malignancy still represent a major challenge for treatment and achieving better outcomes. To identify aberrantly expressed genes in bone marrow (BM) samples from adults with ALL, transcriptomic analysis was performed using Affymetrix Human Transcriptome Array 2.0 (HTA 2.0). Differentially expressed genes (DEGs) (±2-fold change, p-value < 0.05, and FDR < 0.05) were detected using the Transcriptome Analysis Console. Gene Ontology (GO), Database for Annotation, Visualization, and Integrated Discovery (DAVID), and Ingenuity Pathway Analysis (IPA) were employed to identify gene function and define the enriched pathways of DEGs. The protein–protein interactions (PPIs) of DEGs were constructed. A total of 871 genes were differentially expressed, and DNTT, MYB, EBF1, SOX4, and ERG were the top five up-regulated genes. Meanwhile, the top five down-regulated genes were PTGS2, PPBP, ADGRE3, LUCAT1, and VCAN. An association between ERG, CDK6, and SOX4 expression levels and the probability of relapse and death was observed. Regulation of the immune system, immune response, cellular response to stimulus, as well as apoptosis signaling, inflammation mediated by chemokines and cytokines, and T cell activation were among the most altered biological processes and pathways, respectively. Transcriptome analysis of ALL in adults reveals a group of genes consistently associated with hematological malignancies and underscores their relevance in the development of ALL in adults.

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Section: Promising Therapeutic Target Genesmentioning

confidence: 99%

Transcriptome Analysis in Mexican Adults with Acute Lymphoblastic Leukemia

Cruz-Miranda,

Olarte-Carrillo,

Bárcenas-López

et al. 2024

IJMS

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“…Although the permanent downregulation of certain cell types such as B cells in case of anti-CD19/anti-BCMA-CAR T cells results in per se well tolerable hypogammaglobulinaemia, which can be reconstituted by intravenous or subcutaneous IgG application, 32 patients with permanent B cell depletion showed increased risks of infections and, for example, had an inferior outcome when diagnosed with COVID-19. 33 Downregulation of CD4 + T cells, a central driver in several autoimmune diseases, by CD4-directed CAR immune cells as used in preclinical studies [34][35][36] is even more severe, since it leads (similar to HIV infection) to impairment of cellular immunity and opportunistic infections, 37 making the transient CAR T approach even more attractive.…”

Section: Transient Car T Cells For Safe Therapy In Autoimmune Diseases?mentioning

confidence: 99%

CAR T cells for treating autoimmune diseases

Blache,

Tretbar,

Koehl

et al. 2023

RMD Open

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Autoimmune disorders occur when immune cells go wrong and attack the body’s own tissues. Currently, autoimmune disorders are largely treated by broad immunosuppressive agents and blocking antibodies, which can manage the diseases but often are not curative. Thus, there is an urgent need for advanced therapies for patients suffering from severe and refractory autoimmune diseases, and researchers have considered cell therapy as potentially curative approach for several decades. In the wake of its success in cancer therapy, adoptive transfer of engineered T cells modified with chimeric antigen receptors (CAR) for target recognition could now become a therapeutic option for some autoimmune diseases. Here, we review the ongoing developments with CAR T cells in the field of autoimmune disorders. We will cover first clinical results of applying anti-CD19 and anti-B cell maturation antigen CAR T cells for B cell elimination in systemic lupus erythematosus, refractory antisynthetase syndrome and myasthenia gravis, respectively. Furthermore, in preclinical models, researchers have also developed chimeric autoantibody receptor T cells that can eliminate individual B cell clones producing specific autoantibodies, and regulatory CAR T cells that do not eliminate autoreactive immune cells but dampen their wrong activation. Finally, we will address safety and manufacturing aspects for CAR T cells and discuss mRNA technologies and automation concepts for ensuring the future availability of safe and efficient CAR T cell products.

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“…To circumvent CD7-related fratricide, researchers are also focusing on finding more suitable biological markers to differentiate between malignant, healthy, and therapeutic T cells. Recent studies have investigated the T-cell receptor β-chain constant domains TRBC1 and TRBC2 ( 24 , 59 ), CD1a ( 60 ), CD2 ( 61 ), CD4 ( 62 ), CD5 ( 63 , 64 ), CD21 ( 65 ), CD26 ( 66 ), CD38 ( 67 ), CD99 ( 68 , 69 ), CCR9 ( 70 ), the natural CD7 ligand SECTM-1 ( 71 ), and the dual targeting of CD38 and LMP1 ( 72 ). Shaw et al.…”

Section: T-cell Malignanciesmentioning

confidence: 99%

Broadening the horizon: potential applications of CAR-T cells beyond current indications

Karsten,

Matrisch,

Cichutek

et al. 2023

Front. Immunol.

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Engineering immune cells to treat hematological malignancies has been a major focus of research since the first resounding successes of CAR-T-cell therapies in B-ALL. Several diseases can now be treated in highly therapy-refractory or relapsed conditions. Currently, a number of CD19- or BCMA-specific CAR-T-cell therapies are approved for acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), multiple myeloma (MM), and follicular lymphoma (FL). The implementation of these therapies has significantly improved patient outcome and survival even in cases with previously very poor prognosis. In this comprehensive review, we present the current state of research, recent innovations, and the applications of CAR-T-cell therapy in a selected group of hematologic malignancies. We focus on B- and T-cell malignancies, including the entities of cutaneous and peripheral T-cell lymphoma (T-ALL, PTCL, CTCL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), classical Hodgkin-Lymphoma (HL), Burkitt-Lymphoma (BL), hairy cell leukemia (HCL), and Waldenström’s macroglobulinemia (WM). While these diseases are highly heterogenous, we highlight several similarly used approaches (combination with established therapeutics, target depletion on healthy cells), targets used in multiple diseases (CD30, CD38, TRBC1/2), and unique features that require individualized approaches. Furthermore, we focus on current limitations of CAR-T-cell therapy in individual diseases and entities such as immunocompromising tumor microenvironment (TME), risk of on-target-off-tumor effects, and differences in the occurrence of adverse events. Finally, we present an outlook into novel innovations in CAR-T-cell engineering like the use of artificial intelligence and the future role of CAR-T cells in therapy regimens in everyday clinical practice.

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Treatment of aggressive T-cell lymphoma/leukemia with anti-CD4 CAR T cells

Cited by 13 publications

References 53 publications

Transcriptome Analysis in Mexican Adults with Acute Lymphoblastic Leukemia

Transcriptome Analysis in Mexican Adults with Acute Lymphoblastic Leukemia

CAR T cells for treating autoimmune diseases

Broadening the horizon: potential applications of CAR-T cells beyond current indications

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