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Sato-Dahlman M, Miura Y, Hajeri P, Roach B, Jacobsen K, Yamamoto M. Systemic therapy with the infectivity-selective oncolytic adenovirus by targeting mesothelin. MOLECULAR THERAPY. ONCOLOGY 2025; 33:200967. [PMID: 40226846 PMCID: PMC11987630 DOI: 10.1016/j.omton.2025.200967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Revised: 03/09/2025] [Accepted: 03/12/2025] [Indexed: 04/15/2025]
Abstract
Treatment of advanced stage cancers is extremely challenging, and more effective systemic therapy is needed. Oncolytic adenoviruses (OAds) are one of the most promising anti-cancer agents. However, systemic delivery of OAd is challenging due to the low transduction in tumor cells caused by non-selective distribution and sequestration by non-target organs. To overcome this issue, we have previously generated a mesothelin (MSLN)-targeted OAd (AdML-VTIN). Here, we are reporting the potential of MSLN-targeted OAd as an agent for novel systemic treatment using MSLN-expressing lung and pancreatic cancer models. The in vivo biodistribution of AdML-VTIN after intravenous injection showed significantly lower liver sequestration compared to the wild type of OAd (AdML-5WT). By day 7, the intratumoral viral copy number of AdML-VTIN was significantly higher than that of AdML-5WT. For therapeutic efficacy, systemically injected AdML-VTIN exhibited statistically significant anti-tumor effects in both lung and pancreatic cancer xenograft tumor models. In addition, we tested the effect of preexisting immunity using human serum. In a neutralization assay, AdML-VTIN was more resistant to preexisting antibodies, compared to Ad5-WT. Interestingly, the hemagglutination profile of AdML-VTIN was also changed. Our results indicate that MSLN-targeted OAd has great potential to facilitate systemic therapy of advanced cancers.
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Affiliation(s)
- Mizuho Sato-Dahlman
- Department of Surgery, University of Minnesota, Minneapolis, MN, USA
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
| | - Yoshiaki Miura
- Department of Surgery, University of Minnesota, Minneapolis, MN, USA
| | | | - Brett Roach
- Department of Surgery, University of Minnesota, Minneapolis, MN, USA
| | - Kari Jacobsen
- Department of Surgery, University of Minnesota, Minneapolis, MN, USA
| | - Masato Yamamoto
- Department of Surgery, University of Minnesota, Minneapolis, MN, USA
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
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He Y, Kong J, Wang Z, Zhang Y, Qing T, Xie F, Chen T, Han J. Development of a novel molecular probe for visualizing mesothelin on the tumor via positron emission tomography. Eur J Nucl Med Mol Imaging 2025; 52:2605-2616. [PMID: 39878895 DOI: 10.1007/s00259-025-07087-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 01/12/2025] [Indexed: 01/31/2025]
Abstract
OBJECTIVES Mesothelin (MSLN) is an antigen that is overexpressed in various cancers, and its interaction with tumor-associated cancer antigen 125 plays a multifaceted role in tumor metastasis. The serum MSLN expression level can be detected using enzyme-linked immunosorbent assay; however, non-invasive visualization of its expression at the tumor site is currently lacking. Therefore, the aim of this study was to develop a molecular probe for imaging MSLN expression through positron emission tomography (PET). METHODS VHH 269-H4 was obtained via immunization of llama using a fragment of MSLN from residue 360 to residue 597. S-2-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) was conjugated to VHH 269-H4 to yield precursor NOTA 269-H4 for radiolabeling. The chelator-to-VHH ratio was determined by mass spectrometry. The binding kinetics of VHH 269-H4 and NOTA 269-H4 were measured by surface plasmon resonance. Flow cytometry was carried out using the anti-mesothelin monoclonal antibody Anetumab to select MSLN-positive and MSLN-negative cell lines. After radiolabeling, the radiochemical purity and in vitro stability were tested by radio-thin-layer chromatography and size exclusion chromatography, respectively. A saturation binding assay was conducted to measure the dissociation constant (Kd) of [68Ga]Ga-NOTA-269-H4. By mircoPET/CT imaging and biodistribution studies, the in vivo performances of the novel tracer were investigated in NCG mice bearing OVCAR-8, SKOV-3, or patient-derived xenografts. RESULTS VHH 269-H4 targeting MSLN was obtained with a Kd value of 0.3 nM. After conjugation, approximately 27% and 3.2% of VHH were coupled to one and two NOTA chelators, respectively. This yielded precursor NOTA 269-H4 with a Kd value of 1.1 nM. The radiochemistry was accomplished with moderate radiochemical yields (34 ± 14%, n = 9, decay-corrected). [68Ga]Ga-NOTA-269-H4 was obtained with high radiochemical purity (> 99%), and was stable after 90 min incubation at room temperature. The binding affinity of the radioligand towards MSLN was kept in the nanomolar range. Flow cytometry revealed that OVCAR-8 cells possess a high level of MSLN expression, while MSLN expression on SKOV-3 cells was negligible. Consistently, in microPET/CT imaging, [68Ga]Ga-NOTA-269-H4 demonstrated clear tumor visualization using NCG mice bearing OVCAR-8 xenografts, but no radioactivity accumulation was observed in SKOV-3 xenografts, suggesting a high specificity of the tracer in vivo. In biodistribution studies, [68Ga]Ga-NOTA-269-H4 displayed radioactivity accumulation of 2.93 ± 0.39%ID/g in OVCAR-8 xenografts at 30 min post-injection, and the highest tumor-to-blood ratio (~ 3) was achieved at 90 min post-injection. In NCG mice bearing patient-derived xenografts, [68Ga]Ga-NOTA-269-H4 was able to noninvasively detect MSLN expression via microPET/CT imaging. CONCLUSIONS To our knowledge, our studies achieved the first-time to non-invasively detect MSLN expression clearly using a single domain antibody fragment. To sum up, [68Ga]Ga-NOTA-269-H4 is a highly promising PET probe to visualize MSLN expression in vivo and holds great potential to monitor MSLN expression during tumor development.
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Affiliation(s)
- Yingfang He
- Institute of Radiation Medicine, Fudan University, Xietu Road 2094, Shanghai, 200032, China
| | - Jinping Kong
- Department of Physiology, School of Basic Medicine, Guizhou Medical University, Guiyang, 550009, China
| | - Ze Wang
- Institute of Radiation Medicine, Fudan University, Xietu Road 2094, Shanghai, 200032, China
| | - Yu Zhang
- Department of Translational Medicine, Zentera Therapeutics, 183 Hongqiao Road, Shanghai, China
| | - Tingting Qing
- Department of Translational Medicine, Zentera Therapeutics, 183 Hongqiao Road, Shanghai, China
| | - Fang Xie
- Department of Nuclear Medicine & PET center, Huashan Hospital, Fudan University, 200233, Shanghai, China
| | - Tengxiang Chen
- Department of Physiology, School of Basic Medicine, Guizhou Medical University, Guiyang, 550009, China.
| | - Junbin Han
- Institute of Radiation Medicine, Fudan University, Xietu Road 2094, Shanghai, 200032, China.
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de Testas de Folmont A, Fauvel A, Vacherot F, Soyeux P, Abdou A, Chouaib S, Terry S. Targeting Aggressive Prostate Carcinoma Cells with Mesothelin-CAR-T Cells. Biomedicines 2025; 13:1215. [PMID: 40427042 PMCID: PMC12109071 DOI: 10.3390/biomedicines13051215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2025] [Revised: 05/03/2025] [Accepted: 05/13/2025] [Indexed: 05/29/2025] Open
Abstract
Background: Advancing chimeric antigen receptor (CAR) T cell therapy for solid tumors remains a major challenge in cancer immunotherapy. Prostate cancer (PCa), particularly in its aggressive forms, may be a suitable target for CAR-T therapy given the range of associated tumor antigens. However, due to the high plasticity and heterogeneity of aggressive PCa and the complexity of the tumor environment, there is a need to broaden the repertoire of targetable antigens and deepen our understanding of CAR-T behavior in stressed microenvironmental conditions. Growing evidence supports mesothelin as a promising cancer-associated marker and a compelling target for CAR-T cell approaches in solid tumors. Objectives and Methods: Here, we employed gene expression datasets to investigate mesothelin expression in both primary and metastatic PCa tumors. Additionally, we evaluated mesothelin expression across various preclinical PCa models and assessed the therapeutic efficacy of second-generation mesothelin-targeted CAR-T (meso-CAR-T) cells under both normoxic and hypoxic conditions, with hypoxia as a representative tumor-associated stress condition. Results: Our results revealed a significant enrichment of mesothelin in 3-10% of metastatic prostate tumors, contrasting with its minimal expression in primary tumors. In line with these findings, we observed increased mesothelin expression in an aggressive variant of the 22Rv1 cell line, which displayed an epithelial-mesenchymal plasticity (EMP) phenotype. Meso-CAR-T cells demonstrated potent cytotoxicity and remarkable selectivity toward these carcinoma cells under both severe hypoxia (1% O2) or normoxia (21% O2), highlighting their ability to withstand metabolic stress within the tumor microenvironment. Conclusions: Our study underscores the potential of meso-CAR-T cells as a promising strategy for targeting specific subtypes of metastatic prostate cancer.
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Affiliation(s)
- Apolline de Testas de Folmont
- INSERM UMR 1186, Integrative Tumor Immunology and Immunotherapy, Gustave Roussy, University Paris-Saclay, 94805 Villejuif, France; (A.d.T.d.F.); (A.F.); (A.A.); (S.C.)
- INSERM U 932, Institut Curie, PSL Research University, 75005 Paris, France
| | - Angèle Fauvel
- INSERM UMR 1186, Integrative Tumor Immunology and Immunotherapy, Gustave Roussy, University Paris-Saclay, 94805 Villejuif, France; (A.d.T.d.F.); (A.F.); (A.A.); (S.C.)
| | - Francis Vacherot
- TRePCa, Université Paris Est Créteil, 94010 Creteil, France; (F.V.); (P.S.)
| | - Pascale Soyeux
- TRePCa, Université Paris Est Créteil, 94010 Creteil, France; (F.V.); (P.S.)
| | - Abdérémane Abdou
- INSERM UMR 1186, Integrative Tumor Immunology and Immunotherapy, Gustave Roussy, University Paris-Saclay, 94805 Villejuif, France; (A.d.T.d.F.); (A.F.); (A.A.); (S.C.)
| | - Salem Chouaib
- INSERM UMR 1186, Integrative Tumor Immunology and Immunotherapy, Gustave Roussy, University Paris-Saclay, 94805 Villejuif, France; (A.d.T.d.F.); (A.F.); (A.A.); (S.C.)
- Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman 4184, United Arab Emirates
| | - Stéphane Terry
- INSERM UMR 1186, Integrative Tumor Immunology and Immunotherapy, Gustave Roussy, University Paris-Saclay, 94805 Villejuif, France; (A.d.T.d.F.); (A.F.); (A.A.); (S.C.)
- Research Department, Inovarion, 75005 Paris, France
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Zhou X, Xiao L, Lai F, Chen W, Zhou C, Deng Y, Wang T, Xing S, Diao H, Tang M, Guo W, Luo E. Comprehensive overview of antibody drug-related clinical studies in gynecology: insights from ClinicalTrials.gov. Front Med (Lausanne) 2025; 12:1521587. [PMID: 40417700 PMCID: PMC12098050 DOI: 10.3389/fmed.2025.1521587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Accepted: 04/18/2025] [Indexed: 05/27/2025] Open
Abstract
Antibodies have been widely used globally over the past decade and play an increasingly important role in modern medicine. Notably, significant advancements have been achieved in the realm of gynecology, particularly in gynecological cancers. This study endeavors to present a thorough overview of antibody-related drug clinical studies in gynecology registered on ClinicalTrials.gov, focusing on the basic characteristics of trials, geographical distribution, administration routes, indications, and targets. The analysis indicates a rising prevalence of antibody-drug conjugates (ADCs), bispecific antibodies, and Fc-fusion proteins. This study will help develop new ideas for future research on antibodies in gynecology.
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Affiliation(s)
- Xiaoling Zhou
- Department of Pharmacy, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Li Xiao
- Department of Medical Affairs, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Fan Lai
- Department of Obstetrics, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Wei Chen
- Department of Traditional Chinese Medicine, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Congrong Zhou
- Department of Traditional Chinese Medicine, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yi Deng
- Department of Pharmacy, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Tao Wang
- Department of Obstetrics, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Shasha Xing
- Department of Good Clinical Practice, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Haoyang Diao
- Department of Good Clinical Practice, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Mi Tang
- Department of Good Clinical Practice, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Wenmei Guo
- Department of Good Clinical Practice, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Erdan Luo
- Department of Good Clinical Practice, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
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Jiang Q, Yu W, Ma J, Zhao M, Zou J, Mir S, Zhang J, Germain RN, Hassan R. Robust differentiation of NK cells from MSLN.CAR-IL-15-engineered human iPSCs with enhanced antitumor efficacy against solid tumors. SCIENCE ADVANCES 2025; 11:eadt9932. [PMID: 40315330 PMCID: PMC12047432 DOI: 10.1126/sciadv.adt9932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Accepted: 03/28/2025] [Indexed: 05/04/2025]
Abstract
Human induced pluripotent stem cells (iPSCs) offer a promising source for chimeric antigen receptor (CAR)-engineered natural killer (NK) products. However, complex iPSC-NK (iNK) manufacturing challenges clinical use. Here, we identified LiPSC-GR1.1 as a superior iPSC line for iNK production. By engineering LiPSC-GR1.1 with a mesothelin (MSLN)-targeting CAR and interleukin-15 (IL-15), we achieved robust differentiation of iPSCs into mature activated iNK cells with enhanced tumor killing efficacy, superior tumor homing, and vigorous proliferation. Single-cell transcriptomic analysis revealed that transforming growth factor-β (TGF-β)-producing tumor cells up-regulated major histocompatibility complex molecules and down-regulated MSLN post-CAR-IL-15 iNK treatment. Tumor-infiltrating CAR-IL-15 iNK cells exhibited high levels of CAR, IL-15, and NK-activating receptors, negligible checkpoint exhaustion markers, and extremely low levels of NK suppressive factors CISH, TGFBR2, and BATF, enabling them to sustain activation, metabolic fitness, and effective tumor killing within TGF-β-rich hypoxic tumor microenvironment. Overall, we developed MSLN.CAR-IL-15-engineered GR1.1-iNK therapy with enhanced antitumor efficacy for solid tumor treatment.
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Affiliation(s)
- Qun Jiang
- Thoracic and GI Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Weiming Yu
- Lymphocyte Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD, USA
- Center for Advanced Tissue Imaging, NIAID and NCI, NIH, Bethesda, MD, USA
| | - James Ma
- University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Mingming Zhao
- Thoracic and GI Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Jizhong Zou
- iPSC Core, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA
| | - Sameer Mir
- Thoracic and GI Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Jingli Zhang
- Thoracic and GI Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Ronald N. Germain
- Lymphocyte Biology Section, Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD, USA
- Center for Advanced Tissue Imaging, NIAID and NCI, NIH, Bethesda, MD, USA
| | - Raffit Hassan
- Thoracic and GI Malignancies Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA
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Smith KER, Ayers-Ringler JR, Orme JJ, Lucien F, Kim Y, Winters JL, Mansfield AS. Evaluating therapeutic plasma exchange and protease inhibitors as mechanisms to reduce soluble mesothelin. Sci Rep 2025; 15:13174. [PMID: 40240561 PMCID: PMC12003639 DOI: 10.1038/s41598-025-97952-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2024] [Accepted: 04/08/2025] [Indexed: 04/18/2025] Open
Abstract
Cell surface mesothelin (MSLN) can be solubilized and released into the systemic circulation. The resulting soluble MSLN (sMSLN) may interfere with therapies targeting surface MSLN. We investigated the effects of sMSLN on anetumab, an antibody-based therapy against MSLN, anetumab ravtansine, an antibody drug conjugate, and mechanisms to decrease sMSLN. Whole blood samples were collected before and after one plasma volume of therapeutic plasma exchange (TPE). sMSLN levels were measured with ELISA assays in matched pre- and post-TPE plasma samples, and anetumab-immunoprecipitated samples. We also used protease inhibitors (PIs) as a mechanism to stabilize surface MSLN, then evaluated the cytotoxic effects of anetumab ravtansine. Our findings indicate that sMSLN sequesters and may impair the efficacy of this anti-MSLN antibody based on results showing that anetumab decreases the concentration of MSLN in plasma (p < 0.05) and reduced cytotoxicity of anetumab ravtansine in the presence of recombinant MSLN in cell lines, a surrogate for sMSLN. TPE consistently reduced sMSLN (p < 0.05) with an average decrease of 43.6% (15.4 ng/mL). Surface MSLN stabilization was inconsistently observed with PIs. Overall, sMSLN could represent a predictive biomarker for MSLN directed therapies. TPE may be more reliable than PIs to reduce sMSLN and ultimately restore sensitivity to these therapies in patients with high sMSLN.
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Affiliation(s)
| | | | - Jacob J Orme
- Medical Oncology, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA
| | - Fabrice Lucien
- Department of Urology, Mayo Clinic, Rochester, MN, USA
- Department of Immunology, Mayo Clinic, Rochester, MN, USA
| | - Yohan Kim
- Department of Urology, Mayo Clinic, Rochester, MN, USA
| | | | - Aaron S Mansfield
- Medical Oncology, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.
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Ouladan S, Orouji E. Chimeric Antigen Receptor-T Cells in Colorectal Cancer: Pioneering New Avenues in Solid Tumor Immunotherapy. J Clin Oncol 2025; 43:994-1005. [PMID: 39805063 PMCID: PMC11895826 DOI: 10.1200/jco-24-02081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 11/22/2024] [Accepted: 12/11/2024] [Indexed: 01/16/2025] Open
Abstract
Colorectal cancer (CRC) remains a major global health burden, being one of the most prevalent cancers with high mortality rates. Despite advances in conventional treatment modalities, patients with metastatic CRC often face limited options and poor outcomes. Chimeric antigen receptor-T (CAR-T) cell therapy, initially successful in hematologic malignancies, presents a promising avenue for treating solid tumors, including CRC. This review explores the potential of CAR-T cell therapy in CRC by analyzing clinical trials and highlighting prominent CRC-specific targets. We discuss the challenges such as immunosuppressive microenvironment, tumor heterogeneity, and physical barriers that limit CAR-T efficacy. Emerging strategies, such as logic-gated and dual-targeting CAR-T cells, offer practical solutions to overcome these hurdles. Furthermore, we explore the combination of CAR-T cell therapy with immune checkpoint inhibitors to enhance T-cell persistence and tumor infiltration. As the field continues to evolve, CAR-T cell therapies hold significant potential for revolutionizing the treatment landscape of CRC.
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Affiliation(s)
- Shaida Ouladan
- Department of Pathology, McGill University, Montreal, QC, Canada
| | - Elias Orouji
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
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Shin SH, Lee YE, Yoon HN, Yuk CM, An JY, Seo M, Yoon S, Oh MS, Shin SC, Kim JH, Kim YJ, Kim JC, Kim SC, Jang M. An innovative strategy harnessing self-activating CAR-NK cells to mitigate TGF-β1-driven immune suppression. Biomaterials 2025; 314:122888. [PMID: 39423512 DOI: 10.1016/j.biomaterials.2024.122888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 09/19/2024] [Accepted: 10/09/2024] [Indexed: 10/21/2024]
Abstract
The dysfunction of natural killer (NK) cells, mediated by transforming growth factor β1 (TGFβ1) within the tumor microenvironment, impedes antitumor therapy and contributes to poor clinical outcomes. Our study introduces self-activating chimeric antigen receptor (CAR)-NK cells that block TGFβ1 signaling by releasing a specifically designed peptide, P6, which targets mesothelin in pancreatic tumors. P6 originates from the interaction sites between TGFβ1 and TGFβ receptor 1 and effectively disrupts TGFβ1's inhibitory signaling in NK cells. Our analysis demonstrates that P6 treatment interrupts the SMAD2/3 pathway in NK cells, mitigating TGFβ1-mediated suppression of NK cell activity, thereby enhancing their metabolic function and cytotoxic response against pancreatic tumors. These CAR-NK cells exhibit potent antitumor capabilities, as evidenced in spheroid cultures with cancer-associated fibroblasts and in vivo mouse models. Our approach marks a substantial advancement in overcoming TGFβ1-mediated immune evasion, offering a promising avenue for revolutionizing cancer immunotherapy.
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Affiliation(s)
- Seung Hun Shin
- Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology, Seoul, Republic of Korea; Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
| | - Young Eun Lee
- Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology, Seoul, Republic of Korea
| | - Han-Na Yoon
- Rare & Pediatric Cancer Branch, Division of Rare and Refractory Cancer, Research Institute, National Cancer Center, Goyang, Republic of Korea
| | - Chae Min Yuk
- Center for Advanced Biomolecular Recognition, Biomedical Research Division, Korea Institute of Science and Technology, Seoul, Republic of Korea
| | - Jun Yop An
- Corporate Research & Development Center, UCI Therapeutics, Seoul, Republic of Korea
| | - Minkoo Seo
- Corporate Research & Development Center, UCI Therapeutics, Seoul, Republic of Korea
| | - Sangwon Yoon
- Corporate Research & Development Center, UCI Therapeutics, Seoul, Republic of Korea
| | - Min-Suk Oh
- Corporate Research & Development Center, UCI Therapeutics, Seoul, Republic of Korea
| | - Sang Chul Shin
- Technological Convergence Center, Korea Institute of Science and Technology, Seoul, Republic of Korea
| | - Ji Hyung Kim
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea
| | - Yong Jun Kim
- Department of Pathology, College of Medicine, Kyung Hee University, Seoul, Republic of Korea; KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul, Republic of Korea
| | - Jin-Chul Kim
- Natural Products Research Institute, Korea Institute of Science and Technology, Gangneung, Republic of Korea
| | - Song Cheol Kim
- Division of Hepato-Biliary and Pancreatic Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Mihue Jang
- Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology, Seoul, Republic of Korea; KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul, Republic of Korea.
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9
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Barjasteh AH, Saebi M, Mahmoudi M, Kheder RK, Hashemy SI, Forouzanfar F, Esmaeili SA. Revolutionizing Cancer Treatment: Unveiling the Power of CAR T-cell Therapy. Curr Pharm Des 2025; 31:1020-1036. [PMID: 39757684 DOI: 10.2174/0113816128336391241107112957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 09/03/2024] [Accepted: 09/11/2024] [Indexed: 01/07/2025]
Abstract
Cancer is a significant health challenge worldwide, causing social and economic burdens. Despite advancements in medicine, it remains a leading cause of death and is projected to increase by 2040. While conventional treatments like surgery, radiation, and chemotherapy are effective, they often have severe side effects. CAR T-cell (chimeric antigen receptor T-cell) treatment is a novel immunotherapy method personalized to the patient's immune system and directly targets cancer cells. It originated in the 1980s, and advancements have made it more effective. However, challenges remain, such as severe side effects, high costs, and manufacturing variability. Despite these challenges, the treatment with CAR T-cells has shown remarkable success, especially in hematologic malignancies. Though, it is new to solid tumours, ongoing research looks promising. CAR T-cell therapy offers hope for fightingcancer, and it stands poised to redefine cancer treatment paradigms, giving renewed optimism to patients globally.
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Affiliation(s)
- Amir Hossein Barjasteh
- Immunology Department, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mostafa Saebi
- Immunology Department, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahmoud Mahmoudi
- Immunology Department, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ramiar Kamal Kheder
- Medical Laboratory Science Department, College of Science, University of Raparin, Ranya, Sulaymaniyah, Iraq
- Department of Medical Analysis, Faculty of Applied Science, Tishk International University, Erbil, Iraq
| | - Seyed Isaac Hashemy
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fatemeh Forouzanfar
- Neuroscience Research Centre, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Neuroscience, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed-Alireza Esmaeili
- Immunology Department, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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10
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Bates M, Mohamed BM, Lewis F, O'Toole S, O'Leary JJ. Biomarkers in high grade serous ovarian cancer. Biochim Biophys Acta Rev Cancer 2024; 1879:189224. [PMID: 39581234 DOI: 10.1016/j.bbcan.2024.189224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Revised: 11/15/2024] [Accepted: 11/15/2024] [Indexed: 11/26/2024]
Abstract
High-grade serous ovarian cancer (HGSC) is the most common subtype of ovarian cancer. HGSC patients typically present with advanced disease, which is often resistant to chemotherapy and recurs despite initial responses to therapy, resulting in the poor prognosis associated with this disease. There is a need to utilise biomarkers to manage the various aspects of HGSC patient care. In this review we discuss the current state of biomarkers in HGSC, focusing on the various available immunohistochemical (IHC) and blood-based biomarkers, which have been examined for their diagnostic, prognostic and theranostic potential in HGSC. These include various routine clinical IHC biomarkers such as p53, WT1, keratins, PAX8, Ki67 and p16 and clinical blood-borne markers and algorithms such as CA125, HE4, ROMA, RMI, ROCA, and others. We also discuss various components of the liquid biopsy as well as a number of novel IHC biomarkers and non-routine blood-borne biomarkers, which have been examined in various ovarian cancer studies. We also discuss the future of ovarian cancer biomarker research and highlight some of the challenges currently facing the field.
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Affiliation(s)
- Mark Bates
- Department of Histopathology, Trinity College Dublin, Dublin, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland; Trinity St James's Cancer Institute, Dublin, Ireland.
| | - Bashir M Mohamed
- Department of Histopathology, Trinity College Dublin, Dublin, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland; Trinity St James's Cancer Institute, Dublin, Ireland
| | - Faye Lewis
- Department of Histopathology, Trinity College Dublin, Dublin, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland; Trinity St James's Cancer Institute, Dublin, Ireland
| | - Sharon O'Toole
- Department of Histopathology, Trinity College Dublin, Dublin, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland; Trinity St James's Cancer Institute, Dublin, Ireland; Department of Obstetrics and Gynaecology, Trinity College Dublin, Dublin, Ireland
| | - John J O'Leary
- Department of Histopathology, Trinity College Dublin, Dublin, Ireland; Emer Casey Molecular Pathology Research Laboratory, Coombe Women & Infants University Hospital, Dublin, Ireland; Trinity St James's Cancer Institute, Dublin, Ireland; Department of Pathology, Coombe Women & Infants University Hospital, Dublin, Ireland
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11
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Wu M, Mao L, Zhai X, Liu J, Wang J, Li L, Duan J, Wang J, Lin S, Li J, Yu S. Microenvironmental alkalization promotes the therapeutic effects of MSLN-CAR-T cells. J Immunother Cancer 2024; 12:e009510. [PMID: 39433427 PMCID: PMC11499857 DOI: 10.1136/jitc-2024-009510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/13/2024] [Indexed: 10/23/2024] Open
Abstract
Triple-negative breast cancer (TNBC) is characterized by high invasion, prone metastasis, frequent recurrence and poor prognosis. Unfortunately, the curative effects of current clinical therapies, including surgery, radiotherapy, chemotherapy and immunotherapy, are still limited in patients with TNBC. In this study, we showed that the heterogeneous expression at the protein level and subcellular location of mesothelin (MSLN), a potential target for chimeric antigen receptor-T (CAR-T) cell therapy in TNBC, which is caused by acidification of the tumor microenvironment, may be the main obstacle to therapeutic efficacy. Alkalization culture or sodium bicarbonate administration significantly promoted the membrane expression of MSLN and enhanced the killing efficiency of MSLN-CAR-T cells both in vitro and in vivo, and the same results were also obtained in other cancers with high MSLN expression, such as pancreatic and ovarian cancers. Moreover, mechanistic exploration revealed that the attenuation of autophagy-lysosome function caused by microenvironmental alkalization inhibited the degradation of MSLN. Hence, alkalization of the microenvironment improves the consistency and high expression of the target antigen MSLN and constitutes a routine method for treating diverse solid cancers via MSLN-CAR-T cells.
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Affiliation(s)
- Min Wu
- Department of Stem Cell and Regenerative Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, Chongqing, China
- Jin-feng Laboratory, Chongqing, Chongqing, China
| | - Ling Mao
- Department of Stem Cell and Regenerative Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, Chongqing, China
| | - Xuejia Zhai
- Department of Stem Cell and Regenerative Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, Chongqing, China
- Deaprtment of Oncology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, Chongqing, China
| | - Jie Liu
- Department of Stem Cell and Regenerative Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, Chongqing, China
| | - Junhan Wang
- Department of Stem Cell and Regenerative Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, Chongqing, China
| | - Langhong Li
- Department of Stem Cell and Regenerative Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, Chongqing, China
| | - Jiangjie Duan
- Department of Stem Cell and Regenerative Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, Chongqing, China
- Jin-feng Laboratory, Chongqing, Chongqing, China
| | - Jun Wang
- Department of Stem Cell and Regenerative Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, Chongqing, China
- Jin-feng Laboratory, Chongqing, Chongqing, China
| | - Shuang Lin
- International Joint Research Center for Precision Biotherapy, Ministry of Science and Technology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, Chongqing, China
| | - Jianjun Li
- Deaprtment of Oncology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, Chongqing, China
| | - Shicang Yu
- Department of Stem Cell and Regenerative Medicine, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, Chongqing, China
- Jin-feng Laboratory, Chongqing, Chongqing, China
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12
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Liu JJ, Pan ZD, Yue YL, Wang SS, Chen J, Jiang H, Zhang BH, Wu MY, Yuan YS, Bian YL, Yin HY, Wang L, Li JY, Gilly J, Xie YQ, Zhu JW. T cell-redirecting antibody for treatment of solid tumors via targeting mesothelin. Acta Pharmacol Sin 2024; 45:2186-2198. [PMID: 38858494 PMCID: PMC11420237 DOI: 10.1038/s41401-024-01316-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 05/15/2024] [Indexed: 06/12/2024]
Abstract
T cell engaging bispecific antibodies (TCBs) have recently become significant in cancer treatment. In this study we developed MSLN490, a novel TCB designed to target mesothelin (MSLN), a glycosylphosphatidylinositol (GPI)-linked glycoprotein highly expressed in various cancers, and evaluated its efficacy against solid tumors. CDR walking and phage display techniques were used to improve affinity of the parental antibody M912, resulting in a pool of antibodies with different affinities to MSLN. From this pool, various bispecific antibodies (BsAbs) were assembled. Notably, MSLN490 with its IgG-[L]-scFv structure displayed remarkable anti-tumor activity against MSLN-expressing tumors (EC50: 0.16 pM in HT-29-hMSLN cells). Furthermore, MSLN490 remained effective even in the presence of non-membrane-anchored MSLN (soluble MSLN). Moreover, the anti-tumor activity of MSLN490 was enhanced when combined with either Atezolizumab or TAA × CD28 BsAbs. Notably, a synergistic effect was observed between MSLN490 and paclitaxel, as paclitaxel disrupted the immunosuppressive microenvironment within solid tumors, enhancing immune cells infiltration and improved anti-tumor efficacy. Overall, MSLN490 exhibits robust anti-tumor activity, resilience to soluble MSLN interference, and enhanced anti-tumor effects when combined with other therapies, offering a promising future for the treatment of a variety of solid tumors. This study provides a strong foundation for further exploration of MSLN490's clinical potential.
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Affiliation(s)
- Jun-Jun Liu
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Zhi-di Pan
- Jecho Institute, Shanghai, 200240, China
| | - Ya-Li Yue
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
| | | | - Jie Chen
- Jecho Institute, Shanghai, 200240, China
| | - Hua Jiang
- Jecho Laboratories, Inc., Frederick, MD, 21704, USA
- Jecho Biopharmaceuticals Co., Ltd, Tianjin, 300450, China
| | - Bao-Hong Zhang
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Ming-Yuan Wu
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Yun-Sheng Yuan
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Yan-Lin Bian
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
| | | | - Lei Wang
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Jun-Yan Li
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - John Gilly
- Jecho Biopharmaceuticals Co., Ltd, Tianjin, 300450, China
| | - Yue-Qing Xie
- Jecho Institute, Shanghai, 200240, China.
- Jecho Laboratories, Inc., Frederick, MD, 21704, USA.
| | - Jian-Wei Zhu
- Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China.
- Jecho Institute, Shanghai, 200240, China.
- Jecho Laboratories, Inc., Frederick, MD, 21704, USA.
- Jecho Biopharmaceuticals Co., Ltd, Tianjin, 300450, China.
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13
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Malik S, Sikander M, Bell N, Zubieta D, Bell MC, Yallapu MM, Chauhan SC. Emerging role of mucins in antibody drug conjugates for ovarian cancer therapy. J Ovarian Res 2024; 17:161. [PMID: 39118097 PMCID: PMC11308542 DOI: 10.1186/s13048-024-01485-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 07/24/2024] [Indexed: 08/10/2024] Open
Abstract
Ovarian cancer stands as the deadliest gynecologic malignancy, responsible for nearly 65% of all gynecologic cancer-related deaths. The challenges in early detection and diagnosis, coupled with the widespread intraperitoneal spread of cancer cells and resistance to chemotherapy, contribute significantly to the high mortality rate of this disease. Due to the absence of specific symptoms and the lack of effective screening methods, most ovarian cancer cases are diagnosed at advanced stages. While chemotherapy is a common treatment, it often leads to tumor recurrence, necessitating further interventions. In recent years, antibody-drug conjugates (ADCs) have emerged as a valuable tool in targeted cancer therapy. These complex biotherapeutics combine an antibody that specifically targets tumor specific/associated antigen(s) with a high potency anti-cancer drug through a linker, offering a promising approach for ovarian cancer treatment. The identification of molecular targets in various human tumors has paved the way for the development of targeted therapies, with ADCs being at the forefront of this innovation. By delivering cytotoxic agents directly to tumors and metastatic lesions, ADCs show potential in managing chemo-resistant ovarian cancers. Mucins such as MUC16, MUC13, and MUC1 have shown significantly higher expression in ovarian tumors as compared to normal and/or benign samples, thus have become promising targets for ADC generation. While traditional markers are limited by their elevated levels in non-cancerous conditions, mucins offer a new possibility for targeted treatment in ovarian cancer. This review comprehensively described the potential of mucins for the generation of ADC therapy, highlighting their importance in the quest to improve the outcome of ovarian cancer patients.
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Affiliation(s)
- Shabnam Malik
- Division of Cancer Immunology and Microbiology, Medicine and Oncology Integrated Service Unit, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, 78504, USA
- South Texas Center of Excellence in Cancer Research (ST-CECR), McAllen, TX, 78504, USA
| | - Mohammed Sikander
- Division of Cancer Immunology and Microbiology, Medicine and Oncology Integrated Service Unit, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, 78504, USA
- South Texas Center of Excellence in Cancer Research (ST-CECR), McAllen, TX, 78504, USA
| | - Natasha Bell
- South Texas Center of Excellence in Cancer Research (ST-CECR), McAllen, TX, 78504, USA
| | - Daniel Zubieta
- Division of Cancer Immunology and Microbiology, Medicine and Oncology Integrated Service Unit, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, 78504, USA
- South Texas Center of Excellence in Cancer Research (ST-CECR), McAllen, TX, 78504, USA
| | - Maria C Bell
- Sanford Health, Sanford Gynecologic Oncology Clinic, Sioux Falls, SD, 57104, USA
| | - Murali M Yallapu
- Division of Cancer Immunology and Microbiology, Medicine and Oncology Integrated Service Unit, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, 78504, USA
- South Texas Center of Excellence in Cancer Research (ST-CECR), McAllen, TX, 78504, USA
| | - Subhash C Chauhan
- Division of Cancer Immunology and Microbiology, Medicine and Oncology Integrated Service Unit, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, 78504, USA.
- South Texas Center of Excellence in Cancer Research (ST-CECR), McAllen, TX, 78504, USA.
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14
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Tarannum M, Dinh K, Vergara J, Birch G, Abdulhamid YZ, Kaplan IE, Ay O, Maia A, Beaver O, Sheffer M, Shapiro R, Ali AK, Dong H, Ham JD, Bobilev E, James S, Cameron AB, Nguyen QD, Ganapathy S, Chayawatto C, Koreth J, Paweletz CP, Gokhale PC, Barbie DA, Matulonis UA, Soiffer RJ, Ritz J, Porter RL, Chen J, Romee R. CAR memory-like NK cells targeting the membrane proximal domain of mesothelin demonstrate promising activity in ovarian cancer. SCIENCE ADVANCES 2024; 10:eadn0881. [PMID: 38996027 PMCID: PMC11244547 DOI: 10.1126/sciadv.adn0881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 06/10/2024] [Indexed: 07/14/2024]
Abstract
Epithelial ovarian cancer (EOC) remains one of the most lethal gynecological cancers. Cytokine-induced memory-like (CIML) natural killer (NK) cells have shown promising results in preclinical and early-phase clinical trials. In the current study, CIML NK cells demonstrated superior antitumor responses against a panel of EOC cell lines, increased expression of activation receptors, and up-regulation of genes involved in cell cycle/proliferation and down-regulation of inhibitory/suppressive genes. CIML NK cells transduced with a chimeric antigen receptor (CAR) targeting the membrane-proximal domain of mesothelin (MSLN) further improved the antitumor responses against MSLN-expressing EOC cells and patient-derived xenograft tumor cells. CAR arming of the CIML NK cells subtanstially reduced their dysfunction in patient-derived ascites fluid with transcriptomic changes related to altered metabolism and tonic signaling as potential mechanisms. Lastly, the adoptive transfer of MSLN-CAR CIML NK cells demonstrated remarkable inhibition of tumor growth and prevented metastatic spread in xenograft mice, supporting their potential as an effective therapeutic strategy in EOC.
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MESH Headings
- Animals
- Female
- Humans
- Mice
- Carcinoma, Ovarian Epithelial/metabolism
- Carcinoma, Ovarian Epithelial/pathology
- Carcinoma, Ovarian Epithelial/immunology
- Carcinoma, Ovarian Epithelial/therapy
- Cell Line, Tumor
- GPI-Linked Proteins/metabolism
- GPI-Linked Proteins/genetics
- Immunologic Memory
- Immunotherapy, Adoptive/methods
- Killer Cells, Natural/immunology
- Killer Cells, Natural/metabolism
- Mesothelin
- Ovarian Neoplasms/metabolism
- Ovarian Neoplasms/pathology
- Ovarian Neoplasms/immunology
- Ovarian Neoplasms/therapy
- Protein Domains
- Receptors, Chimeric Antigen/metabolism
- Receptors, Chimeric Antigen/immunology
- Receptors, Chimeric Antigen/genetics
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Mubin Tarannum
- Division of Transplantation and Cellular Therapies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Khanhlinh Dinh
- Division of Transplantation and Cellular Therapies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Juliana Vergara
- Division of Transplantation and Cellular Therapies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Grace Birch
- Division of Transplantation and Cellular Therapies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Yasmin Z. Abdulhamid
- Division of Transplantation and Cellular Therapies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Isabel E. Kaplan
- Division of Transplantation and Cellular Therapies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Oyku Ay
- Division of Transplantation and Cellular Therapies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Andreia Maia
- Division of Transplantation and Cellular Therapies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Owen Beaver
- Division of Transplantation and Cellular Therapies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Michal Sheffer
- Division of Transplantation and Cellular Therapies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Roman Shapiro
- Division of Transplantation and Cellular Therapies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Alaa Kassim Ali
- Division of Transplantation and Cellular Therapies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Han Dong
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - James Dongjoo Ham
- Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Eden Bobilev
- Division of Transplantation and Cellular Therapies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Sydney James
- Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana Farber Cancer Institute, Boston, MA, USA
| | - Amy B. Cameron
- Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana Farber Cancer Institute, Boston, MA, USA
| | - Quang-De Nguyen
- Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana Farber Cancer Institute, Boston, MA, USA
| | - Suthakar Ganapathy
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Chayapatou Chayawatto
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - John Koreth
- Division of Transplantation and Cellular Therapies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Cloud P. Paweletz
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Prafulla C. Gokhale
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - David A. Barbie
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Division of Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Ursula A. Matulonis
- Division of Gynecologic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Robert J. Soiffer
- Division of Transplantation and Cellular Therapies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Jerome Ritz
- Division of Transplantation and Cellular Therapies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Rebecca L. Porter
- Division of Gynecologic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Jianzhu Chen
- Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Rizwan Romee
- Division of Transplantation and Cellular Therapies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
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15
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Satapathy BP, Sheoran P, Yadav R, Chettri D, Sonowal D, Dash CP, Dhaka P, Uttam V, Yadav R, Jain M, Jain A. The synergistic immunotherapeutic impact of engineered CAR-T cells with PD-1 blockade in lymphomas and solid tumors: a systematic review. Front Immunol 2024; 15:1389971. [PMID: 38799440 PMCID: PMC11116574 DOI: 10.3389/fimmu.2024.1389971] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 04/11/2024] [Indexed: 05/29/2024] Open
Abstract
Currently, therapies such as chimeric antigen receptor-T Cell (CAR-T) and immune checkpoint inhibitors like programmed cell death protein-1 (PD-1) blockers are showing promising results for numerous cancer patients. However, significant advancements are required before CAR-T therapies become readily available as off-the-shelf treatments, particularly for solid tumors and lymphomas. In this review, we have systematically analyzed the combination therapy involving engineered CAR-T cells and anti PD-1 agents. This approach aims at overcoming the limitations of current treatments and offers potential advantages such as enhanced tumor inhibition, alleviated T-cell exhaustion, heightened T-cell activation, and minimized toxicity. The integration of CAR-T therapy, which targets tumor-associated antigens, with PD-1 blockade augments T-cell function and mitigates immune suppression within the tumor microenvironment. To assess the impact of combination therapy on various tumors and lymphomas, we categorized them based on six major tumor-associated antigens: mesothelin, disialoganglioside GD-2, CD-19, CD-22, CD-133, and CD-30, which are present in different tumor types. We evaluated the efficacy, complete and partial responses, and progression-free survival in both pre-clinical and clinical models. Additionally, we discussed potential implications, including the feasibility of combination immunotherapies, emphasizing the importance of ongoing research to optimize treatment strategies and improve outcomes for cancer patients. Overall, we believe combining CAR-T therapy with PD-1 blockade holds promise for the next generation of cancer immunotherapy.
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Affiliation(s)
- Bibhu Prasad Satapathy
- Department of Zoology, Non-Coding RNA and Cancer Biology Laboratory, Central University of Punjab, Bathinda, Punjab, India
| | - Pooja Sheoran
- Department of Zoology, Non-Coding RNA and Cancer Biology Laboratory, Central University of Punjab, Bathinda, Punjab, India
| | - Rohit Yadav
- Department of Zoology, Non-Coding RNA and Cancer Biology Laboratory, Central University of Punjab, Bathinda, Punjab, India
| | - Dewan Chettri
- Department of Zoology, Non-Coding RNA and Cancer Biology Laboratory, Central University of Punjab, Bathinda, Punjab, India
| | - Dhruba Sonowal
- Department of Zoology, Non-Coding RNA and Cancer Biology Laboratory, Central University of Punjab, Bathinda, Punjab, India
| | - Chinmayee Priyadarsini Dash
- Department of Zoology, Non-Coding RNA and Cancer Biology Laboratory, Central University of Punjab, Bathinda, Punjab, India
| | - Prachi Dhaka
- Department of Zoology, Non-Coding RNA and Cancer Biology Laboratory, Central University of Punjab, Bathinda, Punjab, India
| | - Vivek Uttam
- Department of Zoology, Non-Coding RNA and Cancer Biology Laboratory, Central University of Punjab, Bathinda, Punjab, India
| | - Ritu Yadav
- Department of Zoology, Non-Coding RNA and Cancer Biology Laboratory, Central University of Punjab, Bathinda, Punjab, India
| | - Manju Jain
- Department of Biochemistry, School of Basic Sciences, Central University of Punjab, Bathinda, Punjab, India
| | - Aklank Jain
- Department of Zoology, Non-Coding RNA and Cancer Biology Laboratory, Central University of Punjab, Bathinda, Punjab, India
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16
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Zhu Y, Wang K, Yue L, Zuo D, Sheng J, Lan S, Zhao Z, Dong S, Hu S, Chen X, Feng M. Mesothelin CAR-T cells expressing tumor-targeted immunocytokine IL-12 yield durable efficacy and fewer side effects. Pharmacol Res 2024; 203:107186. [PMID: 38641176 DOI: 10.1016/j.phrs.2024.107186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 03/08/2024] [Accepted: 04/12/2024] [Indexed: 04/21/2024]
Abstract
Chimeric antigen receptor (CAR)-modified T cell therapy has achieved remarkable efficacy in treating hematological malignancies, but it confronts many challenges in treating solid tumors, such as the immunosuppressive microenvironment of the solid tumors. These factors reduce the antitumor activity of CAR-T cells in clinical trials. Therefore, we used the immunocytokine interleukin-12 (IL-12) to enhance the efficacy of CAR-T cell therapy. In this study, we engineered CAR-IL12R54 T cells that targeted mesothelin (MSLN) and secreted a single-chain IL-12 fused to a scFv fragment R54 that recognized a different epitope on mesothelin. The evaluation of the anti-tumor activity of the CAR-IL12R54 T cells alone or in combination with anti-PD-1 antibody in vitro and in vivo was followed by the exploration of the functional mechanism by which the immunocytokine IL-12 enhanced the antitumor activity. CAR-IL12R54 T cells had potency to lyse mesothelin positive tumor cells in vitro. In vivo studies demonstrated that CAR-IL12R54 T cells were effective in controlling the growth of established tumors in a xenograft mouse model with fewer side effects than CAR-T cells that secreted naked IL-12. Furthermore, combination of PD-1 blockade antibody with CAR-IL12R54 T cells elicited durable anti-tumor responses. Mechanistic studies showed that IL12R54 enhanced Interferon-γ (IFN-γ) production and dampened the activity of regulatory T cells (Tregs). IL12R54 also upregulated CXCR6 expression in the T cells through the NF-κB pathway, which facilitated T cell infiltration and persistence in the tumor tissues. In summary, the studies provide a good therapeutic option for the clinical treatment of solid tumors.
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Affiliation(s)
- Yuankui Zhu
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan, Hubei 430070, China
| | - Ke Wang
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan, Hubei 430070, China
| | - Linghe Yue
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan, Hubei 430070, China
| | - Dianbao Zuo
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan, Hubei 430070, China
| | - Junfeng Sheng
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan, Hubei 430070, China
| | - Sina Lan
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan, Hubei 430070, China
| | - Zilong Zhao
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan, Hubei 430070, China
| | - Shuang Dong
- Department of Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430079, China
| | - Sheng Hu
- Department of Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430079, China.
| | - Xin Chen
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan, Hubei 430070, China.
| | - Mingqian Feng
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan, Hubei 430070, China; College of Biomedicine and Health, Huazhong Agricultural University, Wuhan, Hubei 430070, China.
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17
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Chakraborty A, Onda M, O’Shea T, Wei J, Liu X, Bera TK, Pastan I. A bispecific antibody that targets the membrane-proximal region of mesothelin and retains high anticancer activity in the presence of shed mesothelin. Mol Cancer Ther 2024; 23:743184. [PMID: 38647528 PMCID: PMC11493849 DOI: 10.1158/1535-7163.mct-23-0233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 09/03/2023] [Accepted: 04/05/2024] [Indexed: 04/25/2024]
Abstract
Mesothelin (MSLN) is a cell-surface protein that is expressed on many cancers, which makes it a popular target for antibody-based cancer therapy. However, MSLN is shed from cancer cells at high levels via proteases that cleave at its membrane-proximal C-terminal region. Shed MSLN accumulates in patient fluids and tumors and can block antibody-based MSLN-targeting drugs from killing cancer cells. A previously established monoclonal antibody (mAb), 15B6, binds MSLN at its protease-sensitive C-terminal region and does not bind shed MSLN. 15B6 variable fragment (Fv)-derived chimeric antigen receptor (CAR) T cells are not inhibited by shed MSLN and kill tumors in mice more effectively than mAb SS1 Fv-derived CAR T cells, which bind an epitope retained in shed MSLN. Here, we have established 15B6 Fv-derived MSLN x CD3 bispecific antibodies (BsAbs) that target MSLN-expressing cancers. We identified our lead candidate, BsAb 5, after screening multiple 15B6-derived BsAb formats in vitro for cytotoxic activity. BsAb 5 activates T cells to kill various cancer cell lines in a MSLN-specific manner. MSLN 296-591 His, a recombinant protein mimicking shed MSLN, does not inhibit 15B6-derived BsAb 5 but completely inhibits humanized SS1-derived BsAb 7. Furthermore, BsAb 5 inhibits and delays tumor growth and is not inhibited by MSLN 296-585 His in mice. Our findings indicate that by targeting the protease-sensitive region of MSLN, BsAb 5 has high MSLN-specific anticancer activity that is not inhibited by shed MSLN. BsAb 5 may be a promising immunotherapy candidate for MSLN-expressing cancers.
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Affiliation(s)
- Anirban Chakraborty
- Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264
| | - Masanori Onda
- Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264
| | - Tara O’Shea
- Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264
| | - Junxia Wei
- Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264
| | - Xiufen Liu
- Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264
| | - Tapan K. Bera
- Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264
| | - Ira Pastan
- Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264
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18
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Hiscox MJ, Wasmuth A, Williams CL, Foot JN, Wiedermann GE, Fadda V, Boiani S, Cornforth TV, Wikiert KA, Bruton S, Cartwright N, Anderson VE, Barnes CS, Vieira JV, Birch-Machin I, Gerry AB, Miller K, Pumphrey NJ. Selection, engineering, and in vivo testing of a human leukocyte antigen-independent T-cell receptor recognizing human mesothelin. PLoS One 2024; 19:e0301175. [PMID: 38574067 PMCID: PMC10994368 DOI: 10.1371/journal.pone.0301175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Accepted: 03/12/2024] [Indexed: 04/06/2024] Open
Abstract
BACKGROUND Canonical α/β T-cell receptors (TCRs) bind to human leukocyte antigen (HLA) displaying antigenic peptides to elicit T cell-mediated cytotoxicity. TCR-engineered T-cell immunotherapies targeting cancer-specific peptide-HLA complexes (pHLA) are generating exciting clinical responses, but owing to HLA restriction they are only able to target a subset of antigen-positive patients. More recently, evidence has been published indicating that naturally occurring α/β TCRs can target cell surface proteins other than pHLA, which would address the challenges of HLA restriction. In this proof-of-concept study, we sought to identify and engineer so-called HLA-independent TCRs (HiTs) against the tumor-associated antigen mesothelin. METHODS Using phage display, we identified a HiT that bound well to mesothelin, which when expressed in primary T cells, caused activation and cytotoxicity. We subsequently engineered this HiT to modulate the T-cell response to varying levels of mesothelin on the cell surface. RESULTS The isolated HiT shows cytotoxic activity and demonstrates killing of both mesothelin-expressing cell lines and patient-derived xenograft models. Additionally, we demonstrated that HiT-transduced T cells do not require CD4 or CD8 co-receptors and, unlike a TCR fusion construct, are not inhibited by soluble mesothelin. Finally, we showed that HiT-transduced T cells are highly efficacious in vivo, completely eradicating xenografted human solid tumors. CONCLUSION HiTs can be isolated from fully human TCR-displaying phage libraries against cell surface-expressed antigens. HiTs are able to fully activate primary T cells both in vivo and in vitro. HiTs may enable the efficacy seen with pHLA-targeting TCRs in solid tumors to be translated to cell surface antigens.
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Affiliation(s)
| | | | | | - Jaelle N. Foot
- Research, Adaptimmune, Abingdon, Oxfordshire, United Kingdom
| | | | - Valeria Fadda
- Research, Adaptimmune, Abingdon, Oxfordshire, United Kingdom
| | - Sara Boiani
- Research, Adaptimmune, Abingdon, Oxfordshire, United Kingdom
| | | | | | - Shaun Bruton
- Research, Adaptimmune, Abingdon, Oxfordshire, United Kingdom
| | - Neil Cartwright
- Research, Adaptimmune, Abingdon, Oxfordshire, United Kingdom
| | | | | | - Joao V. Vieira
- Research, Adaptimmune, Abingdon, Oxfordshire, United Kingdom
| | | | - Andrew B. Gerry
- Research, Adaptimmune, Abingdon, Oxfordshire, United Kingdom
| | - Karen Miller
- Research, Adaptimmune, Abingdon, Oxfordshire, United Kingdom
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19
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Yun KM, Bazhenova L. Emerging New Targets in Systemic Therapy for Malignant Pleural Mesothelioma. Cancers (Basel) 2024; 16:1252. [PMID: 38610930 PMCID: PMC11011044 DOI: 10.3390/cancers16071252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 03/19/2024] [Accepted: 03/21/2024] [Indexed: 04/14/2024] Open
Abstract
Malignant pleural mesothelioma (MPM) is a heterogeneous cancer composed of distinct molecular and pathologic subtypes. Unfortunately, MPM is aggressive, and current therapies for advanced, unresectable disease remain limited to cytotoxic chemotherapy and immunotherapy. Our understanding of the genomic landscape of MPM is steadily growing, while the discovery of effective targeted therapies in MPM has advanced more slowly than in other solid tumors. Given the prevalence of alterations in tumor suppressor genes in MPM, it has been challenging to identify actionable targets. However, efforts to characterize the genetic signatures in MPM over the last decade have led to a range of novel targeted therapeutics entering early-phase clinical trials. In this review, we discuss the advancements made thus far in targeted systemic therapies in MPM and the future direction of targeted strategies in patients with advanced MPM.
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Affiliation(s)
- Karen M. Yun
- Division of Hematology-Oncology, Moores Cancer Center at UC San Diego Health, La Jolla, CA 92093, USA;
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20
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Sakurai Y, Kubota N, Takamoto I, Wada N, Aihara M, Hayashi T, Kubota T, Hiraike Y, Sasako T, Nakao H, Aiba A, Chikaoka Y, Kawamura T, Kadowaki T, Yamauchi T. Overexpression of UBE2E2 in Mouse Pancreatic β-Cells Leads to Glucose Intolerance via Reduction of β-Cell Mass. Diabetes 2024; 73:474-489. [PMID: 38064504 DOI: 10.2337/db23-0150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 12/03/2023] [Indexed: 02/22/2024]
Abstract
Genome-wide association studies have identified several gene polymorphisms, including UBE2E2, associated with type 2 diabetes. Although UBE2E2 is one of the ubiquitin-conjugating enzymes involved in the process of ubiquitin modifications, the pathophysiological roles of UBE2E2 in metabolic dysfunction are not yet understood. Here, we showed upregulated UBE2E2 expression in the islets of a mouse model of diet-induced obesity. The diabetes risk allele of UBE2E2 (rs13094957) in noncoding regions was associated with upregulation of UBE2E2 mRNA in the human pancreas. Although glucose-stimulated insulin secretion was intact in the isolated islets, pancreatic β-cell-specific UBE2E2-transgenic (TG) mice exhibited reduced insulin secretion and decreased β-cell mass. In TG mice, suppressed proliferation of β-cells before the weaning period and while receiving a high-fat diet was accompanied by elevated gene expression levels of p21, resulting in decreased postnatal β-cell mass expansion and compensatory β-cell hyperplasia, respectively. In TG islets, proteomic analysis identified enhanced formation of various types of polyubiquitin chains, accompanied by increased expression of Nedd4 E3 ubiquitin protein ligase. Ubiquitination assays showed that UBE2E2 mediated the elongation of ubiquitin chains by Nedd4. The data suggest that UBE2E2-mediated ubiquitin modifications in β-cells play an important role in regulating glucose homeostasis and β-cell mass.
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Affiliation(s)
- Yoshitaka Sakurai
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Naoto Kubota
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
- Department of Metabolic Medicine, Faculty of Life Science, Kumamoto University, Kumamoto, Japan
- Clinical Nutrition Program, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Iseki Takamoto
- Department of Metabolism and Endocrinology, Ibaraki Medical Center, Tokyo Medical University, Tokyo, Japan
| | - Nobuhiro Wada
- Department of Anatomy I, School of Medicine, Sapporo Medical University, Sapporo, Japan
| | - Masakazu Aihara
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Takanori Hayashi
- Clinical Nutrition Program, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Tetsuya Kubota
- Clinical Nutrition Program, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
- Division of Diabetes and Metabolism, Institute of Medical Science, Asahi Life Foundation, Tokyo, Japan
| | - Yuta Hiraike
- Division for Health Service Promotion, The University of Tokyo, Tokyo, Japan
| | - Takayoshi Sasako
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Harumi Nakao
- Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Atsu Aiba
- Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yoko Chikaoka
- Isotope Science Center, The University of Tokyo, Tokyo, Japan
| | | | | | - Toshimasa Yamauchi
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
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21
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Harriott NC, Ryan AL. Proteomic profiling identifies biomarkers of COVID-19 severity. Heliyon 2024; 10:e23320. [PMID: 38163173 PMCID: PMC10755324 DOI: 10.1016/j.heliyon.2023.e23320] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 11/27/2023] [Accepted: 11/30/2023] [Indexed: 01/03/2024] Open
Abstract
SARS-CoV-2 infection remains a major public health concern, particularly for the aged and those individuals with co-morbidities at risk for developing severe COVID-19. Understanding the pathogenesis and biomarkers associated with responses to SARS-CoV-2 infection remain critical components in developing effective therapeutic approaches, especially in cases of severe and long-COVID-19. In this study blood plasma protein expression was compared in subjects with mild, moderate, and severe COVID-19 disease. Evaluation of an inflammatory protein panel confirms upregulation of proteins including TNFβ, IL-6, IL-8, IL-12, already associated with severe cytokine storm and progression to severe COVID-19. Importantly, we identify several proteins not yet associated with COVID-19 disease, including mesothelin (MSLN), that are expressed at significantly higher levels in severe COVID-19 subjects. In addition, we find a subset of markers associated with T-cell and dendritic cell responses to viral infection that are significantly higher in mild cases and decrease in expression as severity of COVID-19 increases, suggesting that an immediate and effective activation of T-cells is critical in modulating disease progression. Together, our findings identify new targets for further investigation as therapeutic approaches for the treatment of SARS-CoV-2 infection and prevention of complications of severe COVID-19.
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Affiliation(s)
- Noa C. Harriott
- Hastings Center for Pulmonary Research, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Southern California, Los Angeles CA 90033, USA
- Department of Stem Cell Biology and Regenerative Medicine, University of Southern California, Los Angeles CA 90033, USA
- Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City IA 52240, USA
| | - Amy L. Ryan
- Hastings Center for Pulmonary Research, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Southern California, Los Angeles CA 90033, USA
- Department of Stem Cell Biology and Regenerative Medicine, University of Southern California, Los Angeles CA 90033, USA
- Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City IA 52240, USA
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22
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Ma J, Chen Y, Ren J, Zhou T, Wang Z, Li C, Qiu L, Gao T, Ding P, Ding Z, Ou L, Wang J, Xu J, Zhou Z, Jia C, Sun N, Pei R, Zhu W. Purification of Circulating Tumor Cells Based on Multiantibody-Modified Magnetic Nanoparticles and Molecular Analysis toward Epithelial Ovarian Cancer Detection. ACS Sens 2023; 8:3744-3753. [PMID: 37773014 DOI: 10.1021/acssensors.3c01063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/30/2023]
Abstract
Circulating tumor cells (CTCs) are valuable circulating biomarkers of cancer, which carry primary tumor information and may provide real-time assessment of tumor status as well as treatment response in cancer patients. Herein, we developed a novel assay for accurate diagnosis and dynamic monitoring of epithelial ovarian cancer (EOC) using CTC RNA analysis. Multiantibody-modified magnetic nanoparticles were prepared for purification of EOC CTCs from whole blood samples of clinical patients. Subsequently, nine EOC-specific mRNAs of purified CTCs were quantified using droplet digital PCR. The EOC CTC Score was generated using a multivariate logistic regression model for each sample based on the transcripts of the nine genes. This assay exhibited a distinguishing diagnostic performance for the detection of EOC (n = 17) from benign ovarian tumors (n = 30), with an area under the receiver operating characteristic curve (AUC) of 0.96 (95% CI = 0.91-1.00). Moreover, dynamic changes of the EOC CTC Score were observed in patients undergoing treatment, demonstrating the potential of the assay for monitoring EOC. In conclusion, we present an accurate assay for the diagnosis and monitoring of EOC via CTC RNA analysis, and the results suggest that it may provide a promising solution for the detection and treatment response assessment of EOC.
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Affiliation(s)
- Jialing Ma
- Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China
- CAS Key Laboratory for Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China
| | - Ying Chen
- Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China
- CAS Key Laboratory for Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China
| | - Jing Ren
- Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China
- CAS Key Laboratory for Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China
| | - Tongping Zhou
- Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China
- CAS Key Laboratory for Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China
| | - Zhili Wang
- CAS Key Laboratory for Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China
| | - Cheng Li
- CAS Key Laboratory for Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China
| | - Lei Qiu
- CAS Key Laboratory for Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China
- Department of Chemistry, College of Sciences, Shanghai University, Shanghai 200444, China
| | - Tian Gao
- CAS Key Laboratory for Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China
| | - Pi Ding
- CAS Key Laboratory for Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China
| | - Zixin Ding
- CAS Key Laboratory for Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China
- State Key Laboratory of Natural Medicines, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, China
| | - Li Ou
- Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China
| | - Jun Wang
- Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China
| | - Jinni Xu
- Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China
| | - Zhirun Zhou
- Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China
| | - Chenxin Jia
- Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China
| | - Na Sun
- CAS Key Laboratory for Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China
- School of Nano-Tech and Nano-Bionics, University of Science and Technology of China, Hefei 230026, China
| | - Renjun Pei
- CAS Key Laboratory for Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China
- School of Nano-Tech and Nano-Bionics, University of Science and Technology of China, Hefei 230026, China
| | - Weipei Zhu
- Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China
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23
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Qualiotto AN, Baldavira CM, Balancin M, Ab’Saber A, Takagaki T, Capelozzi VL. Mesothelin expression remodeled the immune-matrix tumor microenvironment predicting the risk of death in patients with malignant pleural mesothelioma. Front Immunol 2023; 14:1268927. [PMID: 37901248 PMCID: PMC10601658 DOI: 10.3389/fimmu.2023.1268927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 09/29/2023] [Indexed: 10/31/2023] Open
Abstract
Background The combination of immunobiological agents with immune checkpoint proteins is a promising treatment for malignant pleural mesothelioma (MPM). Mesothelin and anti-PD-L1 antibody-drug conjugates specifically target malignant neoplastic cells, inhibit the migration and invasion of neoplastic cells, and restore the immune landscape. In this study, we confirmed the importance of mesothelin and examined the relationship between mesothelin and the immune landscape of the tumor microenvironment (TME) in two MPM cohorts. Methods The discovery cohort included 82 MPM cases. Tissue microarray slides were generated, and samples were processed for hematoxylin & eosin staining, immunohistochemistry, and immunofluorescence assays. The relationship between mesothelin, biomarkers of histogenesis, histological aggressiveness, PD-L1, immune cells (CD4, CD8, CD20, CD68), and collagen type I and type V fibers was evaluated by quantitative digital analyses. The outcome was the survival time until death from disease recurrence. The exploratory cohort included 87 malignant mesothelioma (MESO) patients from The Cancer Genome Atlas database. Results Most patients were male (70.7%) with a history of asbestos exposure (53.7%) and with the epithelioid subtype (89%). Surgical resection was performed in 85.4% of patients, and 14.6% received chemotherapy; 59.8% of patients died from disease extension to the mediastinum. Low tumor mesothelin expression was associated with tumor necrosis and nuclear grade 1, whereas high mesothelin expression was significantly associated with the epithelioid histotype and high density of T cells CD8+, macrophages CD68+, and collagen type I fibers. Cox multivariate analysis showed a high risk of death for non-operated patients [hazard ratio (HR), 3.42 (1.15-10.16)] with low tumor mesothelin levels [HR, 2.58 (1.09-6.10)] and high PD-L1 and low infiltration of T cells CD4+ [HR, 3.81 (1.58-9.18)]. In the exploratory cohort, low mesothelin and high COL1A1 and COL5A1 expression were associated with poor overall survival. Conclusion Tumor mesothelin expression associated with the TME immune landscape predicts the risk of death for patients with MPM and could be a new target for immunotherapy in MPM.
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Affiliation(s)
- Aline Nery Qualiotto
- Laboratory of Genomic and Histomorphometry, Department of Pathology, University of São Paulo Medical School, São Paulo, Brazil
| | - Camila Machado Baldavira
- Laboratory of Genomic and Histomorphometry, Department of Pathology, University of São Paulo Medical School, São Paulo, Brazil
| | - Marcelo Balancin
- Laboratory of Genomic and Histomorphometry, Department of Pathology, University of São Paulo Medical School, São Paulo, Brazil
| | - Alexandre Ab’Saber
- Laboratory of Genomic and Histomorphometry, Department of Pathology, University of São Paulo Medical School, São Paulo, Brazil
| | - Teresa Takagaki
- Division of Pneumology, Heart Institute (Incor), Faculty of Medicine, University of São Paulo, São Paulo, Brazil
| | - Vera Luiza Capelozzi
- Laboratory of Genomic and Histomorphometry, Department of Pathology, University of São Paulo Medical School, São Paulo, Brazil
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24
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Hagerty BL, Takabe K. Biology of Mesothelin and Clinical Implications: A Review of Existing Literature. World J Oncol 2023; 14:340-349. [PMID: 37869242 PMCID: PMC10588497 DOI: 10.14740/wjon1655] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 08/30/2023] [Indexed: 10/24/2023] Open
Abstract
Since its discovery in 1992, mesothelin (MSLN) has generated significant interest as a therapeutic target. A number of characteristics make it ideal for this purpose. First, it is not expressed on the parenchyma of any vital organs. Second, it is differentially expressed on a number of cancer types that have relatively poor prognosis and lack effective systemic options. Third, it is expressed on the cell membrane making it accessible to large molecule targeted therapies. However, unlike other drug targets that have been exploited for therapeutic benefit, the precise function of MSLN, why it is expressed in certain cancers, and its biological role have not been clearly elucidated. Here the existing literature on the cellular function and expression patterns of MSLN across tumor types is reviewed in order to gain further understanding of this intriguing molecule. In doing so, we conclude that there remains significant ambiguity surrounding its function and role in cellular and tumor biology. Furthermore, the expression of MSLN and its relation of prognosis seems to depend on the type of tumor. Finally, the unified mechanism by which MSLN acts as a protein that conveys tumor aggressiveness remains elusive. What is clear is that there is much yet to be discovered in this realm and doing so may have large implications for treatment of otherwise lethal malignancies.
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Affiliation(s)
- Brendan L Hagerty
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
- Department of Gastroenterological Surgery, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY, USA
- Department of Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan
- Department of Breast Surgery, Fukushima Medical University, Fukushima, Japan
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25
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Thrash HL, Pendergast AM. Multi-Functional Regulation by YAP/TAZ Signaling Networks in Tumor Progression and Metastasis. Cancers (Basel) 2023; 15:4701. [PMID: 37835395 PMCID: PMC10572014 DOI: 10.3390/cancers15194701] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 09/14/2023] [Accepted: 09/22/2023] [Indexed: 10/15/2023] Open
Abstract
The Hippo pathway transcriptional co-activators, YES-associated protein (YAP) and Transcriptional Co-Activator with PDZ Binding Motif (TAZ), have both been linked to tumor progression and metastasis. These two proteins possess overlapping and distinct functions, and their activities lead to the expression of genes involved in multiple cellular processes, including cell proliferation, survival, and migration. The dysregulation of YAP/TAZ-dependent cellular processes can result in altered tumor growth and metastasis. In addition to their well-documented roles in the regulation of cancer cell growth, survival, migration, and invasion, the YAP/TAZ-dependent signaling pathways have been more recently implicated in cellular processes that promote metastasis and therapy resistance in several solid tumor types. This review highlights the role of YAP/TAZ signaling networks in the regulation of tumor cell plasticity mediated by hybrid and reversible epithelial-mesenchymal transition (EMT) states, and the promotion of cancer stem cell/progenitor phenotypes. Mechanistically, YAP and TAZ regulate these cellular processes by targeting transcriptional networks. In this review, we detail recently uncovered mechanisms whereby YAP and TAZ mediate tumor growth, metastasis, and therapy resistance, and discuss new therapeutic strategies to target YAP/TAZ function in various solid tumor types. Understanding the distinct and overlapping roles of YAP and TAZ in multiple cellular processes that promote tumor progression to metastasis is expected to enable the identification of effective therapies to treat solid tumors through the hyper-activation of YAP and TAZ.
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Affiliation(s)
| | - Ann Marie Pendergast
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA
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26
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Hassan R, Butler M, O'Cearbhaill RE, Oh DY, Johnson M, Zikaras K, Smalley M, Ross M, Tanyi JL, Ghafoor A, Shah NN, Saboury B, Cao L, Quintás-Cardama A, Hong D. Mesothelin-targeting T cell receptor fusion construct cell therapy in refractory solid tumors: phase 1/2 trial interim results. Nat Med 2023; 29:2099-2109. [PMID: 37501016 PMCID: PMC10427427 DOI: 10.1038/s41591-023-02452-y] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 06/08/2023] [Indexed: 07/29/2023]
Abstract
The T cell receptor fusion construct (TRuC) gavocabtagene autoleucel (gavo-cel) consists of single-domain anti-mesothelin antibody that integrates into the endogenous T cell receptor (TCR) and engages the signaling capacity of the entire TCR upon mesothelin binding. Here we describe phase 1 results from an ongoing phase1/2 trial of gavo-cel in patients with treatment-refractory mesothelin-expressing solid tumors. The primary objectives were to evaluate safety and determine the recommended phase 2 dose (RP2D). Secondary objectives included efficacy. Thirty-two patients received gavo-cel at increasing doses either as a single agent (n = 3) or after lymphodepletion (LD, n = 29). Dose-limiting toxicities of grade 3 pneumonitis and grade 5 bronchioalveolar hemorrhage were noted. The RP2D was determined as 1 × 108 cells per m2 after LD. Grade 3 or higher pneumonitis was seen in 16% of all patients and in none at the RP2D; grade 3 or higher cytokine release syndrome occurred in 25% of all patients and in 15% at the RP2D. In 30 evaluable patients, the overall response rate and disease control rate were 20% (13% confirmed) and 77%, respectively, and the 6-month overall survival rate was 70%. Gavo-cel warrants further study in patients with mesothelin-expressing cancers given its encouraging anti-tumor activity, but it may have a narrow therapeutic window. ClinicalTrials.gov identifier: NCT03907852 .
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Affiliation(s)
- Raffit Hassan
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
| | - Marcus Butler
- Princess Margaret Cancer Centre, Toronto, ON, Canada
| | - Roisin E O'Cearbhaill
- Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, USA
| | - David Y Oh
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | | | | | | | | | - Janos L Tanyi
- Hospital of the University of Pennsylvania, Abramson Cancer Center, Philadelphia, PA, USA
| | - Azam Ghafoor
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Nirali N Shah
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Babak Saboury
- Department of Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Liang Cao
- Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | | | - David Hong
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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Gustafson MP, Ligon JA, Bersenev A, McCann CD, Shah NN, Hanley PJ. Emerging frontiers in immuno- and gene therapy for cancer. Cytotherapy 2023; 25:20-32. [PMID: 36280438 PMCID: PMC9790040 DOI: 10.1016/j.jcyt.2022.10.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 09/13/2022] [Accepted: 10/05/2022] [Indexed: 12/27/2022]
Abstract
BACKGROUND AIMS The field of cell and gene therapy in oncology has moved rapidly since 2017 when the first cell and gene therapies, Kymriah followed by Yescarta, were approved by the Food and Drug Administration in the United States, followed by multiple other countries. Since those approvals, several new products have gone on to receive approval for additional indications. Meanwhile, efforts have been made to target different cancers, improve the logistics of delivery and reduce the cost associated with novel cell and gene therapies. Here, we highlight various cell and gene therapy-related technologies and advances that provide insight into how these new technologies will speed the translation of these therapies into the clinic. CONCLUSIONS In this review, we provide a broad overview of the current state of cell and gene therapy-based approaches for cancer treatment - discussing various effector cell types and their sources, recent advances in both CAR and non-CAR genetic modifications, and highlighting a few promising approaches for increasing in vivo efficacy and persistence of therapeutic drug products.
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Affiliation(s)
- Michael P Gustafson
- Immuno-Gene Therapy Committee, International Society for Cell and Gene Therapy; Department of Laboratory Medicine and Pathology, Mayo Clinic in Arizona, Phoenix, Arizona, USA
| | - John A Ligon
- Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA; Department of Pediatrics, Division of Pediatric Hematology/Oncology, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Alexey Bersenev
- Immuno-Gene Therapy Committee, International Society for Cell and Gene Therapy; Department of Laboratory Medicine, Yale School of Medicine, Yale University, New Haven, Connecticut, USA
| | - Chase D McCann
- Center for Cancer and Immunology Research, Children's National Hospital, Washington, DC, USA; Department of Pediatrics, The George Washington University, Washington, DC, USA
| | - Nirali N Shah
- Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Patrick J Hanley
- Immuno-Gene Therapy Committee, International Society for Cell and Gene Therapy; Center for Cancer and Immunology Research, Children's National Hospital, Washington, DC, USA; Department of Pediatrics, The George Washington University, Washington, DC, USA.
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28
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Pallares RM, Abergel RJ. Development of radiopharmaceuticals for targeted alpha therapy: Where do we stand? Front Med (Lausanne) 2022; 9:1020188. [PMID: 36619636 PMCID: PMC9812962 DOI: 10.3389/fmed.2022.1020188] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 12/05/2022] [Indexed: 12/24/2022] Open
Abstract
Targeted alpha therapy is an oncological treatment, where cytotoxic doses of alpha radiation are locally delivered to tumor cells, while the surrounding healthy tissue is minimally affected. This therapeutic strategy relies on radiopharmaceuticals made of medically relevant radionuclides chelated by ligands, and conjugated to targeting vectors, which promote the drug accumulation in tumor sites. This review discusses the state-of-the-art in the development of radiopharmaceuticals for targeted alpha therapy, breaking down their key structural components, such as radioisotope, targeting vector, and delivery formulation, and analyzing their pros and cons. Moreover, we discuss current drawbacks that are holding back targeted alpha therapy in the clinic, and identify ongoing strategies in field to overcome those issues, including radioisotope encapsulation in nanoformulations to prevent the release of the daughters. Lastly, we critically discuss potential opportunities the field holds, which may contribute to targeted alpha therapy becoming a gold standard treatment in oncology in the future.
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Affiliation(s)
- Roger M. Pallares
- Lawrence Berkeley National Laboratory, Chemical Sciences Division, Berkeley, CA, United States
| | - Rebecca J. Abergel
- Lawrence Berkeley National Laboratory, Chemical Sciences Division, Berkeley, CA, United States,Department of Nuclear Engineering, University of California, Berkeley, Berkeley, CA, United States,*Correspondence: Rebecca J. Abergel,
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29
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Wang AJ, Gao Y, Shi YY, Dai MY, Cai HB. A review of recent advances on single use of antibody-drug conjugates or combination with tumor immunology therapy for gynecologic cancer. Front Pharmacol 2022; 13:1093666. [PMID: 36618922 PMCID: PMC9813853 DOI: 10.3389/fphar.2022.1093666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 12/12/2022] [Indexed: 12/24/2022] Open
Abstract
Immune checkpoint inhibitors have made significant progress in the treatment of various cancers. However, due to the low ICI responsive rate for the gynecologic cancer, ICI two-drug combination therapy tends to be a predominant way for clinical treatment. Antibody-drug conjugates, a promising therapeutic modality for cancer, have been approved by the FDA for breast cancer, lymphoma, multiple myeloma and gastric cancer. On September 2021, the FDA granted accelerated approval to tisotumab vedotin for patients with recurrent or metastatic cervical cancer. Currently, the role of therapy of ADCs on gynecologic tumors was also included in medication regimens. Now more than 30 ADCs targeting for 20 biomarkers are under clinical trials in the field, including monotherapy or combination with others for multiple lines of therapy. Some ADCs have been proved to enhance the antitumor immunity effect on both pre-clinical models and clinical trials. Therefore, combination of ADCs and ICIs are expected in clinical trials. In this review, we discuss current development of ADCs in gynecologic oncology and the combination effects of ICIs and ADCs.
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Affiliation(s)
- An-Jin Wang
- Department of Gynecological Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China,Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, Hubei, China,Hubei Cancer Clinical Study Center, Wuhan, Hubei, China
| | - Yang Gao
- Department of Gynecological Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China,Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, Hubei, China,Hubei Cancer Clinical Study Center, Wuhan, Hubei, China
| | - Yu-Ying Shi
- Department of Gynecological Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China,Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, Hubei, China,Hubei Cancer Clinical Study Center, Wuhan, Hubei, China
| | - Meng-Yuan Dai
- Department of Gynecological Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China,Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, Hubei, China,Hubei Cancer Clinical Study Center, Wuhan, Hubei, China,*Correspondence: Meng-Yuan Dai, ; Hong-Bing Cai,
| | - Hong-Bing Cai
- Department of Gynecological Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China,Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, Hubei, China,Hubei Cancer Clinical Study Center, Wuhan, Hubei, China,*Correspondence: Meng-Yuan Dai, ; Hong-Bing Cai,
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Mesothelin Gene Variants Affect Soluble Mesothelin-Related Protein Levels in the Plasma of Asbestos-Exposed Males and Mesothelioma Patients from Germany. BIOLOGY 2022; 11:biology11121826. [PMID: 36552335 PMCID: PMC9776112 DOI: 10.3390/biology11121826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/08/2022] [Accepted: 12/12/2022] [Indexed: 12/23/2022]
Abstract
Malignant mesothelioma (MM) is a severe disease mostly caused by asbestos exposure. Today, one of the best available biomarkers is the soluble mesothelin-related protein (SMRP), also known as mesothelin. Recent studies have shown that mesothelin levels are influenced by individual genetic variability. This study aimed to investigate the influence of three mesothelin (MSLN) gene variants (SNPs) in the 5′-untranslated promoter region (5′-UTR), MSLN rs2235503 C > A, rs3764246 A > G, rs3764247 A > C, and one (rs1057147 G > A) in the 3′-untranslated region (3′-UTR) of the MSLN gene on plasma concentrations of mesothelin in 410 asbestos-exposed males without cancer and 43 males with prediagnostic MM (i.e., with MM diagnosed later on) from the prospective MoMar study, as well as 59 males with manifest MM from Germany. The mesothelin concentration differed significantly between the different groups (p < 0.0001), but not between the prediagnostic and manifest MM groups (p = 0.502). Five to eight mutations of the four SNP variants studied were associated with increased mesothelin concentrations (p = 0.001). The highest mesothelin concentrations were observed for homozygous variants of the three promotor SNPs in the 5′-UTR (p < 0.001), and the highest odds ratio for an elevated mesothelin concentration was observed for MSLN rs2235503 C > A. The four studied SNPs had a clear influence on the mesothelin concentration in plasma. Hence, the analysis of these SNPs may help to elucidate the diagnostic background of patients displaying increased mesothelin levels and might help to reduce false-positive results when using mesothelin for MM screening in high-risk groups.
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Amer HT, Eissa RA, El Tayebi HM. A cutting-edge immunomodulatory interlinkage between HOTAIR and MALAT1 in tumor-associated macrophages in breast cancer: A personalized immunotherapeutic approach. Front Mol Biosci 2022; 9:1032517. [PMID: 36387279 PMCID: PMC9649622 DOI: 10.3389/fmolb.2022.1032517] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 10/10/2022] [Indexed: 07/30/2023] Open
Abstract
Breast cancer (BC) is one of the most common cancers, accounting for 2.3 million cases worldwide. BC can be molecularly subclassified into luminal A, luminal B HER2-, luminal B HER2+, HER2+, and triple-negative breast cancer (TNBC). These molecular subtypes differ in their prognosis and treatment strategies; thus, understanding the tumor microenvironment (TME) of BC could lead to new potential treatment strategies. The TME hosts a population of cells that act as antitumorigenic such as tumor-associated eosinophils or pro-tumorigenic such as cancer-associated fibroblasts (CAFs), tumor-associated neutrophils (TANs), monocytic-derived populations such as MDSCs, or most importantly "tumor-associated macrophages (TAMs)," which are derived from CD14+ monocytes. TAMs are reported to have the pro-inflammatory phenotype M1, which is found only in the very early stages of tumor and is not correlated with progression; however, the M2 phenotype is anti-inflammatory that is correlated with tumor progression and metastasis. The current study focused on controlling the anti-inflammatory activity in TAMs of hormonal, HER2+, and TNBC by epigenetic fine-tuning of two immunomodulatory proteins, namely, CD80 and mesothelin (MSLN), which are known to be overexpressed in BC with pro-tumorigenic activity. Long non-coding RNAs are crucial key players in tumor progression whether acting as oncogenic or tumor suppressors. We focused on the regulatory role of MALAT1 and HOTAIR lncRNAs and their role in controlling the tumorigenic activity of TAMs. This study observed the impact of manipulation of MALAT1 and HOTAIR on the expression of both CD80 and MSLN in TAMs of BC. Moreover, we analyzed the interlinkage between HOTAIR and MALAT1 as regulators to one another in TAMs of BC. The current study reported an upstream regulatory effect of HOTAIR on MALAT1. Moreover, our results showed a promising use of MALAT1 and HOTAIR in regulating oncogenic immune-modulatory proteins MSLN and CD80 in TAMs of HER2+ and TNBC. The downregulation of MALAT1 and HOTAIR resulted in the upregulation of CD80 and MSLN, which indicates that they might have a cell-specific activity in TAMs. These data shed light on novel key players affecting the anti-inflammatory activity of TAMs as a possible therapeutic target in HER2+ and TNBC.
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Affiliation(s)
- Hoda T. Amer
- Department of Pharmacology and Toxicology, The Molecular Pharmacology Research Group, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Reda A. Eissa
- Department of Surgery, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Hend M. El Tayebi
- Department of Pharmacology and Toxicology, The Molecular Pharmacology Research Group, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
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Nishio T, Koyama Y, Fuji H, Ishizuka K, Iwaisako K, Taura K, Hatano E, Brenner DA, Kisseleva T. The Role of Mesothelin in Activation of Portal Fibroblasts in Cholestatic Liver Injury. BIOLOGY 2022; 11:1589. [PMID: 36358290 PMCID: PMC9687690 DOI: 10.3390/biology11111589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 10/18/2022] [Accepted: 10/27/2022] [Indexed: 11/05/2022]
Abstract
Fibrosis is a common consequence of abnormal wound healing, which is characterized by infiltration of myofibroblasts and formation of fibrous scar. In liver fibrosis, activated Hepatic Stellate Cells (aHSCs) and activated Portal Fibroblasts (aPFs) are the major contributors to the origin of hepatic myofibroblasts. aPFs are significantly involved in the pathogenesis of cholestatic fibrosis, suggesting that aPFs may be a primary target for anti-fibrotic therapy in cholestatic injury. aPFs are distinguishable from aHSCs by specific markers including mesothelin (Msln), Mucin 16 (Muc16), and Thymus cell antigen 1 (Thy1, CD90) as well as fibulin 2, elastin, Gremlin 1, ecto-ATPase nucleoside triphosphate diphosphohydrolase 2. Msln plays a critical role in activation of PFs, via formation of Msln-Muc16-Thy1 complex that regulates TGFβ1/TGFβRI-mediated fibrogenic signaling. The opposing pro- and anti-fibrogenic effects of Msln and Thy1 are key components of the TGFβ1-induced activation pathway in aPFs. In addition, aPFs and activated lung and kidney fibroblasts share similarities across different organs with expression of common markers and activation cascade including Msln-Thy1 interaction. Here, we summarize the potential function of Msln in activation of PFs and development of cholestatic fibrosis, offering a novel perspective for anti-fibrotic therapy targeting Msln.
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Affiliation(s)
- Takahiro Nishio
- Department of Medicine, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA
- Department of Surgery, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA
- Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawaharacho Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Yukinori Koyama
- Department of Medicine, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA
- Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawaharacho Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Hiroaki Fuji
- Department of Medicine, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA
- Department of Surgery, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA
| | - Kei Ishizuka
- Department of Medicine, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA
- Department of Surgery, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA
| | - Keiko Iwaisako
- Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, 1-3 Tataramiyakodani, Kyotanabe 610-0394, Japan
| | - Kojiro Taura
- Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawaharacho Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
- Department of Gastroenterological Surgery and Oncology, Kitano Hospital Medical Research Institute, 2-4-20 Ogimachi, Kita-ku, Osaka 530-8480, Japan
| | - Etsuro Hatano
- Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawaharacho Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - David A. Brenner
- Department of Medicine, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA
| | - Tatiana Kisseleva
- Department of Surgery, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA
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Wang Q, Gong R. Immunotherapy targeting mesothelin in acute myeloid leukemia. J Leukoc Biol 2022; 112:813-821. [PMID: 35946307 DOI: 10.1002/jlb.5mr0622-483r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 06/06/2022] [Indexed: 11/08/2022] Open
Abstract
Mesothelin (MSLN) is an emerging target that exists in soluble and membrane-associated forms. It is usually used for the diagnosis and treatment of MSLN-positive solid tumors. Interestingly, recent studies have shown that MSLN is highly expressed in 36% of acute myeloid leukemia (AML) patients and barely expressed in normal hematopoietic cells, which makes MSLN a promising target for the treatment of AML. It has been shown that MSLN is detectable as a diagnostic marker in its soluble form. Although the mechanism of action is unclear, MSLN remains a promising target for immunotherapy. Most MSLN research has been conducted in solid tumors, and less research has been conducted in hematopoietic tumors. Increasing research on MSLN is underway in AML, a hematopoietic neoplasm. For example, MSLN is related to extramedullary disease, minimal residual disease, and relapse in AML patients. Decreasing the expression of MSLN reduces the severity of the disease course. This information suggests that MSLN may be an ideal target for the treatment of many AML-related diseases to improve the prognosis and survival rate. At present, there are a few immunotherapies targeting MSLN in AML in preclinical and clinical trials, such as antibody-drug conjugates, bispecific T-cell engagers, and chimeric antigen receptor-T cells, which opens new room for the treatment of MSLN-related AML.
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Affiliation(s)
- Qingguang Wang
- CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Rui Gong
- CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, China.,University of Chinese Academy of Sciences, Beijing, China
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Characterization of Mesothelin Glycosylation in Pancreatic Cancer: Decreased Core Fucosylated Glycoforms in Pancreatic Cancer Patients’ Sera. Biomedicines 2022; 10:biomedicines10081942. [PMID: 36009489 PMCID: PMC9405996 DOI: 10.3390/biomedicines10081942] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 07/27/2022] [Accepted: 08/08/2022] [Indexed: 11/21/2022] Open
Abstract
Currently, there are no reliable biomarkers for the diagnosis of pancreatic cancer (PaC). Glycoproteomic approaches that analyze the glycan determinants on specific glycoproteins have proven useful to develop more specific cancer biomarkers than the corresponding protein levels. In PaC, mesothelin (MSLN) is a neo-expressed glycoprotein. MSLN glycosylation has not been described and could be altered in PaC. In this work, we aimed to characterize MSLN glycans from PaC cells and serum samples to assess their potential usefulness as PaC biomarkers. First, we analyzed MSLN glycans from PaC cell lines and then we developed an enzyme-linked lectin assay to measure core fucosylated-MSLN (Cf-MSLN) glycoforms. MSLN glycans from PaC cells were analyzed by glycan sequencing and through Western blotting with lectins. All of the cell lines secreted MSLN, with its three N-glycosylation sites occupied by complex-type N-glycans, which were mainly α2,3-sialylated, core fucosylated and highly branched. The Cf-MSLN glycoforms were quantified on PaC serum samples, and compared with MSLN protein levels. The Cf-MSLN was significantly decreased in PaC patients compared to control sera, while no differences were detected by using MSLN protein levels. In conclusion, Cf-MSLN glycoforms were differently expressed in PaC, which opens the way to further investigate their usefulness as PaC biomarkers.
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Circulating and non-circulating proteins and nucleic acids as biomarkers and therapeutic molecules in ovarian cancer. Genes Dis 2022. [DOI: 10.1016/j.gendis.2022.07.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Tomar S, Zhang J, Khanal M, Hong J, Venugopalan A, Jiang Q, Sengupta M, Miettinen M, Li N, Pastan I, Ho M, Hassan R. Development of Highly Effective Anti-Mesothelin hYP218 Chimeric Antigen Receptor T Cells With Increased Tumor Infiltration and Persistence for Treating Solid Tumors. Mol Cancer Ther 2022; 21:1195-1206. [PMID: 35499461 PMCID: PMC9256778 DOI: 10.1158/1535-7163.mct-22-0073] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 03/09/2022] [Accepted: 04/18/2022] [Indexed: 11/16/2022]
Abstract
Mesothelin targeting CAR T cells have limited activity in patients. In this study, we sought to determine if efficacy of anti-mesothelin CAR T cells is dependent on the mesothelin epitopes that are recognized by them. To do so, we developed hYP218 (against membrane-proximal epitope) and SS1 (against membrane-distal epitope) CAR T cells. Their efficacy was assessed in vitro using mesothelin-positive tumor cell lines and in vivo in NSG mice with mesothelin-expressing ovarian cancer (OVCAR-8), pancreatic cancer (KLM-1), and mesothelioma patient-derived (NCI-Meso63) tumor xenografts. Persistence and tumor infiltration of CAR T cells was determined using flow cytometry. hYP218 CAR T cells killed cancer cells more efficiently than SS1 CAR T cells, with a two- to fourfold lower ET50 value (effector-to-target ratio for 50% killing of tumor cells). In mice with established tumors, single intravenous administration of hYP218 CAR T cells lead to improved tumor response and survival compared with SS1 CAR T cells, with complete regression of OVCAR-8 and NCI-Meso63 tumors. Compared with SS1 CAR T cells, there was increased peripheral blood expansion, persistence, and tumor infiltration of hYP218 CAR T cells in the KLM-1 tumor model. Persistence of hYP218 CAR T cells in treated mice led to antitumor immunity when rechallenged with KLM-1 tumor cells. Our results show that hYP218 CAR T cells, targeting mesothelin epitope close to cell membrane, are very effective against mesothelin-positive tumors and are associated with increased persistence and tumor infiltration. These results support its clinical development to treat patients with mesothelin-expressing cancers.
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Affiliation(s)
- Sakshi Tomar
- Thoracic and GI Malignancies Branch, CCR, NCI, NIH, Bethesda, Maryland
| | - Jingli Zhang
- Thoracic and GI Malignancies Branch, CCR, NCI, NIH, Bethesda, Maryland
| | - Manakamana Khanal
- Thoracic and GI Malignancies Branch, CCR, NCI, NIH, Bethesda, Maryland
| | - Jessica Hong
- Laboratory of Molecular Biology, CCR, NCI, NIH, Bethesda, Maryland
| | | | - Qun Jiang
- Thoracic and GI Malignancies Branch, CCR, NCI, NIH, Bethesda, Maryland
| | | | | | - Nan Li
- Laboratory of Molecular Biology, CCR, NCI, NIH, Bethesda, Maryland
| | - Ira Pastan
- Laboratory of Molecular Biology, CCR, NCI, NIH, Bethesda, Maryland
| | - Mitchell Ho
- Laboratory of Molecular Biology, CCR, NCI, NIH, Bethesda, Maryland
| | - Raffit Hassan
- Thoracic and GI Malignancies Branch, CCR, NCI, NIH, Bethesda, Maryland
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Sitta J, Claudio PP, Howard CM. Virus-Based Immuno-Oncology Models. Biomedicines 2022; 10:biomedicines10061441. [PMID: 35740462 PMCID: PMC9220907 DOI: 10.3390/biomedicines10061441] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 06/04/2022] [Accepted: 06/15/2022] [Indexed: 12/12/2022] Open
Abstract
Immunotherapy has been extensively explored in recent years with encouraging results in selected types of cancer. Such success aroused interest in the expansion of such indications, requiring a deep understanding of the complex role of the immune system in carcinogenesis. The definition of hot vs. cold tumors and the role of the tumor microenvironment enlightened the once obscure understanding of low response rates of solid tumors to immune check point inhibitors. Although the major scope found in the literature focuses on the T cell modulation, the innate immune system is also a promising oncolytic tool. The unveiling of the tumor immunosuppressive pathways, lead to the development of combined targeted therapies in an attempt to increase immune infiltration capability. Oncolytic viruses have been explored in different scenarios, in combination with various chemotherapeutic drugs and, more recently, with immune check point inhibitors. Moreover, oncolytic viruses may be engineered to express tumor specific pro-inflammatory cytokines, antibodies, and antigens to enhance immunologic response or block immunosuppressive mechanisms. Development of preclinical models capable to replicate the human immunologic response is one of the major challenges faced by these studies. A thorough understanding of immunotherapy and oncolytic viruses’ mechanics is paramount to develop reliable preclinical models with higher chances of successful clinical therapy application. Thus, in this article, we review current concepts in cancer immunotherapy including the inherent and synthetic mechanisms of immunologic enhancement utilizing oncolytic viruses, immune targeting, and available preclinical animal models, their advantages, and limitations.
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Affiliation(s)
- Juliana Sitta
- Department of Radiology, University of Mississippi Medical Center, Jackson, MS 39216, USA;
| | - Pier Paolo Claudio
- Department of BioMolecular Sciences, Department of Radiation Oncology, Cancer Center & Research Institute, University of Mississippi Medical Center, Jackson, MS 39216, USA;
| | - Candace M. Howard
- Department of Radiology, University of Mississippi Medical Center, Jackson, MS 39216, USA;
- Correspondence:
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Teicher BA, Morris J. Antibody-Drug Conjugate Targets, Drugs and Linkers. Curr Cancer Drug Targets 2022; 22:463-529. [PMID: 35209819 DOI: 10.2174/1568009622666220224110538] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 10/22/2021] [Accepted: 11/09/2021] [Indexed: 11/22/2022]
Abstract
Antibody-drug conjugates offer the possibility of directing powerful cytotoxic agents to a malignant tumor while sparing normal tissue. The challenge is to select an antibody target expressed exclusively or at highly elevated levels on the surface of tumor cells and either not all or at low levels on normal cells. The current review explores 78 targets that have been explored as antibody-drug conjugate targets. Some of these targets have been abandoned, 9 or more are the targets of FDA-approved drugs, and most remain active clinical interest. Antibody-drug conjugates require potent cytotoxic drug payloads, several of these small molecules are discussed, as are the linkers between the protein component and small molecule components of the conjugates. Finally, conclusions regarding the elements for the successful antibody-drug conjugate are discussed.
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Affiliation(s)
- Beverly A Teicher
- Developmental Therapeutics Program, DCTD, National Cancer Institute, Bethesda, MD 20892,United States
| | - Joel Morris
- Developmental Therapeutics Program, DCTD, National Cancer Institute, Bethesda, MD 20892,United States
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Engineering of Cytolethal Distending Toxin B by Its Reducing Immunogenicity and Maintaining Stability as a New Drug Candidate for Tumor Therapy; an In Silico Study. Toxins (Basel) 2021; 13:toxins13110785. [PMID: 34822569 PMCID: PMC8624547 DOI: 10.3390/toxins13110785] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Revised: 10/30/2021] [Accepted: 11/01/2021] [Indexed: 12/25/2022] Open
Abstract
The cytolethal distending toxin (CDT), Haemophilus ducreyi, is one of the bacterial toxins that have recently been considered for targeted therapies, especially in cancer therapies. CDT is an A-B2 exotoxin. Its catalytic subunit (CdtB) is capable of inducing DNA double strand breaks, cell cycle arrest and apoptosis in host eukaryotic cells. The sequence alignment indicates that the CdtB is structurally homologyr to phosphatases and deoxyribonucleases I (DNase I). Recently, it has been found that CdtB toxicity is mainly related to its nuclease activity. The immunogenicity of CDT can reduce its effectiveness in targeted therapies. However, the toxin can be very useful if its immunogenicity is significantly reduced. Detecting hotspot ectopic residues by computational servers and then mutating them to eliminate B-cell epitopes is a promising approach to reduce the immunogenicity of foreign protein-based therapeutics. By the mentioned method, in this study, we try to reduce the immunogenicity of the CdtB- protein sequence. This study initially screened residue of the CdtB is B-cell epitopes both linearly and conformationally. By overlapping the B-cell epitopes with the excluded conserve residues, and active and enzymatic sites, four residues were allowed to be mutated. There were two mutein options that show reduced antigenicity probability. Option one was N19F, G74I, and S161F with a VaxiJen score of 0.45 and the immune epitope database (IEDB) score of 1.80, and option two was N19F, G74I, and S161W with a VaxiJen score of 0.45 and IEDB score of 1.88. The 3D structure of the proposed sequences was evaluated and refined. The structural stability of native and mutant proteins was accessed through molecular dynamic simulation. The results showed that the mutations in the mutants caused no considerable changes in their structural stability. However, mutant 1 reveals more thermodynamic stability during the simulation. The applied approaches in this study can be used as rough guidelines for finding hot spot immunogen regions in the therapeutic proteins. Our results provide a new version of CdtB that, due to reduced immunogenicity and increased stability, can be used in toxin-based drugs such as immunotoxins.
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Howell LM, Forbes NS. Bacteria-based immune therapies for cancer treatment. Semin Cancer Biol 2021; 86:1163-1178. [PMID: 34547442 DOI: 10.1016/j.semcancer.2021.09.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 09/03/2021] [Accepted: 09/12/2021] [Indexed: 12/23/2022]
Abstract
Engineered bacterial therapies that target the tumor immune landscape offer a new class of cancer immunotherapy. Salmonella enterica and Listeria monocytogenes are two species of bacteria that have been engineered to specifically target tumors and serve as delivery vessels for immunotherapies. Therapeutic bacteria have been engineered to deliver cytokines, gene silencing shRNA, and tumor associated antigens that increase immune activation. Bacterial therapies stimulate both the innate and adaptive immune system, change the immune dynamics of the tumor microenvironment, and offer unique strategies for targeting tumors. Bacteria have innate adjuvant properties, which enable both the delivered molecules and the bacteria themselves to stimulate immune responses. Bacterial immunotherapies that deliver cytokines and tumor-associated antigens have demonstrated clinical efficacy. Harnessing the diverse set of mechanisms that Salmonella and Listeria use to alter the tumor-immune landscape has the potential to generate many new and effective immunotherapies.
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Affiliation(s)
- Lars M Howell
- Department of Chemical Engineering, University of Massachusetts, Amherst, United States
| | - Neil S Forbes
- Department of Chemical Engineering, University of Massachusetts, Amherst, United States.
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Mashayekhi V, Mocellin O, Fens MH, Krijger GC, Brosens LA, Oliveira S. Targeting of promising transmembrane proteins for diagnosis and treatment of pancreatic ductal adenocarcinoma. Theranostics 2021; 11:9022-9037. [PMID: 34522225 PMCID: PMC8419040 DOI: 10.7150/thno.60350] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 07/12/2021] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal types of cancer due to the relatively late diagnosis and the limited therapeutic options. Current treatment regimens mainly comprise the cytotoxic agents gemcitabine and FOLFIRINOX. These compounds have shown limited efficacy and severe side effects, highlighting the necessity for earlier detection and the development of more effective, and better-tolerated treatments. Although targeted therapies are promising for the treatment of several types of cancer, identification of suitable targets for early diagnosis and targeted therapy of PDAC is challenging. Interestingly, several transmembrane proteins are overexpressed in PDAC cells that show low expression in healthy pancreas and may therefore serve as potential targets for treatment and/or diagnostic purposes. In this review we describe the 11 most promising transmembrane proteins, carefully selected after a thorough literature search. Favorable features and potential applications of each target, as well as the results of the preclinical and clinical studies conducted in the past ten years, are discussed in detail.
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Affiliation(s)
- Vida Mashayekhi
- Cell Biology, Neurobiology and Biophysics, Department of Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, the Netherlands
| | - Orsola Mocellin
- Cell Biology, Neurobiology and Biophysics, Department of Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, the Netherlands
| | - Marcel H.A.M. Fens
- Pharmaceutics, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, the Netherlands
| | - Gerard C. Krijger
- Department of Radiology and Nuclear Medicine, University Medical Center Utrecht, Faculty of Medicine, Utrecht University, 3584 CX Utrecht, the Netherlands
| | - Lodewijk A.A. Brosens
- Department of Pathology, University Medical Center Utrecht, Faculty of Medicine, Utrecht University, 3584 CX Utrecht, the Netherlands
| | - Sabrina Oliveira
- Cell Biology, Neurobiology and Biophysics, Department of Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, the Netherlands
- Pharmaceutics, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, the Netherlands
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Yeo D, Castelletti L, van Zandwijk N, Rasko JEJ. Hitting the Bull's-Eye: Mesothelin's Role as a Biomarker and Therapeutic Target for Malignant Pleural Mesothelioma. Cancers (Basel) 2021; 13:3932. [PMID: 34439085 PMCID: PMC8391149 DOI: 10.3390/cancers13163932] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 07/28/2021] [Accepted: 07/29/2021] [Indexed: 12/16/2022] Open
Abstract
Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited treatment options and poor prognosis. MPM originates from the mesothelial lining of the pleura. Mesothelin (MSLN) is a glycoprotein expressed at low levels in normal tissues and at high levels in MPM. Many other solid cancers overexpress MSLN, and this is associated with worse survival rates. However, this association has not been found in MPM, and the exact biological role of MSLN in MPM requires further exploration. Here, we discuss the current research on the diagnostic and prognostic value of MSLN in MPM patients. Furthermore, MSLN has become an attractive immunotherapy target in MPM, where better treatment strategies are urgently needed. Several MSLN-targeted monoclonal antibodies, antibody-drug conjugates, immunotoxins, cancer vaccines, and cellular therapies have been tested in the clinical setting. The biological rationale underpinning MSLN-targeted immunotherapies and their potential to improve MPM patient outcomes are reviewed.
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Affiliation(s)
- Dannel Yeo
- Li Ka Shing Cell & Gene Therapy Program, The University of Sydney, Camperdown, NSW 2050, Australia; (D.Y.); (L.C.)
- Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia;
- Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney Local Health District (SLHD), Camperdown, NSW 2050, Australia
| | - Laura Castelletti
- Li Ka Shing Cell & Gene Therapy Program, The University of Sydney, Camperdown, NSW 2050, Australia; (D.Y.); (L.C.)
- Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia;
- Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney Local Health District (SLHD), Camperdown, NSW 2050, Australia
| | - Nico van Zandwijk
- Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia;
- Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney Local Health District (SLHD), Camperdown, NSW 2050, Australia
- Concord Repatriation General Hospital, Sydney Local Health District (SLHD), Concord, NSW 2139, Australia
| | - John E. J. Rasko
- Li Ka Shing Cell & Gene Therapy Program, The University of Sydney, Camperdown, NSW 2050, Australia; (D.Y.); (L.C.)
- Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia;
- Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney Local Health District (SLHD), Camperdown, NSW 2050, Australia
- Gene and Stem Cell Therapy Program, Centenary Institute, The University of Sydney, Camperdown, NSW 2050, Australia
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Hagerty B, O'Sullivan TN, Zhang X, Collins NK, Lawrence WC, Bassel LL, Pate N, Xu J, Guerin TM, Kozlov S, Alewine C. Novel humanized mesothelin-expressing genetically engineered mouse models underscore challenges in delivery of complex therapeutics to pancreatic cancers. Mol Cancer Ther 2021; 20:2082-2092. [PMID: 34315768 DOI: 10.1158/1535-7163.mct-21-0017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 04/23/2021] [Accepted: 07/09/2021] [Indexed: 11/16/2022]
Abstract
Antibody-based therapies designed for human use frequently fail to cross-react with the murine isoform of their target. Due to this problem, pre-clinical studies of antibody-based mesothelin-targeted therapeutics in immune competent systems have been limited by the lack of suitable mouse models. Here, we describe two immune-competent humanized mesothelin transgenic mouse lines that can act as tolerant hosts for C57Bl/6-syngeneic cell lines expressing the human isoform of mesothelin. Thyroid peroxidase (TPO) mice have thyroid-restricted human mesothelin expression. Mesothelin (Msl) mice express human mesothelin in the typical serosal membrane distribution and can additionally be utilized to assess on-target, off-tumor toxicity of human mesothelin-targeted therapeutics. Both transgenic strains shed human mesothelin into the serum like human mesothelioma and ovarian cancer patients and serum human mesothelin can be used as a blood-based surrogate of tumor burden. Using these models, we examined the on-target toxicity and anti-tumor activity of human mesothelin-targeted recombinant immunotoxins. We found that immunotoxin treatment causes acute and chronic histologic changes to serosal membranes in Msl mice while human mesothelin-expressing thyroid follicular cells in TPO mice are resistant to immunotoxin despite excellent drug delivery. Furthermore, poor delivery of immunotoxin to syngeneic orthotopic human mesothelin-expressing pancreatic adenocarcinoma limits anti-tumor activity both alone and in combination with immune checkpoint inhibition. In summary, we have developed two high-fidelity, immunocompetent murine models for human cancer that allow for rigorous pre-clinical evaluation of human mesothelin-targeted therapeutics.
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Affiliation(s)
- Brendan Hagerty
- Laboratory of Molecular Biology, NIH- National Cancer Institute Center for Cancer Research
| | - T Norene O'Sullivan
- Center for Advanced Preclinical Research, National Cancer Institute/Center for Cancer Research
| | - Xianyu Zhang
- Laboratory of Molecular Biology, NIH- National Cancer Institute Center for Cancer Research
| | - N Keith Collins
- Center for Advanced Preclinical Research, National Cancer Institute at Frederick, National Institutes of Health
| | - Wendi Custer Lawrence
- Center for Advanced Preclinical Research, Frederick National Laboratory for Cancer Research
| | - Laura L Bassel
- Molecular Histopathology Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research
| | - Nathan Pate
- Center for Advanced Preclinical Research, Leidos Biomedical Research, Inc. Frederick National Laboratory for Cancer Research (FNLCR)
| | - Jian Xu
- Laboratory Molecular Biology, National Cancer Institute
| | - Theresa M Guerin
- Center for Advanced Preclinical Research, SAIC at Frederick National Laboratory for Cancer Research
| | - Serguei Kozlov
- Center for Advanced Preclinical Research, Frederick National Laboratory for Cancer Research
| | - Christine Alewine
- Laboratory of Molecular Biology, NIH- National Cancer Institute Center for Cancer Research
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Immunotherapy-based targeting of MSLN + activated portal fibroblasts is a strategy for treatment of cholestatic liver fibrosis. Proc Natl Acad Sci U S A 2021; 118:2101270118. [PMID: 34253615 DOI: 10.1073/pnas.2101270118] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
We investigated the role of mesothelin (Msln) and thymocyte differentiation antigen 1 (Thy1) in the activation of fibroblasts across multiple organs and demonstrated that Msln-/- mice are protected from cholestatic fibrosis caused by Mdr2 (multidrug resistance gene 2) deficiency, bleomycin-induced lung fibrosis, and UUO (unilateral urinary obstruction)-induced kidney fibrosis. On the contrary, Thy1-/- mice are more susceptible to fibrosis, suggesting that a Msln-Thy1 signaling complex is critical for tissue fibroblast activation. A similar mechanism was observed in human activated portal fibroblasts (aPFs). Targeting of human MSLN+ aPFs with two anti-MSLN immunotoxins killed fibroblasts engineered to express human mesothelin and reduced collagen deposition in livers of bile duct ligation (BDL)-injured mice. We provide evidence that antimesothelin-based therapy may be a strategy for treatment of parenchymal organ fibrosis.
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Finton KAK, Brusniak MY, Jones LA, Lin C, Fioré-Gartland AJ, Brock C, Gafken PR, Strong RK. ARTEMIS: A Novel Mass-Spec Platform for HLA-Restricted Self and Disease-Associated Peptide Discovery. Front Immunol 2021; 12:658372. [PMID: 33986749 PMCID: PMC8111693 DOI: 10.3389/fimmu.2021.658372] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 03/30/2021] [Indexed: 11/25/2022] Open
Abstract
Conventional immunoprecipitation/mass spectroscopy identification of HLA-restricted peptides remains the purview of specializing laboratories, due to the complexity of the methodology, and requires computational post-analysis to assign peptides to individual alleles when using pan-HLA antibodies. We have addressed these limitations with ARTEMIS: a simple, robust, and flexible platform for peptide discovery across ligandomes, optionally including specific proteins-of-interest, that combines novel, secreted HLA-I discovery reagents spanning multiple alleles, optimized lentiviral transduction, and streamlined affinity-tag purification to improve upon conventional methods. This platform fills a middle ground between existing techniques: sensitive and adaptable, but easy and affordable enough to be widely employed by general laboratories. We used ARTEMIS to catalog allele-specific ligandomes from HEK293 cells for seven classical HLA alleles and compared results across replicates, against computational predictions, and against high-quality conventional datasets. We also applied ARTEMIS to identify potentially useful, novel HLA-restricted peptide targets from oncovirus oncoproteins and tumor-associated antigens.
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Affiliation(s)
- Kathryn A K Finton
- Division of Basic Science, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
| | - Mi-Youn Brusniak
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
| | - Lisa A Jones
- Proteomics Shared Resource, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
| | - Chenwei Lin
- Proteomics Shared Resource, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
| | - Andrew J Fioré-Gartland
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
| | - Chance Brock
- Division of Basic Science, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
| | - Philip R Gafken
- Proteomics Shared Resource, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
| | - Roland K Strong
- Division of Basic Science, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
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Li HL, Li QY, Jin MJ, Lu CF, Mu ZY, Xu WY, Song J, Zhang Y, Zhang SY. A review: hippo signaling pathway promotes tumor invasion and metastasis by regulating target gene expression. J Cancer Res Clin Oncol 2021; 147:1569-1585. [PMID: 33864521 DOI: 10.1007/s00432-021-03604-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 03/16/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND The Hippo pathway is widely considered to inhibit cell growth and play an important role in regulating the size of organs. However, recent studies have shown that abnormal regulation of the Hippo pathway can also affect tumor invasion and metastasis. Therefore, finding out how the Hippo pathway promotes tumor development by regulating the expression of target genes provides new ideas for future research on targeted drugs that inhibit tumor progression. METHODS PubMed, Embase, Web of Science, and the Cochrane Library were systematically searched. RESULTS The search strategy identified 1892 hits and 196 publications were finally included in this review. As the core molecule of the Hippo pathway, YAP/TAZ are usually highly expressed in tumors that undergo invasion and migration and are accompanied by abnormally strong nuclear metastasis. Through its interaction with nuclear transcription factors TEADs, it directly or indirectly regulates and the expressions of target genes related to tumor metastasis and invasion. These target genes can induce the formation of invasive pseudopodia in tumor cells, reduce intercellular adhesion, degrade extracellular matrix (ECM), and cause epithelial-mesenchymal transition (EMT), or indirectly promote through other signaling pathways, such as mitogen-activated protein kinases (MAPK), TGF/Smad, etc, which facilitate the invasion and metastasis of tumors. CONCLUSION This article mainly introduces the research progress of YAP/TAZ which are the core molecules of the Hippo pathway regulating related target genes to promote tumor invasion and metastasis. Focus on the target genes that affect tumor invasion and metastasis, providing the possibility for the selection of clinical drug treatment targets, to provide some help for a more in-depth study of tumor invasion and migration mechanism and the development of clinical drugs.
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Affiliation(s)
- Hong-Li Li
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Qian-Yu Li
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Min-Jie Jin
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Chao-Fan Lu
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Zhao-Yang Mu
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Wei-Yi Xu
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
| | - Jian Song
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China. .,School of Pharmaceutical Sciences, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Institute of Drug Discovery and Development, Zhengzhou, 450001, China.
| | - Yan Zhang
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
| | - Sai-Yang Zhang
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China. .,School of Pharmaceutical Sciences, Key Laboratory of Advanced Drug Preparation Technologies (Ministry of Education), Zhengzhou University, Institute of Drug Discovery and Development, Zhengzhou, 450001, China. .,Zhengzhou University, Henan Institute of Advanced Technology, Zhengzhou, 450001, China.
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Takihata Y, Einama T, Kobayashi K, Suzuki T, Yonamine N, Fujinuma I, Tsunenari T, Yamagishi Y, Iwasaki T, Miyata Y, Shinto E, Ogata S, Tsujimoto H, Ueno H, Kishi Y. Different role of MSLN and CA125 co-expression as a prognostic predictor between perihilar and distal bile duct carcinoma. Oncol Lett 2021; 21:414. [PMID: 33841575 PMCID: PMC8020376 DOI: 10.3892/ol.2021.12675] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 02/15/2021] [Indexed: 01/03/2023] Open
Abstract
Recent studies have suggested that the interaction of mesothelin (MSLN) and cancer antigen 125 (CA125) enhances tumor metastases. The aim of the present study was to clarify the impact of MSLN and CA125 co-expression on the prognosis of patients with extrahepatic bile duct carcinoma (BDC). Tissue samples from patients who underwent surgical resection between 2007 and 2015 for perihilar or distal BDC were immunohistochemically examined. The expression levels of MSLN and CA125 in tumor cells were analyzed. The expression in <50% and ≥50% of the total tumor cells were defined as low- and high-level expression, respectively. Tissue samples were obtained from 31 patients with perihilar BDC and 43 patients with distal BDC. Lymph node metastases were associated with MSLN and CA125 co-expression in patients with perihilar BDC (P=0.002), while there was no association between lymph node metastasis and co-expression in patients with distal BDC (P=0.362). MSLN and CA125 co-expression was associated with a worse overall survival rate in patients with perihilar BDC (5-year overall survival rate, co-expression positive vs. negative, 24 vs. 63%; P=0.038). To the best of our knowledge, the present study is the first to report an association between co-expression of MSLN and CA125 with a poor prognosis in patients with perihilar BDC. The current findings suggested that the significance of co-expression differed according to the BDC location.
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Affiliation(s)
- Yasuhiro Takihata
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
| | - Takahiro Einama
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
| | - Kazuki Kobayashi
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
| | - Takafumi Suzuki
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
| | - Naoto Yonamine
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
| | - Ibuki Fujinuma
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
| | - Takazumi Tsunenari
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
| | - Yoji Yamagishi
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
| | - Toshimitsu Iwasaki
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
| | - Yoichi Miyata
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
| | - Eiji Shinto
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
| | - Sho Ogata
- Department of Pathology and Laboratory Medicine, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
| | - Hironori Tsujimoto
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
| | - Hideki Ueno
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
| | - Yoji Kishi
- Department of Surgery, National Defense Medical College, Tokorozawa, Saitama 359-8513, Japan
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A Novel 89Zr-labeled DDS Device Utilizing Human IgG Variant (scFv): "Lactosome" Nanoparticle-Based Theranostics for PET Imaging and Targeted Therapy. Life (Basel) 2021; 11:life11020158. [PMID: 33670777 PMCID: PMC7923095 DOI: 10.3390/life11020158] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 02/13/2021] [Accepted: 02/15/2021] [Indexed: 12/22/2022] Open
Abstract
“Theranostics,” a new concept of medical advances featuring a fusion of therapeutic and diagnostic systems, provides promising prospects in personalized medicine, especially cancer. The theranostics system comprises a novel 89Zr-labeled drug delivery system (DDS), derived from the novel biodegradable polymeric micelle, “Lactosome” nanoparticles conjugated with specific shortened IgG variant, and aims to successfully deliver therapeutically effective molecules, such as the apoptosis-inducing small interfering RNA (siRNA) intracellularly while offering simultaneous tumor visualization via PET imaging. A 27 kDa-human single chain variable fragment (scFv) of IgG to establish clinically applicable PET imaging and theranostics in cancer medicine was fabricated to target mesothelin (MSLN), a 40 kDa-differentiation-related cell surface glycoprotein antigen, which is frequently and highly expressed by malignant tumors. This system coupled with the cell penetrating peptide (CPP)-modified and photosensitizer (e.g., 5, 10, 15, 20-tetrakis (4-aminophenyl) porphyrin (TPP))-loaded Lactosome particles for photochemical internalized (PCI) driven intracellular siRNA delivery and the combination of 5-aminolevulinic acid (ALA) photodynamic therapy (PDT) offers a promising nano-theranostic-based cancer therapy via its targeted apoptosis-inducing feature. This review focuses on the combined advances in nanotechnology and material sciences utilizing the “89Zr-labeled CPP and TPP-loaded Lactosome particles” and future directions based on important milestones and recent developments in this platform.
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Oda SK, Anderson KG, Ravikumar P, Bonson P, Garcia NM, Jenkins CM, Zhuang S, Daman AW, Chiu EY, Bates BM, Greenberg PD. A Fas-4-1BB fusion protein converts a death to a pro-survival signal and enhances T cell therapy. J Exp Med 2020; 217:e20191166. [PMID: 32860705 PMCID: PMC7953733 DOI: 10.1084/jem.20191166] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 06/02/2020] [Accepted: 08/03/2020] [Indexed: 12/20/2022] Open
Abstract
Adoptive T cell therapy (ACT) with genetically modified T cells has shown impressive results against some hematologic cancers, but efficacy in solid tumors can be limited by restrictive tumor microenvironments (TMEs). For example, Fas ligand is commonly overexpressed in TMEs and induces apoptosis in tumor-infiltrating, Fas receptor-positive lymphocytes. We engineered immunomodulatory fusion proteins (IFPs) to enhance ACT efficacy, combining an inhibitory receptor ectodomain with a costimulatory endodomain to convert negative into positive signals. We developed a Fas-4-1BB IFP that replaces the Fas intracellular tail with costimulatory 4-1BB. Fas-4-1BB IFP-engineered murine T cells exhibited increased pro-survival signaling, proliferation, antitumor function, and altered metabolism in vitro. In vivo, Fas-4-1BB ACT eradicated leukemia and significantly improved survival in the aggressive KPC pancreatic cancer model. Fas-4-1BB IFP expression also enhanced primary human T cell function in vitro. Thus, Fas-4-1BB IFP expression is a novel strategy to improve multiple T cell functions and enhance ACT against solid tumors and hematologic malignancies.
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Affiliation(s)
- Shannon K. Oda
- Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA
| | | | - Pranali Ravikumar
- Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Patrick Bonson
- Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Nicolas M. Garcia
- Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Cody M. Jenkins
- Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Summer Zhuang
- Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Andrew W. Daman
- Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Edison Y. Chiu
- Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Breanna M. Bates
- Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Philip D. Greenberg
- Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA
- Department of Medicine/Oncology, University of Washington, Seattle, WA
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Significance of mesothelin expression in preoperative endoscopic biopsy specimens for colorectal cancer prognosis. Oncotarget 2020; 11:3807-3817. [PMID: 33196692 PMCID: PMC7597413 DOI: 10.18632/oncotarget.27774] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 09/29/2020] [Indexed: 01/30/2023] Open
Abstract
Mesothelin (MSLN) is a cell surface glycoprotein that is normally expressed in the mesothelial cells but highly expressed in several malignant tumors, where the high expression is generally associated with poor prognosis. In this work, 512 patients with stage III colorectal cancer (CRC) were examined to ascertain the prognostic value of MSLN expression in preoperative endoscopic biopsy specimens. MSLN expression was evaluated by immunohistochemical staining. The tumor cells were MSLN-positive in 61 of the 512 patients (11.9%). MSLN expression was associated with a shorter disease-specific survival (DSS) period (5-year DSS = 68.7%, P = 0.0008). Besides, by multivariate analysis, MSLN expression was identified to be a marker of poor prognosis by multivariate analysis (P = 0.0033, hazard ratio (HR) = 2.31) as well as macroscopic type (P = 0.047, HR = 1.82) among the factors that can be evaluated preoperatively. MSLN-positive patients had a significantly poorer prognosis regardless of adjuvant chemotherapy administration (P = 0.0081 and P = 0.0018 for surgery alone and chemotherapy, respectively). MSLN-positive patients in the adjuvant chemotherapy group exhibited a significantly lower risk of recurrence when compared with those in the surgery alone group (P = 0.0090). In conclusion, high MSLN expression observed in preoperative endoscopic biopsy specimens of stage III CRC was an independent poor prognostic factor. Preoperative evaluation of MSLN by immunohistochemical staining might be applied to select individuals for intensive preoperative chemotherapy among the stage III CRC patients.
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