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      Low-dose carboplatin modifies the tumor microenvironment to augment CAR T cell efficacy in human prostate cancer models

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          Abstract

          Chimeric antigen receptor (CAR) T cells have transformed the treatment landscape for hematological malignancies. However, CAR T cells are less efficient against solid tumors, largely due to poor infiltration resulting from the immunosuppressive nature of the tumor microenvironment (TME). Here, we assessed the efficacy of Lewis Y antigen (Le Y)-specific CAR T cells in patient-derived xenograft (PDX) models of prostate cancer. In vitro, Le Y CAR T cells directly killed organoids derived from androgen receptor (AR)-positive or AR-null PDXs. In vivo, although Le Y CAR T cells alone did not reduce tumor growth, a single prior dose of carboplatin reduced tumor burden. Carboplatin had a pro-inflammatory effect on the TME that facilitated early and durable CAR T cell infiltration, including an altered cancer-associated fibroblast phenotype, enhanced extracellular matrix degradation and re-oriented M1 macrophage differentiation. In a PDX less sensitive to carboplatin, CAR T cell infiltration was dampened; however, a reduction in tumor burden was still observed with increased T cell activation. These findings indicate that carboplatin improves the efficacy of CAR T cell treatment, with the extent of the response dependent on changes induced within the TME.

          Abstract

          Although CAR T therapy has greatly improved the therapeutic prospects for haematological malignancies, it is not yet widely used for solid tumors, such as prostate cancer. Here, using prostate cancer patient-derived xenografts, the authors demonstrate the efficacy of CAR T cells specific for Lewis Y antigen when combined with low-dose carboplatin.

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          Most cited references49

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          Fiji: an open-source platform for biological-image analysis.

          Fiji is a distribution of the popular open-source software ImageJ focused on biological-image analysis. Fiji uses modern software engineering practices to combine powerful software libraries with a broad range of scripting languages to enable rapid prototyping of image-processing algorithms. Fiji facilitates the transformation of new algorithms into ImageJ plugins that can be shared with end users through an integrated update system. We propose Fiji as a platform for productive collaboration between computer science and biology research communities.
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            Integrating single-cell transcriptomic data across different conditions, technologies, and species

            Computational single-cell RNA-seq (scRNA-seq) methods have been successfully applied to experiments representing a single condition, technology, or species to discover and define cellular phenotypes. However, identifying subpopulations of cells that are present across multiple data sets remains challenging. Here, we introduce an analytical strategy for integrating scRNA-seq data sets based on common sources of variation, enabling the identification of shared populations across data sets and downstream comparative analysis. We apply this approach, implemented in our R toolkit Seurat (http://satijalab.org/seurat/), to align scRNA-seq data sets of peripheral blood mononuclear cells under resting and stimulated conditions, hematopoietic progenitors sequenced using two profiling technologies, and pancreatic cell 'atlases' generated from human and mouse islets. In each case, we learn distinct or transitional cell states jointly across data sets, while boosting statistical power through integrated analysis. Our approach facilitates general comparisons of scRNA-seq data sets, potentially deepening our understanding of how distinct cell states respond to perturbation, disease, and evolution.
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              Chimeric antigen receptor T cells for sustained remissions in leukemia.

              Relapsed acute lymphoblastic leukemia (ALL) is difficult to treat despite the availability of aggressive therapies. Chimeric antigen receptor-modified T cells targeting CD19 may overcome many limitations of conventional therapies and induce remission in patients with refractory disease. We infused autologous T cells transduced with a CD19-directed chimeric antigen receptor (CTL019) lentiviral vector in patients with relapsed or refractory ALL at doses of 0.76×10(6) to 20.6×10(6) CTL019 cells per kilogram of body weight. Patients were monitored for a response, toxic effects, and the expansion and persistence of circulating CTL019 T cells. A total of 30 children and adults received CTL019. Complete remission was achieved in 27 patients (90%), including 2 patients with blinatumomab-refractory disease and 15 who had undergone stem-cell transplantation. CTL019 cells proliferated in vivo and were detectable in the blood, bone marrow, and cerebrospinal fluid of patients who had a response. Sustained remission was achieved with a 6-month event-free survival rate of 67% (95% confidence interval [CI], 51 to 88) and an overall survival rate of 78% (95% CI, 65 to 95). At 6 months, the probability that a patient would have persistence of CTL019 was 68% (95% CI, 50 to 92) and the probability that a patient would have relapse-free B-cell aplasia was 73% (95% CI, 57 to 94). All the patients had the cytokine-release syndrome. Severe cytokine-release syndrome, which developed in 27% of the patients, was associated with a higher disease burden before infusion and was effectively treated with the anti-interleukin-6 receptor antibody tocilizumab. Chimeric antigen receptor-modified T-cell therapy against CD19 was effective in treating relapsed and refractory ALL. CTL019 was associated with a high remission rate, even among patients for whom stem-cell transplantation had failed, and durable remissions up to 24 months were observed. (Funded by Novartis and others; CART19 ClinicalTrials.gov numbers, NCT01626495 and NCT01029366.).
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                Author and article information

                Contributors
                renea.taylor@monash.edu
                gail.risbridger@monash.edu
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                2 September 2023
                2 September 2023
                2023
                : 14
                : 5346
                Affiliations
                [1 ]GRID grid.1002.3, ISNI 0000 0004 1936 7857, Prostate Cancer Research Group, Monash Biomedicine Discovery Institute, Cancer Program, Department of Anatomy and Developmental Biology, , Monash University, ; Clayton, VIC 3800 Australia
                [2 ]GRID grid.1055.1, ISNI 0000000403978434, Cancer Immunology Program, Cancer Research Division, , Peter MacCallum Cancer Centre, ; Melbourne, VIC 3000 Australia
                [3 ]GRID grid.1008.9, ISNI 0000 0001 2179 088X, Sir Peter MacCallum Department of Oncology, , The University of Melbourne, ; Parkville, VIC 3010 Australia
                [4 ]GRID grid.1002.3, ISNI 0000 0004 1936 7857, Prostate Cancer Research Group, Monash Biomedicine Discovery Institute, Cancer Program, Department of Physiology, , Monash University, ; Clayton, VIC 3800 Australia
                [5 ]GRID grid.1055.1, ISNI 0000000403978434, Cancer Research Division, , Peter MacCallum Cancer Centre, ; Melbourne, VIC 3000 Australia
                [6 ]GRID grid.1055.1, ISNI 0000000403978434, Computational Cancer Biology Program, , Peter MacCallum Cancer Centre, ; Melbourne, VIC 3000 Australia
                [7 ]GRID grid.1055.1, ISNI 0000000403978434, Department of Pathology, , Peter MacCallum Cancer Centre, ; Melbourne, Victoria Australia
                [8 ]GRID grid.1055.1, ISNI 0000000403978434, Department of Medical Oncology, , Peter MacCallum Cancer Centre, ; Melbourne, VIC 3000 Australia
                [9 ]GRID grid.1024.7, ISNI 0000000089150953, Queensland Bladder Cancer Initiative, School of Biomedical Science, Faculty of Health, , Queensland University of Technology, ; Brisbane, QLD 4102 Australia
                [10 ]GRID grid.1024.7, ISNI 0000000089150953, Australian Prostate Cancer Research Center, School of Biomedical Science, Faculty of Health, , Queensland University of Technology, ; Brisbane, QLD 4102 Australia
                [11 ]GRID grid.412744.0, ISNI 0000 0004 0380 2017, Department of Urology, , Princess Alexandra Hospital, ; Brisbane, QLD 4102 Australia
                [12 ]GRID grid.1055.1, ISNI 0000000403978434, Molecular Imaging and Therapeutic Nuclear Medicine, , Peter MacCallum Cancer Centre, ; Melbourne, VIC 3000 Australia
                [13 ]GRID grid.1055.1, ISNI 0000000403978434, Prostate Cancer Theranostics and Imaging Centre of Excellence (ProsTIC), , Peter MacCallum Cancer Centre, ; Melbourne, VIC 3000 Australia
                Author information
                http://orcid.org/0000-0003-4416-7040
                http://orcid.org/0000-0001-7350-5622
                http://orcid.org/0000-0002-2729-5887
                http://orcid.org/0000-0002-5303-9561
                http://orcid.org/0000-0003-2609-2380
                http://orcid.org/0000-0003-3089-4028
                Article
                40852
                10.1038/s41467-023-40852-3
                10475084
                37660083
                3619cb68-5d3e-457b-b6dc-5d3cdcd02b01
                © Springer Nature Limited 2023

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 6 September 2022
                : 11 August 2023
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100000925, Department of Health | National Health and Medical Research Council (NHMRC);
                Award ID: APP1102752
                Award ID: APP1136680
                Award ID: APP1102752
                Award ID: APP2011391
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100008018, Victorian Cancer Agency (VCA);
                Award ID: MCRF15023
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100008719, Movember Foundation (Movember);
                Funded by: FundRef https://doi.org/10.13039/501100000951, Cancer Council Victoria;
                Award ID: TP834128
                Award Recipient :
                Categories
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                © Springer Nature Limited 2023

                Uncategorized
                cancer microenvironment,tumour immunology
                Uncategorized
                cancer microenvironment, tumour immunology

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