The Great War of Today: Modifications of CAR-T Cells to Effectively Combat Malignancies

Zhylko, Andriy; Winiarska, Magdalena; Graczyk-Jarzynka, Agnieszka

doi:10.3390/cancers12082030

Cited by 21 publications

(19 citation statements)

References 224 publications

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“…Despite all the recent advances in cancer research, including immune checkpoint targeting and chimeric antigen receptors (CARs), metastatic UM continues to elude the therapy [ 20 , 23 , 56 , 57 ]. Curative treatments are scarce and can be rarely achieved, urging for the development of novel therapies.…”

Section: Discussionmentioning

confidence: 99%

Bioinformatic Analysis Reveals Central Role for Tumor-Infiltrating Immune Cells in Uveal Melanoma Progression

Lachota

Lennikov

Malmberg

et al. 2021

Journal of Immunology Research

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Tumor-infiltrating immune cells are capable of effective cancer surveillance, and their abundance is linked to better prognosis in numerous tumor types. However, in uveal melanoma (UM), extensive immune infiltrate is associated with poor survival. This study aims to decipher the role of different tumor-infiltrating cell subsets in UM in order to identify potential targets for future immunotherapeutic treatment. We have chosen the TCGA-UVM cohort as a training dataset and GSE22138 as a testing dataset by mining publicly available databases. The abundance of 22 immune cell types was estimated using CIBERSORTx. Then, to determine the significance of tumor-infiltrating cell subsets in UM, we built a multicell type prognostic signature, which was validated in the testing cohort. The created signature was built upon the negative prognostic role of CD8+ T cells and M0 macrophages and the positive role of neutrophils. Based on the created signature score, we divided the patients into low- and high-risk groups. Kaplan-Meier, Cox, and ROC analyses demonstrated superior performance of our risk score compared to either clinical or pathologic characteristics of both cohorts. Further, we found the molecular pathways associated with cancer immunoevasion and metastasis to be enriched in the high-risk group, explaining both the lack of adequate immune surveillance despite increased infiltration of CD8+ T cells as well as the higher metastatic potential. Genes associated with tryptophan metabolism (IDO1 and KYNU) and metalloproteinases were among the most differentially expressed between the high- and low-risk groups. Our correlation analyses interpreted in context of published in vitro data strongly suggest the central role of CD8+ T cells in shifting the UM tumor microenvironment towards suppressive and metastasis-promoting. Therefore, we propose further investigations of IDO1 and metalloproteinases as novel targets for immunotherapy in lymphocyte-rich metastatic UM patients.

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Section: Discussionmentioning

confidence: 99%

Bioinformatic Analysis Reveals Central Role for Tumor-Infiltrating Immune Cells in Uveal Melanoma Progression

Lachota

Lennikov

Malmberg

et al. 2021

Journal of Immunology Research

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“…Adoptive cell transfer with T or NK cells engineered to express chimeric antigen receptors is one of the particularly promising strategies to fight cancer. CAR is a synthetic molecule composed of an extracellular domain (scFv), that allows surface antigen recognition, combined with intracellular signaling domain derived from physiological T cell receptor (CD3ζ chain), and various co-stimulatory domains (e.g., CD28, 4-1BB, ICOS, OX40) (reviewed in [ 132 , 133 , 134 , 135 , 136 , 137 ]). CARs can recognize a wide range of cell surface antigens, including glycolipids, carbohydrates, and proteins derived from tumors in a non-MHC-restricted manner which helps overcome MHC downregulation as a mechanism of tumor escape.…”

Section: Immunotherapeutic Strategies In Breast Cancermentioning

confidence: 99%

The Immune Landscape of Breast Cancer: Strategies for Overcoming Immunotherapy Resistance

Retecki

Seweryn

Graczyk-Jarzynka

et al. 2021

Cancers

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Breast cancer (BC) has traditionally been considered to be not inherently immunogenic and insufficiently represented by immune cell infiltrates. Therefore, for a long time, it was thought that the immunotherapies targeting this type of cancer and its microenvironment were not justified and would not bring benefits for breast cancer patients. Nevertheless, to date, a considerable number of reports have indicated tumor-infiltrating lymphocytes (TILs) as a prognostic and clinically relevant biomarker in breast cancer. A high TILs expression has been demonstrated in primary tumors, of both, HER2-positive BC and triple-negative (TNBC), of patients before treatment, as well as after treatment with adjuvant and neoadjuvant chemotherapy. Another milestone was reached in advanced TNBC immunotherapy with the help of the immune checkpoint inhibitors directed against the PD-L1 molecule. Although those findings, together with the recent developments in chimeric antigen receptor T cell therapies, show immense promise for significant advancements in breast cancer treatments, there are still various obstacles to the optimal activity of immunotherapeutics in BC treatment. Of these, the immunosuppressive tumor microenvironment constitutes a key barrier that greatly hinders the success of immunotherapies in the most aggressive types of breast cancer, HER2-positive and TNBC. Therefore, the improvement of the current and the demand for the development of new immunotherapeutic strategies is strongly warranted.

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“…Novel CAR constructs are being continuously developed, which can possess altered intracellular co-stimulatory domains and/or targeting domains. Latter can consist of different molecules, such as nanobodies, designed ankyrin repeat proteins (DARPins), ligands, or receptors instead of scFvs [4][5][6][7]. Furthermore, the so-called adapter CARs have been developed by splitting antigen recognition and CAR-immune cell activation.…”

Section: Background On Chimeric Antigen Receptor (Car) Therapymentioning

confidence: 99%

Current status and perspective of CAR-T and CAR-NK cell therapy trials in Germany

2021

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Chimeric antigen receptor (CAR)-T cell therapies are on the verge of becoming powerful immunotherapeutic tools for combating hematological diseases confronted with pressing medical needs. Lately, CAR-NK cell therapies have also come into focus as novel therapeutic options to address hurdles related to CAR-T cell therapies, such as therapy-induced side effects. Currently, more than 500 CAR-T and 17 CAR-NK cell trials are being conducted worldwide including the four CAR-T cell products Kymriah, Yescarta, Tecartus and Breyanzi, which are already available on the market. Most CAR-T cell-based gene therapy products that are under clinical evaluation consist of autologous enriched T cells, whereas CAR-NK cell-based approaches can be generated from allogeneic donors. Besides modification based on a second-generation CAR, more advanced CAR-immune cell therapeutics are being tested, which utilize precise insertion of genes to circumvent graft-versus-host disease (GvHD) or employ a dual targeting approach and adapter CARs in order to avoid therapy resistance caused by antigen loss. In this review, we are going to take a closer look at the commercial CAR-T cell therapies, as well as on CAR-T and CAR-NK cell products, which are currently under evaluation in clinical trials, that are being conducted in Germany.

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The Great War of Today: Modifications of CAR-T Cells to Effectively Combat Malignancies

Cited by 21 publications

References 224 publications

Bioinformatic Analysis Reveals Central Role for Tumor-Infiltrating Immune Cells in Uveal Melanoma Progression

Bioinformatic Analysis Reveals Central Role for Tumor-Infiltrating Immune Cells in Uveal Melanoma Progression

The Immune Landscape of Breast Cancer: Strategies for Overcoming Immunotherapy Resistance

Current status and perspective of CAR-T and CAR-NK cell therapy trials in Germany

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