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      Complete remission of advanced pancreatic cancer induced by claudin18.2-targeted CAR-T cell therapy: a case report

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          Abstract

          Pancreatic cancer (PC) is one of the most malignant tumors in digestive system due to its highly invasive and metastatic properties. At present, conventional treatment strategies for PC show the limited clinical efficacy. Therefore, novel effective therapeutic strategies are urgently needed. Here, we report a case of complete remission of advanced PC induced by claudin18.2-targeted CAR-T cell therapy. The patient was a 72-year-old man who was diagnosed with pancreatic ductal adenocarcinoma 2 years ago, and he experienced tumor recurrence and multiple metastases after pancreaticoduodenectomy and multi-line chemotherapies, including liver, peritoneum, and cervical lymph node metastases. Then, the patient was referred to our department for further treatment of metastatic PC, and he was enrolled in a clinical trial of claudin18.2-targeted CAR-T cell therapy. After lymphodepleting chemotherapy, the patient received claudin18.2-targeted CAR-T cell infusion at a dose of 1.2 × 10 6 cells/kg on November 21, 2022. During CAR-T cell therapy, the patient experienced grade 2 cytokine release syndrome (CRS) and gastric mucosa injury, which were controlled by tocilizumab and conventional symptomatic and supportive treatment. The patient achieved a complete response (CR) 1 month after claudin18.2-targeted CAR-T cell therapy, and remained in clinical remission for 8 months. Unfortunately, the patient experienced claudin18.2-negative relapse in July, 2023. Despite antigen-negative relapse after claudin18.2-targeted CAR-T cell infusion, the patient achieved sustained remission for 8 months, which indicates that claudin18.2-targeted CAR-T cell therapy is an extremely effective therapeutic strategy for the treatment of advanced PC.

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          Most cited references23

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          Pancreatic Cancer : A Review

          Pancreatic ductal adenocarcinoma (PDAC) is a relatively uncommon cancer, with approximately 60 430 new diagnoses expected in 2021 in the US. The incidence of PDAC is increasing by 0.5% to 1.0% per year, and it is projected to become the second-leading cause of cancer-related mortality by 2030.
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            Distant Metastasis Occurs Late during the Genetic Evolution of Pancreatic Cancer

            Summary Metastasis, the dissemination and growth of neoplastic cells in an organ distinct from that in which they originated 1 2 , is the most common cause of death in cancer patients. This is particularly true for pancreatic cancers, where most patients are diagnosed with metastatic disease and few show a sustained response to chemo- or radiation therapy 3 . Whether the dismal prognosis of patients with pancreatic cancer compared to patients with other types of cancer is a result of late diagnosis or early dissemination of disease to distant organs is not known. Here we rely on data generated by sequencing the genomes of seven pancreatic cancer metastases to evaluate the clonal relationships among primary and metastatic cancers. We find that clonal populations that give rise to distant metastases are represented within the primary carcinoma, but these clones are genetically evolved from the original parental, non-metastatic clone. Thus, genetic heterogeneity of metastases reflects that within the primary carcinoma. A quantitative analysis of the timing of the genetic evolution of pancreatic cancer was performed, indicating at least a decade between the occurrence of the initiating mutation and the birth of the parental, non-metastatic founder cell. At least five more years are required for the acquisition of metastatic ability and patients die an average of two years thereafter. These data provide novel insights into the genetic features underlying pancreatic cancer progression and define a broad time window of opportunity for early detection to prevent deaths from metastatic disease.
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              Activity of Mesothelin-Specific Chimeric Antigen Receptor T Cells Against Pancreatic Carcinoma Metastases in a Phase 1 Trial.

              Pancreatic ductal adenocarcinoma (PDAC) is resistant to T-cell-mediated immunotherapy. We engineered T cells to transiently express a messenger RNA encoding a chimeric antigen receptor (CAR) specific for mesothelin, a protein that is overexpressed by PDAC cells. We performed a phase I study to evaluate the safety and efficacy of adoptive cell therapy with autologous mesothelin-specific CAR T cells (CARTmeso cells) in 6 patients with chemotherapy-refractory metastatic PDAC. Patients were given intravenous CARTmeso cells 3 times weekly for 3 weeks. None of the patients developed cytokine release syndrome or neurologic symptoms and there were no dose-limiting toxicities. Disease stabilized in 2 patients, with progression-free survival times of 3.8 and 5.4 months. We used 18F-2-fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography/computed tomography imaging to monitor the metabolic active volume (MAV) of individual tumor lesions. The total MAV remained stable in 3 patients and decreased by 69.2% in 1 patient with biopsy-proven mesothelin expression; in this patient, all liver lesions had a complete reduction in FDG uptake at 1 month compared with baseline, although there was no effect on the primary PDAC. Transient CAR expression was detected in patients' blood after infusion and led to expansion of new immunoglobulin G proteins. Our results provide evidence for the potential antitumor activity of messenger RNA CARTmeso cells, as well as PDAC resistance to the immune response.
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                Author and article information

                Contributors
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                URI : https://loop.frontiersin.org/people/2611648Role: Role: Role: Role:
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                URI : https://loop.frontiersin.org/people/2612098Role: Role: Role:
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                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                29 February 2024
                2024
                : 15
                : 1325860
                Affiliations
                [1] 1 Department of Hematology and Oncology, Shenzhen University General Hospital, International Cancer Center, Shenzhen Key Laboratory, Hematology Institution of Shenzhen University, Shenzhen University Health Science Center, Shenzhen University , Shenzhen, China
                [2] 2 Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical School , Shenzhen, China
                [3] 3 R&D Department, Shenzhen Haoshi Biotechnology Co., Ltd , Shenzhen, China
                [4] 4 Biomedical Laboratory, Shenzhen University-Haoshi Cell Therapy Institute , Shenzhen, China
                Author notes

                Edited by: Simon Völkl, University Hospital Erlangen, Germany

                Reviewed by: Amar Yeware, The Pennsylvania State University (PSU), United States

                Dongxu Wang, Jilin University, China

                *Correspondence: Li Yu, yuli@ 123456szu.edu.cn ; Yisheng Li, ysli@ 123456haoshibio.com

                †These authors have contributed equally to this work and share first authorship

                Article
                10.3389/fimmu.2024.1325860
                10937427
                38487523
                cc6a266c-6882-4a6c-8e35-82e3c3f78019
                Copyright © 2024 Zhong, Zhang, Guo, Gao, Zhao, Liu, Chen, Qiao, Yu, Wang, Li and Yu

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 22 October 2023
                : 13 February 2024
                Page count
                Figures: 4, Tables: 1, Equations: 0, References: 23, Pages: 7, Words: 3473
                Funding
                Funded by: National Natural Science Foundation of China , doi 10.13039/501100001809;
                Award ID: 82030076, 82070161, 81970151, 81670162 and 81870134
                Funded by: Science and Technology Foundation of Shenzhen City , doi 10.13039/100017380;
                Award ID: JCYJ20190808163601776, JCYJ20200109113810154
                Funded by: Shenzhen Key Laboratory Fund , doi 10.13039/501100017621;
                Award ID: ZDSYS20200811143757022
                Funded by: Sanming Project of Medicine in Shenzen Municipality , doi 10.13039/501100012151;
                Award ID: SZSM202111004
                The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by Chinese National Major Project for New Drug Innovation (2019ZX09201002003), National Natural Science Foundation of China (82030076, 82070161, 81970151, 81670162 and 81870134), Shenzhen Science and Technology Foundation (JCYJ20190808163601776, JCYJ20200109113810154), Shenzhen Key Laboratory Foundation (ZDSYS20200811143757022), and Sanming Project of Medicine in Shenzhen (SZSM202111004).
                Categories
                Immunology
                Case Report
                Custom metadata
                Cancer Immunity and Immunotherapy

                Immunology
                car-t cell therapy,advanced pancreatic cancer,claudin18.2,complete remission,antigen-negative relapse

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