1
|
Tang S, Che X, Wang J, Li C, He X, Hou K, Zhang X, Guo J, Yang B, Li D, Cao L, Qu X, Wang Z, Liu Y. T-bet +CD8 + T cells govern anti-PD-1 responses in microsatellite-stable gastric cancers. Nat Commun 2025; 16:3905. [PMID: 40280928 PMCID: PMC12032036 DOI: 10.1038/s41467-025-58958-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Accepted: 04/04/2025] [Indexed: 04/29/2025] Open
Abstract
More than 90% of advanced gastric cancers (GC) are microsatellite-stable (MSS). Compared to the high response rate of immune checkpoint inhibitors (ICI) in microsatellite-instability-high (MSI-H) GCs, only 10% of unstratified MSS GCs respond to ICIs. In this study, we apply semi-supervised learning to stratify potential ICI responders in MSS GCs, achieving high accuracy, quantified by an area under the curve of 0.924. Spatial analysis of the tumor microenvironment of ICI-sensitive GCs reveals a high level of T-bet+ CD8 + T cell infiltration in their tumor compartments. T-bet+ CD8 + T cells exhibit superior anti-tumor activity due to their increased ability to infiltrate tumors and secrete cytotoxic molecules. Adoptive transfer of T-bet+ CD8 + T cells boosts anti-tumor immunity and confers susceptibility to ICIs in immune-ignorant MSS GCs in a humanized mouse model. Spatial RNA sequencing suggests a positive-feedback loop between T-bet+ T cells and PD-L1+ tumor cells, which eventually drives T cell exhaustion and can therefore be leveraged for ICI therapy. In summary, our research provides insights into the underlying mechanism of anti-tumor immunity and deepens our understanding of varied ICI responses in MSS GCs.
Collapse
Affiliation(s)
- Shiying Tang
- Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China
- Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China
| | - Xiaofang Che
- Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China
- Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China
| | - Jinyan Wang
- Department of Immunology, College of Basic Medical Sciences, China Medical University, No. 77, Puhe Road, Shenyang, Liaoning, China
| | - Ce Li
- Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China
- Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China
| | - Xin He
- Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China
- Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China
| | - Kezuo Hou
- Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China
- Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China
| | - Xiaojie Zhang
- Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China
- Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China
| | - Jia Guo
- Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China
- Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China
| | - Bowen Yang
- Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China
- Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China
| | - Danni Li
- Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China
- Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China
| | - Lili Cao
- Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China
- Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China
| | - Xiujuan Qu
- Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China.
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China.
- Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China.
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China.
| | - Zhenning Wang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, No.155, Nanjing Street, Shenyang, Liaoning, China.
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, China Medical University, Shenyang, Liaoning, China.
- Institute of Health Sciences, China Medical University, Shenyang, Liaoning, China.
| | - Yunpeng Liu
- Department of Medical Oncology, The First Hospital of China Medical University, No. 155, Nanjing Street, Shenyang, Liaoning, China.
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, China.
- Clinical Cancer Research Center of Shenyang, the First Hospital of China Medical University, Shenyang, China.
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, Ministry of Education, Shenyang, Liaoning, China.
| |
Collapse
|
2
|
Kulkarni AD, Mukarrama T, Barlow BR, Kim J. Recent advances in non-invasive in vivo tracking of cell-based cancer immunotherapies. Biomater Sci 2025; 13:1939-1959. [PMID: 40099377 PMCID: PMC11980607 DOI: 10.1039/d4bm01677g] [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] [Indexed: 03/19/2025]
Abstract
Immunotherapy has been at the forefront of cancer treatment research in recent years due to an increased understanding of the immune system's role in cancer and the substantial benefits it has demonstrated compared to conventional treatment methods. In particular, immune cell-based approaches utilizing T cells, natural killer (NK) cells, macrophages, and more have shown great potential as cancer treatments. While these treatments hold promise, there are still numerous issues that limit their clinical translation, including a lack of understanding of their mechanisms and inconsistent responses to treatment. Traditionally, tissue or blood samples are collected as a means of monitoring treatment progression. However, these in vitro diagnostics are invasive and provide limited information about the real-time status of the treatment or its long-term effectiveness. To address these limitations, novel non-invasive imaging modalities have been developed. These include optical imaging, X-ray computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET) and single-photon emission computed tomography (SPECT), and photoacoustic (PA) imaging. This review focuses on methods for tracking cell-based cancer immunotherapies using these in vivo imaging modalities, thereby enhancing real-time monitoring of their therapeutic effect and predictions of their long-term efficacy.
Collapse
Affiliation(s)
- Anika D Kulkarni
- Department of Biomedical Engineering, University of California, Davis, Davis, 95616, USA.
| | - Tasneem Mukarrama
- Department of Surgery, School of Medicine, University of California, Davis, Sacramento, 95817, USA
| | - Brendan R Barlow
- Department of Surgery, School of Medicine, University of California, Davis, Sacramento, 95817, USA
| | - Jinhwan Kim
- Department of Biomedical Engineering, University of California, Davis, Davis, 95616, USA.
- Department of Surgery, School of Medicine, University of California, Davis, Sacramento, 95817, USA
| |
Collapse
|
3
|
Kar S, Verma D, Mehrotra S, Prajapati VK. Reconfiguring the immune system to target cancer: Therapies based on T cells, cytokines, and vaccines. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2025; 144:77-150. [PMID: 39978976 DOI: 10.1016/bs.apcsb.2024.10.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/22/2025]
Abstract
Over the years, extensive research has been dedicated to performing in-depth analysis of cancer to uncover the intricate details of its nature - including the types of cancer, causative agents, stimulators of disease progression, factors contributing to poor prognosis, and efficient therapies to restrict the metastatic aggressiveness. This chapter highlights the mechanisms through which different arms of the host immune system - namely cytokines, lymphocytes, antigen-presenting cells (APCs) -can be mobilized to eradicate cancer. Most malignant tumors are either poorly immunogenic, or are harbored in a highly immuno-suppressive microenvironment. This is why reinforcing the host's anti-tumor defenses, through infusion of pro-inflammatory cytokines, tumor antigen-loaded APCs, and anti-tumor cytotoxic cells has emerged as a viable treatment option against cancer. The chapter also highlights the ongoing preclinical and clinical studies in different malignancies and the outcome of various therapies. Although these methods are not foolproof, and antigen escape variants can still evade or develop resistance to customized therapies, they achieve disease stabilization in several cases when conventional treatments fail. In many instances, combination therapies involving cytokines, T cells, and vaccinations prove more effective than monotherapies. The limitations of the current therapies are also discussed, along with ongoing modifications aimed at improving efficacy.
Collapse
Affiliation(s)
- Sramona Kar
- Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, Dhaula Kuan, New Delhi, India
| | - Divya Verma
- Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, Dhaula Kuan, New Delhi, India
| | - Sanjana Mehrotra
- Department of Human Genetics, Guru Nanak Dev University, Amritsar, Punjab, India
| | - Vijay Kumar Prajapati
- Department of Biochemistry, University of Delhi South Campus, Benito Juarez Road, Dhaula Kuan, New Delhi, India.
| |
Collapse
|
4
|
Steffin D, Ghatwai N, Montalbano A, Rathi P, Courtney AN, Arnett AB, Fleurence J, Sweidan R, Wang T, Zhang H, Masand P, Maris JM, Martinez D, Pogoriler J, Varadarajan N, Thakkar SG, Lyon D, Lapteva N, Zhuyong M, Patel K, Lopez-Terrada D, Ramos CA, Lulla P, Armaghany T, Grilley BJ, Gottschalk S, Dotti G, Metelitsa LS, Heslop HE, Brenner MK, Sumazin P, Heczey A. Interleukin-15-armoured GPC3 CAR T cells for patients with solid cancers. Nature 2025; 637:940-946. [PMID: 39604730 DOI: 10.1038/s41586-024-08261-8] [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: 03/14/2024] [Accepted: 10/21/2024] [Indexed: 11/29/2024]
Abstract
Interleukin-15 (IL-15) promotes the survival of T lymphocytes and enhances the antitumour properties of chimeric antigen receptor (CAR) T cells in preclinical models of solid neoplasms in which CAR T cells have limited efficacy1-4. Glypican-3 (GPC3) is expressed in a group of solid cancers5-10, and here we report the evaluation in humans of the effects of IL-15 co-expression on GPC3-expressing CAR T cells (hereafter GPC3 CAR T cells). Cohort 1 patients ( NCT02905188 and NCT02932956 ) received GPC3 CAR T cells, which were safe but produced no objective antitumour responses and reached peak expansion at 2 weeks. Cohort 2 patients ( NCT05103631 and NCT04377932 ) received GPC3 CAR T cells that co-expressed IL-15 (15.CAR), which mediated significantly increased cell expansion and induced a disease control rate of 66% and antitumour response rate of 33%. Infusion of 15.CAR T cells was associated with increased incidence of cytokine release syndrome, which was controlled with IL-1/IL-6 blockade or rapidly ameliorated by activation of the inducible caspase 9 safety switch. Compared with non-responders, tumour-infiltrating 15.CAR T cells from responders showed repression of SWI/SNF epigenetic regulators and upregulation of FOS and JUN family members, as well as of genes related to type I interferon signalling. Collectively, these results demonstrate that IL-15 increases the expansion, intratumoural survival and antitumour activity of GPC3 CAR T cells in patients.
Collapse
Affiliation(s)
- David Steffin
- Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
- Center for Advanced Innate Cell Therapy, Baylor College of Medicine, Houston, TX, USA
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital, Houston, TX, USA
| | - Nisha Ghatwai
- Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
- Center for Advanced Innate Cell Therapy, Baylor College of Medicine, Houston, TX, USA
| | - Antonino Montalbano
- Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
- Center for Advanced Innate Cell Therapy, Baylor College of Medicine, Houston, TX, USA
| | - Purva Rathi
- Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
- Center for Advanced Innate Cell Therapy, Baylor College of Medicine, Houston, TX, USA
| | - Amy N Courtney
- Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
- Center for Advanced Innate Cell Therapy, Baylor College of Medicine, Houston, TX, USA
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
| | - Azlann B Arnett
- Center for Advanced Innate Cell Therapy, Baylor College of Medicine, Houston, TX, USA
- Department of Immunology and Microbiology, Baylor College of Medicine, Houston, TX, USA
| | - Julien Fleurence
- Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
| | - Ramy Sweidan
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital, Houston, TX, USA
| | - Tao Wang
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
| | - Huimin Zhang
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital, Houston, TX, USA
| | - Prakash Masand
- Department of Radiology, Baylor College of Medicine, Houston, TX, USA
| | - John M Maris
- Department of Pediatrics, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Daniel Martinez
- Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Jennifer Pogoriler
- Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Navin Varadarajan
- William A. Brookshire Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX, USA
| | - Sachin G Thakkar
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital, Houston, TX, USA
| | - Deborah Lyon
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital, Houston, TX, USA
| | - Natalia Lapteva
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital, Houston, TX, USA
- Pathology and Immunology Graduate Program, Baylor College of Medicine, Houston, TX, USA
- Department of Pathology, Baylor College of Medicine, Houston, TX, USA
| | - Mei Zhuyong
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital, Houston, TX, USA
| | - Kalyani Patel
- Department of Pathology, Baylor College of Medicine, Houston, TX, USA
| | | | - Carlos A Ramos
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital, Houston, TX, USA
| | - Premal Lulla
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital, Houston, TX, USA
| | - Tannaz Armaghany
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
| | - Bambi J Grilley
- Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
- Center for Advanced Innate Cell Therapy, Baylor College of Medicine, Houston, TX, USA
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital, Houston, TX, USA
| | - Stephen Gottschalk
- Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Gianpietro Dotti
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
| | - Leonid S Metelitsa
- Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
- Center for Advanced Innate Cell Therapy, Baylor College of Medicine, Houston, TX, USA
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital, Houston, TX, USA
| | - Helen E Heslop
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital, Houston, TX, USA
| | - Malcolm K Brenner
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital, Houston, TX, USA
| | - Pavel Sumazin
- Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA
| | - Andras Heczey
- Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
- Center for Advanced Innate Cell Therapy, Baylor College of Medicine, Houston, TX, USA.
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital, Houston, TX, USA.
- Texas Children's Hospital Liver Tumor Program, Houston, TX, USA.
| |
Collapse
|
5
|
Ajmal I, Farooq MA, Duan Y, Yao J, Gao Y, Hui X, Ge Y, Chen Y, Ren Y, Du B, Jiang W. Intrinsic ADRB2 inhibition improves CAR-T cell therapy efficacy against prostate cancer. Mol Ther 2024; 32:3539-3557. [PMID: 39228124 PMCID: PMC11489547 DOI: 10.1016/j.ymthe.2024.08.028] [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: 01/07/2024] [Revised: 06/20/2024] [Accepted: 08/30/2024] [Indexed: 09/05/2024] Open
Abstract
Chimeric antigen receptor (CAR)-T cell therapy has shown limited success in patients with solid tumors. Recent in vitro and in vivo data have shown that adrenoceptor beta-2 (ADRB2) is a novel checkpoint receptor that inhibits T cell-mediated anti-tumor responses. To inhibit ADRB2-mediated inhibitory signaling, we downregulated ADRB2 in CAR-T (shβ2-CAR-T) cells via RNA interference, assessed different parameters, and compared them with conventional second-generation CAR-T cells. ADRB2 knockdown CAR-T cells exhibited enhanced cytotoxicity against prostate cancer cell lines in vitro, by increasing CD69, CD107a, GzmB, IFN-γ, T-bet, and GLUT-1. In addition, ADRB2 deficiency led to improved proliferation, increased CD8/CD4 T cell ratio, and decreased apoptosis in CAR-T cells. shβ2-CAR-T cells expressed more Bcl-2 and led to the generation of more significant proportions of T central memory cells. Finally, the ZAP-70/NF-κB signaling axis was shown to be responsible for the improved functions of novel CAR-T cells. In tumor-bearing mice, shβ2-CAR-T cells performed better than conventional CAR-T cells in eradicating prostate tumors. The study provides the basis for future clinical and translational CAR-T cell research to focus on adrenergic stress-mediated challenges in the tumor microenvironment of stressed tumors.
Collapse
Affiliation(s)
- Iqra Ajmal
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Muhammad Asad Farooq
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Yixin Duan
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Jie Yao
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Yaoxin Gao
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China; Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
| | - Xinhui Hui
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Yujia Ge
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Yiran Chen
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Yaojun Ren
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China; College of Life Science, Xinjiang Normal University, Urumqi 830053, China
| | - Bingtan Du
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Wenzheng Jiang
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, China.
| |
Collapse
|
6
|
Si Q, Bai M, Wang X, Wang T, Qin Y. Photonanozyme-Kras-ribosome combination treatment of non-small cell lung cancer after COVID-19. Front Immunol 2024; 15:1420463. [PMID: 39308869 PMCID: PMC11412844 DOI: 10.3389/fimmu.2024.1420463] [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: 04/20/2024] [Accepted: 08/14/2024] [Indexed: 09/25/2024] Open
Abstract
With the outbreak of the coronavirus disease 2019 (COVID-19), reductions in T-cell function and exhaustion have been observed in patients post-infection of COVID-19. T cells are key mediators of anti-infection and antitumor, and their exhaustion increases the risk of compromised immune function and elevated susceptibility to cancer. Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer with high incidence and mortality. Although the survival rate after standard treatment such as surgical treatment and chemotherapy has improved, the therapeutic effect is still limited due to drug resistance, side effects, and recurrence. Recent advances in molecular biology and immunology enable the development of highly targeted therapy and immunotherapy for cancer, which has driven cancer therapies into individualized treatments and gradually entered clinicians' views for treating NSCLC. Currently, with the development of photosensitizer materials, phototherapy has been gradually applied to the treatment of NSCLC. This review provides an overview of recent advancements and limitations in different treatment strategies for NSCLC under the background of COVID-19. We discuss the latest advances in phototherapy as a promising treatment method for NSCLC. After critically examining the successes, challenges, and prospects associated with these treatment modalities, their profound prospects were portrayed.
Collapse
Affiliation(s)
- Qiaoyan Si
- School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing, China
- School of Biomedical Engineering, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, China
- Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Mingjian Bai
- School of Biomedical Engineering, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, China
| | - Xiaolong Wang
- School of Biomedical Engineering, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, China
| | - Tianyu Wang
- School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing, China
| | - Yan Qin
- School of Biomedical Engineering, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, China
- Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| |
Collapse
|
7
|
Shi Y, Kotchetkov IS, Dobrin A, Hanina SA, Rajasekhar VK, Healey JH, Sadelain M. GLUT1 overexpression enhances CAR T cell metabolic fitness and anti-tumor efficacy. Mol Ther 2024; 32:2393-2405. [PMID: 38720457 PMCID: PMC11286825 DOI: 10.1016/j.ymthe.2024.05.006] [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: 12/04/2023] [Revised: 04/02/2024] [Accepted: 05/03/2024] [Indexed: 05/20/2024] Open
Abstract
The tumor microenvironment presents many obstacles to effective chimeric antigen receptor (CAR) T cell therapy, including glucose competition from tumor and myeloid cells. Using mouse models of acute lymphoblastic leukemia (ALL), renal cell carcinoma (RCC), and glioblastoma (GBM), we show that enforced expression of the glucose transporter GLUT1 enhances anti-tumor efficacy and promotes favorable CAR-T cell phenotypes for two clinically relevant CAR designs, 19-28z and IL13Rα2-BBz. In the NALM6 ALL model, 19-28z-GLUT1 promotes T stem cell-like memory formation and prolongs survival. RNA sequencing of these CAR-T cells reveals that the overexpression of GLUT1, but not GLUT3, enriches for genes involved in glycolysis, mitochondrial respiration, and memory precursor phenotypes. Extending these data, 19-28z-GLUT1 CAR-T cells improve tumor control and response to rechallenge in an RCC patient-derived xenograft model. Furthermore, IL13Rα2-BBz CAR-T cells overexpressing GLUT1 prolong the survival of mice bearing orthotopic GBMs and exhibit decreased exhaustion markers. This novel engineering approach can offer a competitive advantage to CAR-T cells in harsh tumor environments where glucose is limiting.
Collapse
Affiliation(s)
- Yuzhe Shi
- Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Ivan S Kotchetkov
- Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Anton Dobrin
- Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Sophie A Hanina
- Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Vinagolu K Rajasekhar
- Orthopedic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - John H Healey
- Orthopedic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Michel Sadelain
- Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
| |
Collapse
|
8
|
Wu Y, Yu G, Jin K, Qian J. Advancing non-small cell lung cancer treatment: the power of combination immunotherapies. Front Immunol 2024; 15:1349502. [PMID: 39015563 PMCID: PMC11250065 DOI: 10.3389/fimmu.2024.1349502] [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: 12/04/2023] [Accepted: 06/10/2024] [Indexed: 07/18/2024] Open
Abstract
Non-small cell lung cancer (NSCLC) remains an unsolved challenge in oncology, signifying a substantial global health burden. While considerable progress has been made in recent years through the emergence of immunotherapy modalities, such as immune checkpoint inhibitors (ICIs), monotherapies often yield limited clinical outcomes. The rationale behind combining various immunotherapeutic or other anticancer agents, the mechanistic underpinnings, and the clinical evidence supporting their utilization is crucial in NSCLC therapy. Regarding the synergistic potential of combination immunotherapies, this study aims to provide insights to help the landscape of NSCLC treatment and improve clinical outcomes. In addition, this review article discusses the challenges and considerations of combination regimens, including toxicity management and patient selection.
Collapse
Affiliation(s)
- Yuanlin Wu
- Department of Thoracic Surgery, Shaoxing People’s Hospital, Shaoxing, Zhejiang, China
| | - Guangmao Yu
- Department of Thoracic Surgery, Shaoxing People’s Hospital, Shaoxing, Zhejiang, China
| | - Ketao Jin
- Department of Gastrointestinal, Colorectal and Anal Surgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, Zhejiang, China
| | - Jun Qian
- Department of Colorectal Surgery, Xinchang People’s Hospital, Affiliated Xinchang Hospital, Wenzhou Medical University, Xinchang, Zhejiang, China
| |
Collapse
|
9
|
Bidgood GM, Keating N, Doggett K, Nicholson SE. SOCS1 is a critical checkpoint in immune homeostasis, inflammation and tumor immunity. Front Immunol 2024; 15:1419951. [PMID: 38947335 PMCID: PMC11211259 DOI: 10.3389/fimmu.2024.1419951] [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: 04/19/2024] [Accepted: 05/28/2024] [Indexed: 07/02/2024] Open
Abstract
The Suppressor of Cytokine Signaling (SOCS) family proteins are important negative regulators of cytokine signaling. SOCS1 is the prototypical member of the SOCS family and functions in a classic negative-feedback loop to inhibit signaling in response to interferon, interleukin-12 and interleukin-2 family cytokines. These cytokines have a critical role in orchestrating our immune defence against viral pathogens and cancer. The ability of SOCS1 to limit cytokine signaling positions it as an important immune checkpoint, as evidenced by the detection of detrimental SOCS1 variants in patients with cytokine-driven inflammatory and autoimmune disease. SOCS1 has also emerged as a key checkpoint that restricts anti-tumor immunity, playing both a tumor intrinsic role and impacting the ability of various immune cells to mount an effective anti-tumor response. In this review, we describe the mechanism of SOCS1 action, focusing on the role of SOCS1 in autoimmunity and cancer, and discuss the potential for new SOCS1-directed cancer therapies that could be used to enhance adoptive immunotherapy and immune checkpoint blockade.
Collapse
Affiliation(s)
- Grace M. Bidgood
- Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia
| | - Narelle Keating
- Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia
| | - Karen Doggett
- Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia
| | - Sandra E. Nicholson
- Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia
| |
Collapse
|
10
|
Yu T, Lu Y, Fang J, Jiang X, Lu Y, Zheng J, Shang X, Shen H, Fu P. Chimeric antigen receptor-based immunotherapy in breast cancer: Recent progress in China. Cancer 2024; 130:1378-1391. [PMID: 37950749 DOI: 10.1002/cncr.35096] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 09/11/2023] [Accepted: 10/11/2023] [Indexed: 11/13/2023]
Abstract
Breast cancer (BC) is the fourth most prevalent cancer in China. Despite conventional treatment strategies, BC patients often have poor therapeutic outcomes, leading to significant global cancer mortality rates. Chimeric antigen receptor (CAR)-based immunotherapy is a promising and innovative approach for cancer treatment that redirects immune cells to attack tumor cells expressing selected tumor antigens (TAs). T cells, natural killer (NK) cells, and macrophages, key components of the immune system, are used in CAR-based immunotherapies. Although remarkable progress has been made with CAR-T cells in hematologic malignancies, the application of CAR-based immunotherapy to BC has lagged. This is partly due to obstacles such as tumor heterogeneity, which is further associated with the TA and BC subtypes, and the immunosuppressive tumor microenvironment (TME). Several combinatorial approaches, including the use of immune checkpoint inhibitors, oncolytic viruses, and antitumor drugs, have been proposed to overcome these obstacles in BC treatment. Furthermore, several CAR-based immunotherapies for BC have been translated into clinical trials. This review provides an overview of the recent progress in CAR-based immunotherapy for BC treatment, including targeting of TAs, consideration of BC subtypes, assessment of the TME, and exploration of combinatorial therapies. The authors focused on preclinical studies and clinical trials of CAR-T cells, CAR-NK cells, and CAR-macrophages especially conducted in China, followed by an internal comparison and discussion of current limits. In conclusion, this review elucidates China's contribution to CAR-based immunotherapies for BC and provides inspiration for further research. PLAIN LANGUAGE SUMMARY: Despite conventional treatment strategies, breast cancer (BC) patients in China often have poor therapeutic outcomes. Chimeric antigen receptor (CAR)-based immunotherapy, a promising approach, can redirect immune cells to kill tumor cells expressing selected tumor antigens (TAs). However, obstacles such as TA selection, BC subtypes, and immunosuppressive tumor microenvironment still exist. Therefore, various combinatorial approaches have been proposed. This article elucidates several Chinese CAR-based preclinical and clinical studies in BC treatment with comparisons of foreign research, and CAR-immune cells are analyzed, providing inspiration for further research.
Collapse
Affiliation(s)
- Tianze Yu
- Department of Breast Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- School of Medicine, Zhejiang University, Hangzhou, China
| | - Yuexin Lu
- Department of Breast Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- School of Medicine, Zhejiang University, Hangzhou, China
| | - Jianwen Fang
- Department of Breast Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaocong Jiang
- Department of Breast Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- School of Medicine, Zhejiang University, Hangzhou, China
| | - Yue Lu
- Department of Breast and Thyroid Surgery, First Affiliated Hospital of Huzhou University, Huzhou, China
| | - Jingyan Zheng
- Department of Breast and Thyroid Surgery, Lishui People's Hospital, The Sixth Affiliated Hospital of Wenzhou Medical University, Lishui, China
| | - Xi Shang
- Department of Breast and Thyroid Surgery, Taizhou Hospital, Zhejiang University, Taizhou, China
| | - Haixing Shen
- Department of Breast and Thyroid Surgery, Cixi People's Hospital, Cixi, China
| | - Peifen Fu
- Department of Breast Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| |
Collapse
|
11
|
Rojas-Quintero J, Díaz MP, Palmar J, Galan-Freyle NJ, Morillo V, Escalona D, González-Torres HJ, Torres W, Navarro-Quiroz E, Rivera-Porras D, Bermúdez V. Car T Cells in Solid Tumors: Overcoming Obstacles. Int J Mol Sci 2024; 25:4170. [PMID: 38673757 PMCID: PMC11050550 DOI: 10.3390/ijms25084170] [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: 11/03/2023] [Revised: 03/12/2024] [Accepted: 03/13/2024] [Indexed: 04/28/2024] Open
Abstract
Chimeric antigen receptor T cell (CAR T cell) therapy has emerged as a prominent adoptive cell therapy and a therapeutic approach of great interest in the fight against cancer. This approach has shown notorious efficacy in refractory hematological neoplasm, which has bolstered its exploration in the field of solid cancers. However, successfully managing solid tumors presents considerable intrinsic challenges, which include the necessity of guiding the modified cells toward the tumoral region, assuring their penetration and survival in adverse microenvironments, and addressing the complexity of identifying the specific antigens for each type of cancer. This review focuses on outlining the challenges faced by CAR T cell therapy when used in the treatment of solid tumors, as well as presenting optimizations and emergent approaches directed at improving its efficacy in this particular context. From precise localization to the modulation of the tumoral microenvironment and the adaptation of antigen recognition strategies, diverse pathways will be examined to overcome the current limitations and buttress the therapeutic potential of CAR T cells in the fight against solid tumors.
Collapse
Affiliation(s)
- Joselyn Rojas-Quintero
- Medicine, Pulmonary, Critical Care, and Sleep Medicine Department, Baylor College of Medicine, Houston, TX 77030, USA;
| | - María P. Díaz
- Facultad de Medicina, Centro de Investigaciones Endocrino—Metabólicas, Universidad del Zulia, Maracaibo 4001, Venezuela (J.P.); (V.M.); (D.E.); (W.T.)
| | - Jim Palmar
- Facultad de Medicina, Centro de Investigaciones Endocrino—Metabólicas, Universidad del Zulia, Maracaibo 4001, Venezuela (J.P.); (V.M.); (D.E.); (W.T.)
| | - Nataly J. Galan-Freyle
- Centro de Investigaciones en Ciencias de la Vida, Universidad Simón Bolívar, Barranquilla 080002, Colombia; (N.J.G.-F.); (E.N.-Q.)
| | - Valery Morillo
- Facultad de Medicina, Centro de Investigaciones Endocrino—Metabólicas, Universidad del Zulia, Maracaibo 4001, Venezuela (J.P.); (V.M.); (D.E.); (W.T.)
| | - Daniel Escalona
- Facultad de Medicina, Centro de Investigaciones Endocrino—Metabólicas, Universidad del Zulia, Maracaibo 4001, Venezuela (J.P.); (V.M.); (D.E.); (W.T.)
| | | | - Wheeler Torres
- Facultad de Medicina, Centro de Investigaciones Endocrino—Metabólicas, Universidad del Zulia, Maracaibo 4001, Venezuela (J.P.); (V.M.); (D.E.); (W.T.)
| | - Elkin Navarro-Quiroz
- Centro de Investigaciones en Ciencias de la Vida, Universidad Simón Bolívar, Barranquilla 080002, Colombia; (N.J.G.-F.); (E.N.-Q.)
- Facultad de Ciencias Básicas y Biomédicas, Barranquilla 080002, Colombia
| | - Diego Rivera-Porras
- Facultad de Ciencias Jurídicas y Sociales, Universidad Simón Bolívar, Cúcuta 540001, Colombia;
| | - Valmore Bermúdez
- Centro de Investigaciones en Ciencias de la Vida, Universidad Simón Bolívar, Barranquilla 080002, Colombia; (N.J.G.-F.); (E.N.-Q.)
- Facultad de Ciencias de la Salud, Universidad Simón Bolívar, Barranquilla 080002, Colombia;
| |
Collapse
|
12
|
Qian S, Chen J, Zhao Y, Zhu X, Dai D, Qin L, Hong J, Xu Y, Yang Z, Li Y, Guijo I, Jiménez-Galanes S, Guadalajara H, García-Arranz M, García-Olmo D, Shen J, Villarejo-Campos P, Qian C. Intraperitoneal administration of carcinoembryonic antigen-directed chimeric antigen receptor T cells is a robust delivery route for effective treatment of peritoneal carcinomatosis from colorectal cancer in pre-clinical study. Cytotherapy 2024; 26:113-125. [PMID: 37999667 DOI: 10.1016/j.jcyt.2023.10.007] [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: 07/05/2023] [Revised: 10/03/2023] [Accepted: 10/19/2023] [Indexed: 11/25/2023]
Abstract
BACKGROUND AIMS Peritoneal carcinomatosis (PC) from colorectal cancer (CRC) is a highly challenging disease to treat. Systemic chimeric antigen receptor (CAR) T cells have shown impressive efficacy in hematologic malignancies but have been less effective in solid tumors. We explored whether intraperitoneal (i.p.) administration of CAR T cells could provide an effective and robust route of treatment for PC from CRC. METHODS We generated second-generation carcinoembryonic antigen (CEA)-specific CAR T cells. Various animal models of PC with i.p. and extraperitoneal metastasis were treated by i.p. or intravenous (i.v.) administration of CEA CAR T cells. RESULTS Intraperitoneally administered CAR T cells exhibited superior anti-tumor activity compared with systemic i.v. cell infusion in an animal model of PC. In addition, i.p. administration conferred a durable effect and protection against tumor recurrence and exerted strong anti-tumor activity in an animal model of PC with metastasis in i.p. or extraperitoneal organs. Moreover, compared with systemic delivery, i.p. transfer of CAR T cells provided increased anti-tumor activity in extraperitoneal tumors without PC. This phenomenon was further confirmed in an animal model of pancreatic carcinoma after i.p. administration of our newly constructed prostate stem cell antigen-directed CAR T cells. CONCLUSIONS Taken together, our data suggest that i.p. administration of CAR T cells may be a robust delivery route for effective treatment of cancer.
Collapse
Affiliation(s)
- Siyuan Qian
- Department of Surgery, Fundación Jiménez Díaz University Hospital, Madrid, Spain.
| | - Jun Chen
- Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing Precision Biotechnology Co Ltd, Chongqing, China
| | - Yongchun Zhao
- Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing Precision Biotechnology Co Ltd, Chongqing, China
| | - Xiuxiu Zhu
- Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing Precision Biotechnology Co Ltd, Chongqing, China
| | - Depeng Dai
- Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing Precision Biotechnology Co Ltd, Chongqing, China
| | - Lei Qin
- Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing Precision Biotechnology Co Ltd, Chongqing, China
| | - Juan Hong
- Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing Precision Biotechnology Co Ltd, Chongqing, China
| | - Yanming Xu
- Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing Precision Biotechnology Co Ltd, Chongqing, China
| | - Zhi Yang
- Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing Precision Biotechnology Co Ltd, Chongqing, China
| | - Yunyan Li
- Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing Precision Biotechnology Co Ltd, Chongqing, China
| | - Ismael Guijo
- Department of Surgery, Fundación Jiménez Díaz University Hospital, Madrid, Spain
| | | | - Héctor Guadalajara
- Department of Surgery, Fundación Jiménez Díaz University Hospital, Madrid, Spain; Department of Surgery, Universidad Autónoma de Madrid, Madrid, Spain
| | - Mariano García-Arranz
- Department of Surgery, Fundación Jiménez Díaz University Hospital, Madrid, Spain; Department of Surgery, Universidad Autónoma de Madrid, Madrid, Spain
| | - Damián García-Olmo
- Department of Surgery, Fundación Jiménez Díaz University Hospital, Madrid, Spain; Department of Surgery, Universidad Autónoma de Madrid, Madrid, Spain
| | - Junjie Shen
- Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing Precision Biotechnology Co Ltd, Chongqing, China.
| | - Pedro Villarejo-Campos
- Department of Surgery, Fundación Jiménez Díaz University Hospital, Madrid, Spain; Department of Surgery, Universidad Autónoma de Madrid, Madrid, Spain.
| | - Cheng Qian
- Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing Precision Biotechnology Co Ltd, Chongqing, China.
| |
Collapse
|
13
|
Tang Y, Yang X, Hu H, Jiang H, Xiong W, Mei H, Hu Y. Elevating the potential of CAR-T cell therapy in solid tumors: exploiting biomaterials-based delivery techniques. Front Bioeng Biotechnol 2024; 11:1320807. [PMID: 38312512 PMCID: PMC10835794 DOI: 10.3389/fbioe.2023.1320807] [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: 10/13/2023] [Accepted: 12/05/2023] [Indexed: 02/06/2024] Open
Abstract
Chimeric antigen receptor (CAR) T cells exhibit promising progress in addressing hematologic malignancies. However, CAR-T therapy for solid tumors remains limited, with no FDA-approved CAR-T products available for clinical use at present. Primary reasons include insufficient infiltration, accumulation, tumor immunosuppression of the microenvironment, and related side effects. Single utilization of CAR-T cannot effectively overcome these unfavorable obstacles. A probable effective pathway to achieve a better CAR-T therapy effect would be to combine the benefits of biomaterials-based technology. In this article, comprehensive biomaterials strategies to break through these obstacles of CAR-T cell therapy at the tumor sites are summarized, encompassing the following aspects: 1) generating orthotopic CAR-T cells; 2) facilitating CAR-T cell trafficking; 3) stimulating CAR-T cell expansion and infiltration; 4) improving CAR-T cell activity and persistence; 5) reprogramming the immunosuppressive microenvironments. Additionally, future requirements for the development of this field, with a specific emphasis on promoting innovation and facilitating clinical translation, are thoroughly discussed.
Collapse
Affiliation(s)
- Yuxiang Tang
- Tongji Medical College, Union Hospital, Institute of Hematology, Huazhong University of Science and Technology, Wuhan, China
- Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, Wuhan, China
| | - Xiaoyu Yang
- Department of Pharmacy, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Hang Hu
- School of Pharmacy, ChangZhou University, Changzhou, China
| | - Huiwen Jiang
- Tongji Medical College, Union Hospital, Institute of Hematology, Huazhong University of Science and Technology, Wuhan, China
- Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, Wuhan, China
| | - Wei Xiong
- Wuhan Sian Medical Technology Co., Ltd., Wuhan, China
| | - Heng Mei
- Tongji Medical College, Union Hospital, Institute of Hematology, Huazhong University of Science and Technology, Wuhan, China
- Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, Wuhan, China
| | - Yu Hu
- Tongji Medical College, Union Hospital, Institute of Hematology, Huazhong University of Science and Technology, Wuhan, China
- Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, Wuhan, China
| |
Collapse
|
14
|
Schlabach MR, Lin S, Collester ZR, Wrocklage C, Shenker S, Calnan C, Xu T, Gannon HS, Williams LJ, Thompson F, Dunbar PR, LaMothe RA, Garrett TE, Colletti N, Hohmann AF, Tubo NJ, Bullock CP, Le Mercier I, Sofjan K, Merkin JJ, Keegan S, Kryukov GV, Dugopolski C, Stegmeier F, Wong K, Sharp FA, Cadzow L, Benson MJ. Rational design of a SOCS1-edited tumor-infiltrating lymphocyte therapy using CRISPR/Cas9 screens. J Clin Invest 2023; 133:e163096. [PMID: 38099496 PMCID: PMC10721144 DOI: 10.1172/jci163096] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 10/10/2023] [Indexed: 12/18/2023] Open
Abstract
Cell therapies such as tumor-infiltrating lymphocyte (TIL) therapy have shown promise in the treatment of patients with refractory solid tumors, with improvement in response rates and durability of responses nevertheless sought. To identify targets capable of enhancing the antitumor activity of T cell therapies, large-scale in vitro and in vivo clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 screens were performed, with the SOCS1 gene identified as a top T cell-enhancing target. In murine CD8+ T cell-therapy models, SOCS1 served as a critical checkpoint in restraining the accumulation of central memory T cells in lymphoid organs as well as intermediate (Texint) and effector (Texeff) exhausted T cell subsets derived from progenitor exhausted T cells (Texprog) in tumors. A comprehensive CRISPR tiling screen of the SOCS1-coding region identified sgRNAs targeting the SH2 domain of SOCS1 as the most potent, with an sgRNA with minimal off-target cut sites used to manufacture KSQ-001, an engineered TIL therapy with SOCS1 inactivated by CRISPR/Cas9. KSQ-001 possessed increased responsiveness to cytokine signals and enhanced in vivo antitumor function in mouse models. These data demonstrate the use of CRISPR/Cas9 screens in the rational design of T cell therapies.
Collapse
|
15
|
Zarei M, Abdoli S, Farazmandfar T, Shahbazi M. Lenalidomide improves NKG2D-based CAR-T cell activity against colorectal cancer cells invitro. Heliyon 2023; 9:e20460. [PMID: 37790973 PMCID: PMC10543764 DOI: 10.1016/j.heliyon.2023.e20460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 09/13/2023] [Accepted: 09/26/2023] [Indexed: 10/05/2023] Open
Abstract
Introduction Although CAR-based immunotherapy is viewed as a promising treatment for tumors, particularly hematological malignancies, solid tumors can pose challenges. It has been suggested that the immunomodulatory medication Lenalidomide (LEN) may increase the effectiveness of CAR T cells in the treatment of solid tumors. The purpose of our study was to investigate the effect of NKG2D-based CAR T cell therapy on colorectal cancer cell lines, and then we assessed combinatorial therapy using NKG2D CAR T cells and lenalidomide in vitro. Methods and results To prepare NKG2D CAR T cells, a second-generation NKG2D-CAR construct was designed and transfected into the T cells using a lentiviral system. The NKG2D CAR T cells showed significantly higher cytotoxic activity against colorectal cancer cell lines, HCT116 and SW480, compared to untransduced T cells. In addition, our data demonstrated that the cytotoxicity and cytokine secretion of NKG2D CAR T cells significantly increased in the presence of higher doses of lenalidomide. Conclusions The study findings suggest that combinational therapy, utilizing NKG2D-based CAR T cells and lenalidomide, has a high potential for effectively eliminating tumor cells in vitro.
Collapse
Affiliation(s)
- Mahdi Zarei
- Medical Cellular and Molecular Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Shahriyar Abdoli
- Medical Cellular and Molecular Research Center, Golestan University of Medical Sciences, Gorgan, Iran
- School of Advanced Technologies in Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Touraj Farazmandfar
- Medical Cellular and Molecular Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Majid Shahbazi
- Medical Cellular and Molecular Research Center, Golestan University of Medical Sciences, Gorgan, Iran
- AryaTina Gene (ATG) Biopharmaceutical Company Gorgan, Iran
| |
Collapse
|
16
|
Al Zein M, Boukhdoud M, Shammaa H, Mouslem H, El Ayoubi LM, Iratni R, Issa K, Khachab M, Assi HI, Sahebkar A, Eid AH. Immunotherapy and immunoevasion of colorectal cancer. Drug Discov Today 2023; 28:103669. [PMID: 37328052 DOI: 10.1016/j.drudis.2023.103669] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 05/20/2023] [Accepted: 06/08/2023] [Indexed: 06/18/2023]
Abstract
The tremendous success of immunotherapy in clinical trials has led to its establishment as a new pillar of cancer therapy. However, little clinical efficacy has been achieved in microsatellite stable colorectal cancer (MSS-CRC), which constitutes most CRC tumors. Here, we discuss the molecular and genetic heterogeneity of CRC. We review the immune escape mechanisms, and focus on the latest advances in immunotherapy as a treatment modality for CRC. By providing a better understanding of the tumor microenvironment (TME) and the molecular mechanisms underlying immunoevasion, this review offers an insight into developing therapeutic strategies that are effective for patients with various subsets of CRC.
Collapse
Affiliation(s)
- Mohammad Al Zein
- Faculty of Medical Sciences, Lebanese University, Hadath, Beirut, Lebanon
| | - Mona Boukhdoud
- Faculty of Medical Sciences, Lebanese University, Hadath, Beirut, Lebanon
| | - Hadi Shammaa
- Faculty of Medical Sciences, Lebanese University, Hadath, Beirut, Lebanon
| | - Hadi Mouslem
- Faculty of Medical Sciences, Lebanese University, Hadath, Beirut, Lebanon
| | | | - Rabah Iratni
- Department of Biology, College of Science, United Arab Emirates University, Al-Ain, UAE
| | - Khodr Issa
- University of Lille, Proteomics, Inflammatory Response, Mass Spectrometry, INSERM U-1192, Lille, France
| | - Maha Khachab
- Faculty of Medicine, University of Balamand, Lebanon
| | - Hazem I Assi
- Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali H Eid
- Department of Basic Medical Sciences, College of Medicine, Qatar University, QU Health, Doha, Qatar.
| |
Collapse
|
17
|
Haas AR, Golden RJ, Litzky LA, Engels B, Zhao L, Xu F, Taraszka JA, Ramones M, Granda B, Chang WJ, Jadlowsky J, Shea KM, Runkle A, Chew A, Dowd E, Gonzalez V, Chen F, Liu X, Fang C, Jiang S, Davis MM, Sheppard NC, Zhao Y, Fraietta JA, Lacey SF, Plesa G, Melenhorst JJ, Mansfield K, Brogdon JL, Young RM, Albelda SM, June CH, Tanyi JL. Two cases of severe pulmonary toxicity from highly active mesothelin-directed CAR T cells. Mol Ther 2023; 31:2309-2325. [PMID: 37312454 PMCID: PMC10422001 DOI: 10.1016/j.ymthe.2023.06.006] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 05/13/2023] [Accepted: 06/08/2023] [Indexed: 06/15/2023] Open
Abstract
Multiple clinical studies have treated mesothelin (MSLN)-positive solid tumors by administering MSLN-directed chimeric antigen receptor (CAR) T cells. Although these products are generally safe, efficacy is limited. Therefore, we generated and characterized a potent, fully human anti-MSLN CAR. In a phase 1 dose-escalation study of patients with solid tumors, we observed two cases of severe pulmonary toxicity following intravenous infusion of this product in the high-dose cohort (1-3 × 108 T cells per m2). Both patients demonstrated progressive hypoxemia within 48 h of infusion with clinical and laboratory findings consistent with cytokine release syndrome. One patient ultimately progressed to grade 5 respiratory failure. An autopsy revealed acute lung injury, extensive T cell infiltration, and accumulation of CAR T cells in the lungs. RNA and protein detection techniques confirmed low levels of MSLN expression by benign pulmonary epithelial cells in affected lung and lung samples obtained from other inflammatory or fibrotic conditions, indicating that pulmonary pneumocyte and not pleural expression of mesothelin may lead to dose-limiting toxicity. We suggest patient enrollment criteria and dosing regimens of MSLN-directed therapies consider the possibility of dynamic expression of mesothelin in benign lung with a special concern for patients with underlying inflammatory or fibrotic conditions.
Collapse
Affiliation(s)
- Andrew R Haas
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Pulmonary, Allergy, and Critical Care, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
| | - Ryan J Golden
- Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Leslie A Litzky
- Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Boris Engels
- Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA
| | - Linlin Zhao
- Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA
| | - Fangmin Xu
- Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA
| | - John A Taraszka
- Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA
| | - Melissa Ramones
- Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA
| | - Brian Granda
- Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA
| | - Wan-Jung Chang
- Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Julie Jadlowsky
- Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Kim-Marie Shea
- Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Adam Runkle
- Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Anne Chew
- Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Emily Dowd
- Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Vanessa Gonzalez
- Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Fang Chen
- Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Xiaojun Liu
- Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Chongyun Fang
- Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Shuguang Jiang
- Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Megan M Davis
- Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Neil C Sheppard
- Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Yangbing Zhao
- Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Joseph A Fraietta
- Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Simon F Lacey
- Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Gabriela Plesa
- Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - J Joseph Melenhorst
- Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Keith Mansfield
- Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA
| | | | - Regina M Young
- Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Steven M Albelda
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Pulmonary, Allergy, and Critical Care, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
| | - Carl H June
- Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Janos L Tanyi
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Pennsylvania, Philadelphia, PA 19104, USA.
| |
Collapse
|
18
|
Kim D, Jo S, Lee D, Kim SM, Seok JM, Yeo SJ, Lee JH, Lee JJ, Lee K, Kim TD, Park SA. NK cells encapsulated in micro/macropore-forming hydrogels via 3D bioprinting for tumor immunotherapy. Biomater Res 2023; 27:60. [PMID: 37349810 DOI: 10.1186/s40824-023-00403-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 06/01/2023] [Indexed: 06/24/2023] Open
Abstract
BACKGROUND Patients face a serious threat if a solid tumor leaves behind partial residuals or cannot be completely removed after surgical resection. Immunotherapy has attracted attention as a method to prevent this condition. However, the conventional immunotherapy method targeting solid tumors, that is, intravenous injection, has limitations in homing in on the tumor and in vivo expansion and has not shown effective clinical results. METHOD To overcome these limitations, NK cells (Natural killer cells) were encapsulated in micro/macropore-forming hydrogels using 3D bioprinting to target solid tumors. Sodium alginate and gelatin were used to prepare micro-macroporous hydrogels. The gelatin contained in the alginate hydrogel was removed because of the thermal sensitivity of the gelatin, which can generate interconnected micropores where the gelatin was released. Therefore, macropores can be formed through bioprinting and micropores can be formed using thermally sensitive gelatin to make macroporous hydrogels. RESULTS It was confirmed that intentionally formed micropores could help NK cells to aggregate easily, which enhances cell viability, lysis activity, and cytokine release. Macropores can be formed using 3D bioprinting, which enables NK cells to receive the essential elements. We also characterized the functionality of NK 92 and zEGFR-CAR-NK cells in the pore-forming hydrogel. The antitumor effects on leukemia and solid tumors were investigated using an in vitro model. CONCLUSION We demonstrated that the hydrogel encapsulating NK cells created an appropriate micro-macro environment for clinical applications of NK cell therapy for both leukemia and solid tumors via 3D bioprinting. 3D bioprinting makes macro-scale clinical applications possible, and the automatic process shows potential for development as an off-the-shelf immunotherapy product. This immunotherapy system could provide a clinical option for preventing tumor relapse and metastasis after tumor resection. Micro/macropore-forming hydrogel with NK cells fabricated by 3D bioprinting and implanted into the tumor site.
Collapse
Affiliation(s)
- Dahong Kim
- Nano Convergence & Manufacturing Systems, Korea Institute of Machinery and Materials (KIMM), Daejeon, 34103, Republic of Korea
- Department of Applied Bioengineering, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, Republic of Korea
| | - Seona Jo
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, 34113, Republic of Korea
| | - Dongjin Lee
- Nano Convergence & Manufacturing Systems, Korea Institute of Machinery and Materials (KIMM), Daejeon, 34103, Republic of Korea
| | - Seok-Min Kim
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, 34113, Republic of Korea
| | - Ji Min Seok
- Nano Convergence & Manufacturing Systems, Korea Institute of Machinery and Materials (KIMM), Daejeon, 34103, Republic of Korea
- Department of Applied Bioengineering, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, Republic of Korea
| | - Seon Ju Yeo
- Nano Convergence & Manufacturing Systems, Korea Institute of Machinery and Materials (KIMM), Daejeon, 34103, Republic of Korea
| | - Jun Hee Lee
- Nano Convergence & Manufacturing Systems, Korea Institute of Machinery and Materials (KIMM), Daejeon, 34103, Republic of Korea
| | - Jae Jong Lee
- Nano Convergence & Manufacturing Systems, Korea Institute of Machinery and Materials (KIMM), Daejeon, 34103, Republic of Korea
| | - Kangwon Lee
- Department of Applied Bioengineering, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, Republic of Korea
- Research Institute for Convergence Science, Seoul National University, Seoul, 08826, Republic of Korea
| | - Tae-Don Kim
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea.
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon, 34113, Republic of Korea.
- Biomedical Mathematics Group, Institute for Basic Science, Daejeon, 34126, Republic of Korea.
- Department of Biopharmaceutical Convergence, School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
| | - Su A Park
- Nano Convergence & Manufacturing Systems, Korea Institute of Machinery and Materials (KIMM), Daejeon, 34103, Republic of Korea.
| |
Collapse
|
19
|
Yin L, Chen GL, Xiang Z, Liu YL, Li XY, Bi JW, Wang Q. Current progress in chimeric antigen receptor-modified T cells for the treatment of metastatic breast cancer. Biomed Pharmacother 2023; 162:114648. [PMID: 37023621 DOI: 10.1016/j.biopha.2023.114648] [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: 01/23/2023] [Revised: 03/30/2023] [Accepted: 03/31/2023] [Indexed: 04/07/2023] Open
Abstract
Breast cancer is the leading cancer in women. Around 20-30% breast cancer patients undergo invasion or metastasis after radical surgical resection and eventually die. Number of breast cancer patients show poor sensitivity toward treatments despite the advances in chemotherapy, endocrine therapy, and molecular targeted treatments. Therapeutic resistance and tumor recurrence or metastasis develop with the ongoing treatments. Conducive treatment strategies are thus required. Chimeric antigen receptor (CAR)-modified T-cell therapy has progressed as a part of tumor immunotherapy. However, CAR-T treatment has not been effective in solid tumors because of tumor microenvironment complexity, inhibitory effects of extracellular matrix, and lacking ideal tumor antigens. Herein, the prospects of CAR-T cell therapy for metastatic breast cancer are discussed, and the targets for CAR-T therapy in breast cancer (HER-2, C-MET, MSLN, CEA, MUC1, ROR1, EGFR) at clinical level are reviewed. Moreover, solutions are proposed for the challenges of breast cancer CAR-T therapy regarding off-target effects, heterogeneous antigen expression by tumor cells and immunosuppressive tumor microenvironment. Ideas for improving the therapeutics of CAR-T cell therapy in metastatic breast cancer are suggested.
Collapse
Affiliation(s)
- Li Yin
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, 250023 Jinan, China; Oncology Department, Shandong Second Provincial General Hospital, 250023 Jinan, China; Shandong University of Traditional Chinese Medicine, 250355 Jinan, China
| | - Gui-Lai Chen
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, 250023 Jinan, China; Oncology Department, Shandong Second Provincial General Hospital, 250023 Jinan, China
| | - Zhuo Xiang
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, 250023 Jinan, China; Oncology Department, Shandong Second Provincial General Hospital, 250023 Jinan, China
| | - Yu-Lin Liu
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, 250023 Jinan, China; Oncology Department, Shandong Second Provincial General Hospital, 250023 Jinan, China
| | - Xing-Yu Li
- Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 266003 Qingdao, China
| | - Jing-Wang Bi
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, 250023 Jinan, China; Oncology Department, Shandong Second Provincial General Hospital, 250023 Jinan, China.
| | - Qiang Wang
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, 250023 Jinan, China; Oncology Department, Shandong Second Provincial General Hospital, 250023 Jinan, China; Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 266003 Qingdao, China.
| |
Collapse
|
20
|
van Schaik TA, Moreno-Lama L, Aligholipour Farzani T, Wang M, Chen KS, Li W, Cai L, Zhang YS, Shah K. Engineered cell-based therapies in ex vivo ready-made CellDex capsules have therapeutic efficacy in solid tumors. Biomed Pharmacother 2023; 162:114665. [PMID: 37062216 PMCID: PMC10165501 DOI: 10.1016/j.biopha.2023.114665] [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: 12/12/2022] [Revised: 03/24/2023] [Accepted: 04/03/2023] [Indexed: 04/18/2023] Open
Abstract
Encapsulated cell-based therapies for solid tumors have shown promising results in pre-clinical settings. However, the inability to culture encapsulated therapeutic cells prior to their transplantation has limited their translation into clinical settings. In this study, we created a wide variety of engineered therapeutic cells (ThC) loaded in micropore-forming gelatin methacryloyl (GelMA) hydrogel (CellDex) capsules that can be cultured in vitro prior to their transplantation in surgically debulked solid tumors. We show that both allogeneic and autologous engineered cells, such as stem cells (SCs), macrophages, NK cells, and T cells, proliferate within CellDex capsules and migrate out of the gel in vitro and in vivo. Furthermore, tumor cell specific therapeutic proteins and oncolytic viruses released from CellDex capsules retain and prolong their anti-tumor effects. In vivo, ThCs in pre-manufactured Celldex capsules persist long-term and track tumor cells. Moreover, chimeric antigen receptor (CAR) T cell bearing CellDex (T-CellDex) and human SC releasing therapeutic proteins (hSC-CellDex) capsules show therapeutic efficacy in metastatic and primary brain tumor resection models that mimic standard of care of tumor resection in patients. Overall, this unique approach of pre-manufactured micropore-forming CellDex capsules offers an effective off-the-shelf clinically viable strategy to treat solid tumors locally.
Collapse
Affiliation(s)
- Thijs A van Schaik
- Center for Stem Cell and Translational Immunotherapy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Lucia Moreno-Lama
- Center for Stem Cell and Translational Immunotherapy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Touraj Aligholipour Farzani
- Center for Stem Cell and Translational Immunotherapy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Mian Wang
- Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139, USA
| | - Kok-Siong Chen
- Center for Stem Cell and Translational Immunotherapy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Wanlu Li
- Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139, USA
| | - Ling Cai
- Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139, USA
| | - Yu Shrike Zhang
- Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139, USA
| | - Khalid Shah
- Center for Stem Cell and Translational Immunotherapy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
| |
Collapse
|
21
|
Bandi DSR, Sarvesh S, Farran B, Nagaraju GP, El-Rayes BF. Targeting the metabolism and immune system in pancreatic ductal adenocarcinoma: Insights and future directions. Cytokine Growth Factor Rev 2023; 71-72:26-39. [PMID: 37407355 DOI: 10.1016/j.cytogfr.2023.06.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 06/29/2023] [Accepted: 06/29/2023] [Indexed: 07/07/2023]
Abstract
Pancreatic cancer, specifically pancreatic ductal adenocarcinoma (PDAC), presents a challenging landscape due to its complex nature and the highly immunosuppressive tumor microenvironment (TME). This immunosuppression severely limits the effectiveness of immune-based therapies. Studies have revealed the critical role of immunometabolism in shaping the TME and influencing PDAC progression. Genetic alterations, lysosomal dysfunction, gut microbiome dysbiosis, and altered metabolic pathways have been shown to modulate immunometabolism in PDAC. These metabolic alterations can significantly impact immune cell functions, including T-cells, myeloid-derived suppressor cells (MDSCs), and macrophages, evading anti-tumor immunity. Advances in immunotherapy offer promising avenues for overcoming immunosuppressive TME and enhancing patient outcomes. This review highlights the challenges and opportunities for future research in this evolving field. By exploring the connections between immunometabolism, genetic alterations, and the microbiome in PDAC, it is possible to tailor novel approaches capable of improving immunotherapy outcomes and addressing the limitations posed by immunosuppressive TME. Ultimately, these insights may pave the way for improved treatment options and better outcomes for PDAC patients.
Collapse
Affiliation(s)
- Dhana Sekhar Reddy Bandi
- Department of Hematology and Oncology, Heersink School of Medicine, University of Alabama, Birmingham, AL 35233, USA
| | - Sujith Sarvesh
- Department of Hematology and Oncology, Heersink School of Medicine, University of Alabama, Birmingham, AL 35233, USA
| | - Batoul Farran
- Department of Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Ganji Purnachandra Nagaraju
- Department of Hematology and Oncology, Heersink School of Medicine, University of Alabama, Birmingham, AL 35233, USA.
| | - Bassel F El-Rayes
- Department of Hematology and Oncology, Heersink School of Medicine, University of Alabama, Birmingham, AL 35233, USA.
| |
Collapse
|
22
|
Shen T, Yang S, Qu X, Chen Z, Zeng L, Sun X, Lin Y, Luo M, Lei B, Yue C, Ma C, Hu N, Wang W, Zhang L. A bionic "Trojan horse"-like gene delivery system hybridized with tumor and macrophage cell membrane for cancer therapy. J Control Release 2023; 358:204-218. [PMID: 37121518 DOI: 10.1016/j.jconrel.2023.04.046] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 04/13/2023] [Accepted: 04/27/2023] [Indexed: 05/02/2023]
Abstract
MiRNA-based gene therapy as a novel targeted therapy has yielded promising results in experimental cancer treatment, however, the inefficient delivery of miRNA to target tissues has limited its application in vivo. Here a unique dual-membrane-camouflaged miRNA21 antagomir delivery nanoplatform (M@NPs/miR21) with immune escape and homologous targeting properties was constructed by cancer cell membrane and macrophage membrane. Different from the single-cell membrane camouflage strategy, the dual-membrane camouflage miRNA21 antagomir delivery nanoplatform based on modification of CD47 protein with immune escape signal and galectin-3 protein with tumor cell aggregation enables efficient, safe and targeted therapy for colon cancer and lung metastases. Camouflaged with the dual-cell membrane, the "Trojan horse" like "pseudo-tumor cell" and/or "pseudo-macrophage" (M@NPs/miR21) carried the target gene miR21 antagomir to the tumor site and showed significant anti-tumor properties at the periphery and the core of subcutaneous tumor tissues. In addition, M@NPs/miR21 was more likely to penetrate dense tumor tissues and function within the tumor mass than NPs/miR21 without membrane coating. M@NPs/miR21 can deliver miR21 antagomir into MC38 cancer cells and tumor tissues, promote tumor apoptosis, and regulate the expression of Bcl2 and Ki67. Moreover, the M@NPs/miR21 gene delivery system not only can effectively inhibit the progression of subcutaneous tumors and lung metastases, but also showed minimal toxicity and good biosafety, making this delivery system particularly attractive for future translational research.
Collapse
Affiliation(s)
- Tianli Shen
- Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Shuanying Yang
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Xiaoyan Qu
- Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an 710054, China
| | - Zilu Chen
- Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Lizhong Zeng
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Xuejun Sun
- Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Yuyao Lin
- Department of Plastic, Aesthetic and Maxillofacial Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Meng Luo
- Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an 710054, China
| | - Bo Lei
- Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an 710054, China
| | - Chenyang Yue
- Department of Biology, York University, Toronto, Ontario, Canada
| | - Chunhong Ma
- Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Nan Hu
- Department of Rheumatology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Wei Wang
- Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
| | - Long Zhang
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China.
| |
Collapse
|
23
|
Domínguez-Prieto V, Qian S, Villarejo-Campos P, Meliga C, González-Soares S, Guijo Castellano I, Jiménez-Galanes S, García-Arranz M, Guadalajara H, García-Olmo D. Understanding CAR T cell therapy and its role in ovarian cancer and peritoneal carcinomatosis from ovarian cancer. Front Oncol 2023; 13:1104547. [PMID: 37274261 PMCID: PMC10233107 DOI: 10.3389/fonc.2023.1104547] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 05/05/2023] [Indexed: 06/06/2023] Open
Abstract
Ovarian cancer is the seventh most common cancer worldwide in women and the most lethal gynecologic malignancy due to the lack of accurate screening tools for early detection and late symptom onset. The absence of early-onset symptoms often delays diagnosis until the disease has progressed to advanced stages, frequently when there is peritoneal involvement. Although ovarian cancer is a heterogeneous malignancy with different histopathologic types, treatment for advanced tumors is usually based on chemotherapy and cytoreduction surgery. CAR T cells have shown promise for the treatment of hematological malignancies, though their role in treating solid tumors remains unclear. Outcomes are less favorable owing to the low capacity of CAR T cells to migrate to the tumor site, the influence of the protective tumor microenvironment, and the heterogeneity of surface antigens on tumor cells. Despite these results, CAR T cells have been proposed as a treatment approach for peritoneal carcinomatosis from colorectal and gastric origin. Local intraperitoneal administration of CAR T cells has been found to be superior to systemic administration, as this route is associated with increased tumor reduction, a more durable effect, protection against local relapse and distant metastases, and fewer systemic adverse effects. In this article we review the application of CAR T cells for the treatment of ovarian cancer and peritoneal carcinomatosis from ovarian cancer.
Collapse
Affiliation(s)
| | - Siyuan Qian
- Department of Surgery, Fundación Jimenez Diaz University Hospital, Madrid, Spain
| | | | - Cecilia Meliga
- Department of Surgery, Fundación Jimenez Diaz University Hospital, Madrid, Spain
| | - Sara González-Soares
- Department of Surgery, Fundación Jimenez Diaz University Hospital, Madrid, Spain
| | | | | | - Mariano García-Arranz
- Department of Surgery, Universidad Autónoma de Madrid, Madrid, Spain
- New Therapies Laboratory, Health Research Institute-Fundación Jiménez Díaz University Hospital (IIS-FJD), Madrid, Spain
| | - Héctor Guadalajara
- Department of Surgery, Fundación Jimenez Diaz University Hospital, Madrid, Spain
- Department of Surgery, Universidad Autónoma de Madrid, Madrid, Spain
| | - Damián García-Olmo
- Department of Surgery, Fundación Jimenez Diaz University Hospital, Madrid, Spain
- Department of Surgery, Universidad Autónoma de Madrid, Madrid, Spain
- New Therapies Laboratory, Health Research Institute-Fundación Jiménez Díaz University Hospital (IIS-FJD), Madrid, Spain
| |
Collapse
|
24
|
Wang Y, Zhao Y, Li M, Hou H, Jian Z, Li W, Li P, Ma F, Liu M, Liu H, Xue H. Conversion of primary liver cancer after targeted therapy for liver cancer combined with AFP-targeted CAR T-cell therapy: a case report. Front Immunol 2023; 14:1180001. [PMID: 37256142 PMCID: PMC10225497 DOI: 10.3389/fimmu.2023.1180001] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Accepted: 05/02/2023] [Indexed: 06/01/2023] Open
Abstract
Primary liver cancer (PLC) that originates in the liver is a malignant tumor with the worst prognosis. Hepatocellular carcinoma (HCC) is the most common type of PLC. Most PLC cases are diagnosed at advanced stages mainly due to their insidious onset and rapid progression. Patients with PLC undergo surgical intervention or localized treatment, but their survival is often affected by its high relapse rate. Medical treatment is the primary option for patients with liver cancer, especially with advanced extrahepatic metastases. Molecular targeted therapy exerts an anti-tumor effect by acting on various signaling pathways involved in molecular pathogenesis; however, high drug resistance and low therapeutic responsiveness of PLC to molecular targets challenge the treatment option. In recent years, after surgical intervention, radiotherapy, chemotherapy, and/or molecular targeted therapy, autologous cell immunotherapy has been adopted for PLC. As a typical autologous cell immunotherapy, CAR T-cell therapy uses genetically modified T cells to express tumor-specific chimeric antigen receptors (CARs). Its targeting ability, persistent nature, and tumor-killing function result in a significant impact on the treatment of hematological tumors. However, no breakthrough has happened in the research specific to the curation of lung cancer, liver cancer, breast cancer, and other common solid tumors. In this context, a combination of molecular targeted therapy and CAR T-cell therapy was used to treat a patient with advanced HCC to achieve a partial remission(PR) and facilitate further liver transplantation.
Collapse
|
25
|
Hadiloo K, Tahmasebi S, Esmaeilzadeh A. CAR-NKT cell therapy: a new promising paradigm of cancer immunotherapy. Cancer Cell Int 2023; 23:86. [PMID: 37158883 PMCID: PMC10165596 DOI: 10.1186/s12935-023-02923-9] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 04/10/2023] [Indexed: 05/10/2023] Open
Abstract
Today, cancer treatment is one of the fundamental problems facing clinicians and researchers worldwide. Efforts to find an excellent way to treat this illness continue, and new therapeutic strategies are developed quickly. Adoptive cell therapy (ACT) is a practical approach that has been emerged to improve clinical outcomes in cancer patients. In the ACT, one of the best ways to arm the immune cells against tumors is by employing chimeric antigen receptors (CARs) via genetic engineering. CAR equips cells to target specific antigens on tumor cells and selectively eradicate them. Researchers have achieved promising preclinical and clinical outcomes with different cells by using CARs. One of the potent immune cells that seems to be a good candidate for CAR-immune cell therapy is the Natural Killer-T (NKT) cell. NKT cells have multiple features that make them potent cells against tumors and would be a powerful replacement for T cells and natural killer (NK) cells. NKT cells are cytotoxic immune cells with various capabilities and no notable side effects on normal cells. The current study aimed to comprehensively provide the latest advances in CAR-NKT cell therapy for cancers.
Collapse
Affiliation(s)
- Kaveh Hadiloo
- Student Research Committee, Department of immunology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Safa Tahmasebi
- Student Research Committee, Department of immunology, School of Medicine, Shahid beheshti University of Medical Sciences, Tehran, Iran.
| | - Abdolreza Esmaeilzadeh
- Department of Immunology, Zanjan University of Medical Sciences, Zanjan, Iran.
- Cancer Gene Therapy Research Center (CGRC), Zanjan University of Medical Sciences, Zanjan, Iran.
| |
Collapse
|
26
|
Minaei N, Ramezankhani R, Tamimi A, Piryaei A, Zarrabi A, Aref AR, Mostafavi E, Vosough M. Immunotherapeutic approaches in Hepatocellular carcinoma: Building blocks of hope in near future. Eur J Cell Biol 2023; 102:151284. [PMID: 36584598 DOI: 10.1016/j.ejcb.2022.151284] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 11/30/2022] [Accepted: 12/16/2022] [Indexed: 12/23/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary hepatic cancer and is among the major causes of mortality due to cancer. Due to the lack of efficient conventional therapeutic options for this cancer, particularly in advanced cases, novel treatments including immunotherapy have been considered. However, despite the encouraging clinical outcomes after implementing these innovative approaches, such as oncolytic viruses (OVs), adoptive cell therapies (ACT), immune checkpoint blockades (ICBs), and cancer vaccines, several factors have restricted their therapeutic effect. The main concern is the existence of an immunosuppressive tumor microenvironment (TME). Combination of different ICBs or ICBs plus tyrosine kinase inhibitors have shown promising results in overcoming these limiting factors to some extent. Combination of programmed cell death ligand-1 (PD-L1) antibody Atezolizumab and vascular endothelial growth factor (VEGF) antibody Bevacizumab has become the standard of care in the first-line therapy for untestable HCC, approved by regulatory agencies. This paper highlighted a wide overview of the direct and indirect immunotherapeutic strategies proposed for the treatment of HCC patients and the common challenges that have hindered their further clinical applications.
Collapse
Affiliation(s)
- Neda Minaei
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran; Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
| | - Roya Ramezankhani
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran; Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran; Department of Development and Regeneration, KU Leuven Stem Cell Institute, Leuven, Belgium
| | - Atena Tamimi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran
| | - Abbas Piryaei
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul 34396, Turkey
| | - Amir Reza Aref
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Ebrahim Mostafavi
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran; Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research (ACECR), Tehran, Iran; Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institutet and Karolinska University Hospital-Huddinge, Sweden.
| |
Collapse
|
27
|
Mandlik DS, Mandlik SK, Choudhary HB. Immunotherapy for hepatocellular carcinoma: Current status and future perspectives. World J Gastroenterol 2023; 29:1054-1075. [PMID: 36844141 PMCID: PMC9950866 DOI: 10.3748/wjg.v29.i6.1054] [Citation(s) in RCA: 57] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 12/23/2022] [Accepted: 01/20/2023] [Indexed: 02/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the world’s deadliest and fastest-growing tumors, with a poor prognosis. HCC develops in the context of chronic liver disease. Curative resection, surgery (liver transplantation), trans-arterial chemoembolization, radioembolization, radiofrequency ablation and chemotherapy are common treatment options for HCC, however, they will only assist a limited percentage of patients. Current treatments for advanced HCC are ineffective and aggravate the underlying liver condition. Despite promising preclinical and early-phase clinical trials for some drugs, existing systemic therapeutic methods for advanced tumor stages remain limited, underlining an unmet clinical need. In current years, cancer immunotherapy has made significant progress, opening up new treatment options for HCC. HCC, on the other hand, has a variety of causes and can affects the body’s immune system via a variety of mechanisms. With the speedy advancement of synthetic biology and genetic engineering, a range of innovative immunotherapies, such as immune checkpoint inhibitors [anti-programmed cell death-1 (PD-1), anti-cytotoxic T lymphocyte antigen-4, and anti-PD ligand 1 cell death antibodies], therapeutic cancer vaccines, engineered cytokines, and adoptive cell therapy have all been used for the treatment of advanced HCC. In this review, we summarize the present clinical and preclinical landscape of immunotherapies in HCC, critically discuss recent clinical trial outcomes, and address future perspectives in the field of liver cancer.
Collapse
Affiliation(s)
- Deepa S Mandlik
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Satish K Mandlik
- Department of Pharmaceutics, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Heena B Choudhary
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| |
Collapse
|
28
|
Li W, Duan X, Chen X, Zhan M, Peng H, Meng Y, Li X, Li XY, Pang G, Dou X. Immunotherapeutic approaches in EBV-associated nasopharyngeal carcinoma. Front Immunol 2023; 13:1079515. [PMID: 36713430 PMCID: PMC9875085 DOI: 10.3389/fimmu.2022.1079515] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 12/23/2022] [Indexed: 01/13/2023] Open
Abstract
Epstein-Barr virus (EBV) was the first tumor virus in humans. Nasopharyngeal carcinoma (NPC) accounts for approximately 60% of the 200,000 new tumor cases caused by EBV infection worldwide each year. NPC has an insidious onset and is highly malignant, with more than 70% of patients having intermediate to advanced disease at the time of initial diagnosis, and is strongly implicated in epithelial cancers as well as malignant lymphoid and natural killer/T cell lymphomas. Over 90% of patients with confirmed undifferentiated NPC are infected with EBV. In recent decades, much progress has been made in understanding the molecular mechanisms of NPC and developing therapeutic approaches. Radiotherapy and chemotherapy are the main treatment options for NPC; however, they have a limited efficacy in patients with locally advanced or distant metastatic tumors. Tumor immunotherapy, including vaccination, adoptive cell therapy, and immune checkpoint blockade, represents a promising therapeutic approach for NPC. Significant breakthroughs have recently been made in the application of immunotherapy for patients with recurrent or metastatic NPC (RM-NPC), indicating a broad prospect for NPC immunotherapy. Here, we review important research findings regarding immunotherapy for NPC patients and provide insights for future research.
Collapse
Affiliation(s)
- Wenting Li
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China
| | - Xiaobing Duan
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China
| | - Xingxing Chen
- Department of Urology, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China
| | - Meixiao Zhan
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China
| | - Haichuan Peng
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China
| | - Ya Meng
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China,Faculty of Health Sciences, University of Macau, Macau, Macau SAR, China
| | - Xiaobin Li
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China
| | - Xian-Yang Li
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China,Department of R&D, OriCell Therapeutics Co. Ltd, Pudong, Shanghai, China,*Correspondence: Xiaohui Dou, ; Guofu Pang, ; Xian-Yang Li,
| | - Guofu Pang
- Department of Urology, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China,*Correspondence: Xiaohui Dou, ; Guofu Pang, ; Xian-Yang Li,
| | - Xiaohui Dou
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China,Health Management Center, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China,*Correspondence: Xiaohui Dou, ; Guofu Pang, ; Xian-Yang Li,
| |
Collapse
|
29
|
Yu I, Dakwar A, Takabe K. Immunotherapy: Recent Advances and Its Future as a Neoadjuvant, Adjuvant, and Primary Treatment in Colorectal Cancer. Cells 2023; 12:cells12020258. [PMID: 36672193 PMCID: PMC9856401 DOI: 10.3390/cells12020258] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 01/02/2023] [Accepted: 01/04/2023] [Indexed: 01/10/2023] Open
Abstract
Immunotherapy in colorectal cancer (CRC) has made great strides within the past decade. Immune checkpoint inhibitors are a class of immunotherapy and have been shown to greatly improve patient outcomes in mismatch repair-deficient (dMMR) CRC. Now, they are part of the standard of care for this subset of CRC. Because of this, there has been a growing interest in the efficacy and timing of immunotherapy for other subsets of CRC, including locally advanced, metastatic, and microsatellite stable (MSS). In this review, we aim to examine the three main classes of immunotherapy for CRC-immune checkpoint inhibitors (ICIs), adoptive cell transfer therapy (ACT), and tumor vaccines-and discuss the most recent advances and future directions for each.
Collapse
Affiliation(s)
- Irene Yu
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY 14214, USA
| | - Anthony Dakwar
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY 14214, USA
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY 14214, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
- Department of Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 160-8402, Japan
- Department of Breast Surgery, Fukushima Medical University, Fukushima 960-1295, Japan
- Correspondence: ; Tel.: +1-716-845-5128
| |
Collapse
|
30
|
Nasr D, Kumar PA, Zerdan MB, Ghelani G, Dutta D, Graziano S, Lim SH. Radioimmunoconjugates in the age of modern immuno-oncology. Life Sci 2022; 310:121126. [DOI: 10.1016/j.lfs.2022.121126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 10/14/2022] [Accepted: 10/22/2022] [Indexed: 11/09/2022]
|
31
|
Rao P, Furst L, Meyran D, Mayoh C, Neeson PJ, Terry R, Khuong-Quang DA, Mantamadiotis T, Ekert PG. Advances in CAR T cell immunotherapy for paediatric brain tumours. Front Oncol 2022; 12:873722. [PMID: 36505819 PMCID: PMC9727400 DOI: 10.3389/fonc.2022.873722] [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: 02/20/2022] [Accepted: 11/02/2022] [Indexed: 11/24/2022] Open
Abstract
Brain tumours are the most common solid tumour in children and the leading cause of cancer related death in children. Current treatments include surgery, chemotherapy and radiotherapy. The need for aggressive treatment means many survivors are left with permanent severe disability, physical, intellectual and social. Recent progress in immunotherapy, including genetically engineered T cells with chimeric antigen receptors (CARs) for treating cancer, may provide new avenues to improved outcomes for patients with paediatric brain cancer. In this review we discuss advances in CAR T cell immunotherapy, the major CAR T cell targets that are in clinical and pre-clinical development with a focus on paediatric brain tumours, the paediatric brain tumour microenvironment and strategies used to improve CAR T cell therapy for paediatric tumours.
Collapse
Affiliation(s)
- Padmashree Rao
- Translational Tumour Biology, Children’s Cancer Institute, Randwick, NSW, Australia
| | - Liam Furst
- Department of Microbiology & Immunology, The University of Melbourne, Victoria, VIC, Australia,Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, VIC, Australia
| | - Deborah Meyran
- Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia,Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia,Université de Paris, Inserm, U976 Human Immunology Pathophysiology Immunotherapy (HIPI) Unit, Institut de Recherche Saint-Louis, Paris, France,Children’s Cancer Centre, Royal Children’s Hospital, Parkville, VIC, Australia
| | - Chelsea Mayoh
- Translational Tumour Biology, Children’s Cancer Institute, Randwick, NSW, Australia,School of Women and Children’s Health, University of New South Wales, Randwick, NSW, Australia
| | - Paul J. Neeson
- Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia,Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia
| | - Rachael Terry
- Translational Tumour Biology, Children’s Cancer Institute, Randwick, NSW, Australia,School of Women and Children’s Health, University of New South Wales, Randwick, NSW, Australia
| | - Dong-Anh Khuong-Quang
- Translational Tumour Biology, Children’s Cancer Institute, Randwick, NSW, Australia,Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, VIC, Australia,Children’s Cancer Centre, Royal Children’s Hospital, Parkville, VIC, Australia
| | - Theo Mantamadiotis
- Department of Microbiology & Immunology, The University of Melbourne, Victoria, VIC, Australia,Department of Surgery Royal Melbourne Hospital (RMH), The University of Melbourne, Parkville, VIC, Australia,*Correspondence: Theo Mantamadiotis, ; Paul G. Ekert,
| | - Paul G. Ekert
- Translational Tumour Biology, Children’s Cancer Institute, Randwick, NSW, Australia,Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, VIC, Australia,Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia,Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia,School of Women and Children’s Health, University of New South Wales, Randwick, NSW, Australia,Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia,*Correspondence: Theo Mantamadiotis, ; Paul G. Ekert,
| |
Collapse
|
32
|
Jung IY, Narayan V, McDonald S, Rech AJ, Bartoszek R, Hong G, Davis MM, Xu J, Boesteanu AC, Barber-Rotenberg JS, Plesa G, Lacey SF, Jadlowsky JK, Siegel DL, Hammill DM, Cho-Park PF, Berger SL, Haas NB, Fraietta JA. BLIMP1 and NR4A3 transcription factors reciprocally regulate antitumor CAR T cell stemness and exhaustion. Sci Transl Med 2022; 14:eabn7336. [PMID: 36350986 PMCID: PMC10257143 DOI: 10.1126/scitranslmed.abn7336] [Citation(s) in RCA: 65] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/01/2023]
Abstract
Chimeric antigen receptor (CAR) T cells have not induced meaningful clinical responses in solid tumors. Loss of T cell stemness, poor expansion capacity, and exhaustion during prolonged tumor antigen exposure are major causes of CAR T cell therapeutic resistance. Single-cell RNA-sequencing analysis of CAR T cells from a first-in-human trial in metastatic prostate cancer identified two independently validated cell states associated with antitumor potency or lack of efficacy. Low expression of PRDM1, encoding the BLIMP1 transcription factor, defined highly potent TCF7 [encoding T cell factor 1 (TCF1)]-expressing CD8+ CAR T cells, whereas enrichment of HAVCR2 [encoding T cell immunoglobulin and mucin-domain containing-3 (TIM-3)]-expressing CD8+ T cells with elevated PRDM1 was associated with poor outcomes. PRDM1 knockout promoted TCF7-dependent CAR T cell stemness and proliferation, resulting in marginally enhanced leukemia control in mice. However, in the setting of PRDM1 deficiency, a negative epigenetic feedback program of nuclear factor of activated T cells (NFAT)-driven T cell dysfunction was identified. This program was characterized by compensatory up-regulation of NR4A3 and other genes encoding exhaustion-related transcription factors that hampered T cell effector function in solid tumors. Dual knockout of PRDM1 and NR4A3 skewed CAR T cell phenotypes away from TIM-3+CD8+ and toward TCF1+CD8+ to counter exhaustion of tumor-infiltrating CAR T cells and improve antitumor responses, effects that were not achieved with PRDM1 and NR4A3 single knockout alone. These data underscore dual targeting of PRDM1 and NR4A3 as a promising approach to advance adoptive cell immuno-oncotherapy.
Collapse
Affiliation(s)
- In-Young Jung
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (19104)
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (19104)
- Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (19104)
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (19104)
| | - Vivek Narayan
- Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (19104)
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (19104)
| | - Sierra McDonald
- Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA (19104)
- Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (19104)
- Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (19104)
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (19104)
| | - Andrew J. Rech
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (19104)
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (19104)
- Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA (19104)
| | - Robert Bartoszek
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (19104)
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (19104)
- Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (19104)
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (19104)
| | - Gwanui Hong
- Department of Systems Pharmacology & Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (19104)
| | - Megan M. Davis
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (19104)
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (19104)
| | - Jun Xu
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (19104)
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (19104)
| | - Alina C. Boesteanu
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (19104)
| | - Julie S. Barber-Rotenberg
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (19104)
| | - Gabriela Plesa
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (19104)
| | - Simon F. Lacey
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (19104)
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (19104)
| | - Julie K. Jadlowsky
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (19104)
| | - Donald L. Siegel
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (19104)
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (19104)
| | - Dana M. Hammill
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (19104)
| | - Park F. Cho-Park
- Department of Systems Pharmacology & Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (19104)
| | - Shelley L. Berger
- Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, PA (19104)
- Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (19104)
- Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (19104)
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (19104)
| | - Naomi B. Haas
- Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (19104)
- Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (19104)
| | - Joseph A. Fraietta
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (19104)
- Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (19104)
- Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (19104)
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (19104)
| |
Collapse
|
33
|
Vandghanooni S, Eskandani M, Sanaat Z, Omidi Y. Recent advances in the production, reprogramming, and application of CAR-T cells for treating hematological malignancies. Life Sci 2022; 309:121016. [PMID: 36179813 DOI: 10.1016/j.lfs.2022.121016] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Revised: 09/26/2022] [Accepted: 09/26/2022] [Indexed: 10/31/2022]
Abstract
As genetically engineered cells, chimeric antigen receptor (CAR)-T cells express specific receptors on their surface to target and eliminate malignant cells. CAR proteins are equipped with elements that enhance the activity and survival of T cells. Once injected, CAR-T cells act as a "living drug" against tumor cells in the body. Up to now, CAR-T cell therapy has been demonstrated as a robust adoptive cell transfer (ACT) immunotherapeutic modality for eliminating tumor cells in refractory hematological malignancies. CAR-T cell therapy modality involves several steps, including the collecting of the blood from patients, the isolation of peripheral blood mononuclear cells (PBMCs), the enrichment of CD4+/CD8+ T cell, the genetic reprogramming, the expansion of modified T cells, and the injection of genetically engineered T cells. The production of CAR-T cells is a multi-step procedure, which needs precise and safety management systems, including good manufacturing practice (GMP), and in-line quality control and assurance. The current study describes the structure of CARs and concentrates on the next generations of CARs that are engaged in enhancing the anti-tumor responses and safety of the engineered T cells. This paper also highlights the important concerns in quality control and nonclinical research of CAR-T cells, as well as general insights into the manufacture, reprogramming, and application of CAR-T cells based on new and enhanced techniques for treating hematological malignancies. Besides, the application of the CRISPR-Cas9 genome editing technology and nanocarrier-based delivery systems containing CAR coding sequences to overcome the limitations of CAR-T cell therapy has also been explained.
Collapse
Affiliation(s)
- Somayeh Vandghanooni
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Morteza Eskandani
- Research Center for Pharmaceutical Nanotechnology, Biomedicine Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zohreh Sanaat
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Yadollah Omidi
- Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL, USA
| |
Collapse
|
34
|
Chen X, Mirazee JM, Skorupka KA, Matsuo H, Youkharibache P, Taylor N, Walters KJ. The CD8α hinge is intrinsically disordered with a dynamic exchange that includes proline cis-trans isomerization. JOURNAL OF MAGNETIC RESONANCE (SAN DIEGO, CALIF. : 1997) 2022; 340:107234. [PMID: 35617919 PMCID: PMC9237829 DOI: 10.1016/j.jmr.2022.107234] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 05/04/2022] [Accepted: 05/07/2022] [Indexed: 06/15/2023]
Abstract
T cells engineered to express artificial chimeric antigen receptors (CARs) that selectively target tumor-specific antigens or deleterious cell types offer transformative therapeutic possibilities. CARs contain an N-terminal extracellular antigen recognition domain, C-terminal intracellular signal transduction domains, and connecting hinge and transmembrane regions, each of which have been varied to optimize targeting and minimize toxicity. We find that a CD22-targeting CAR harboring a CD8α hinge (H) exhibits greater cytotoxicity against a low antigen density CD22+ leukemia as compared to an equivalent CAR with a CD28 H. We therefore studied the biophysical and dynamic properties of the CD8α H by nuclear magnetic resonance (NMR) spectroscopy. We find that a large region of the CD8α H undergoes dynamic chemical exchange between distinct and observable states. This exchanging region contains proline residues dispersed throughout the sequence that undergo cis-trans isomerization. Up to four signals of differing intensity are observed, with the most abundantly populated being intrinsically disordered and with all prolines in the trans isomerization state. The lesser populated states all contain cis prolines and evidence of local structural motifs. Altogether, our data suggest that the CD8α H lacks long-range structural order but has local structural motifs that transiently exchange with a dominant disordered state. We propose that structural plasticity and local structural motifs promoted by cis proline states within the CD8α H are important for relaying and amplifying antigen-binding effects to the transmembrane and signal transduction domains.
Collapse
Affiliation(s)
- Xiang Chen
- Center for Structural Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA
| | - Justin M Mirazee
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20814, USA; Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20894, USA; Johns Hopkins University Department of Biology, 3400 N. Charles Street, Baltimore, MD 21218, USA
| | - Katarzyna A Skorupka
- Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA
| | - Hiroshi Matsuo
- Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA
| | - Philippe Youkharibache
- Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20894, USA.
| | - Naomi Taylor
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20814, USA.
| | - Kylie J Walters
- Center for Structural Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
| |
Collapse
|
35
|
Sagnella SM, White AL, Yeo D, Saxena P, van Zandwijk N, Rasko JEJ. Locoregional delivery of CAR-T cells in the clinic. Pharmacol Res 2022; 182:106329. [PMID: 35772645 DOI: 10.1016/j.phrs.2022.106329] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 06/03/2022] [Accepted: 06/24/2022] [Indexed: 12/26/2022]
Abstract
Cellular therapies utilizing T cells expressing chimeric antigen receptors (CARs) have garnered significant interest due to their clinical success in hematological malignancies. Unfortunately, this success has not been replicated in solid tumors, with only a small fraction of patients achieving complete responses. A number of obstacles to effective CAR-T cell therapy in solid tumors have been identified including tumor antigen heterogeneity, poor T cell fitness and persistence, inefficient trafficking and inability to penetrate into the tumor, immune-related adverse events due to on-target/off-tumor toxicity, and the immunosuppressive tumor microenvironment. Many preclinical studies have focused on improvements to CAR design to try to overcome some of these hurdles. However, a growing body of work has also focused on the use of local and/or regional delivery of CAR-T cells as a means to overcome poor T cell trafficking and inefficient T cell penetration into tumors. Most trials that incorporate locoregional delivery of CAR-T cells have targeted tumors of the central nervous system - repurposing an Ommaya/Rickham reservoir for repeated delivery of cells directly to the tumor cavity or ventricles. Hepatic artery infusion is another technique used for locoregional delivery to hepatic tumors. Locoregional delivery theoretically permits increased numbers of CAR-T cells within the tumor while reducing the risk of immune-related systemic toxicity. Studies to date have been almost exclusively phase I. The growing body of evidence indicates that locoregional delivery of CAR-T cells is both safe and feasible. This review focuses specifically on the use of locoregional delivery of CAR-T cells in clinical trials.
Collapse
Affiliation(s)
- Sharon M Sagnella
- Cell & Molecular Therapies, Royal Prince Alfred Hospital, Sydney Local Health District, Camperdown 2050, Australia
| | - Amy L White
- Faculty of Medicine and Health, The University of Sydney, Camperdown 2050, Australia
| | - Dannel Yeo
- Cell & Molecular Therapies, Royal Prince Alfred Hospital, Sydney Local Health District, Camperdown 2050, Australia; Faculty of Medicine and Health, The University of Sydney, Camperdown 2050, Australia; Li Ka Shing Cell & Gene Therapy Program, The University of Sydney, Camperdown 2050, Australia
| | - Payal Saxena
- Faculty of Medicine and Health, The University of Sydney, Camperdown 2050, Australia; Division of Gastroenterology, Department of Medicine, Royal Prince Alfred Hospital, Sydney Local Health District, Camperdown 2050, Australia
| | - Nico van Zandwijk
- Faculty of Medicine and Health, The University of Sydney, Camperdown 2050, Australia; Li Ka Shing Cell & Gene Therapy Program, The University of Sydney, Camperdown 2050, Australia; Concord Repatriation General Hospital, Sydney Local Health District, Concord 2139, Australia
| | - John E J Rasko
- Cell & Molecular Therapies, Royal Prince Alfred Hospital, Sydney Local Health District, Camperdown 2050, Australia; Faculty of Medicine and Health, The University of Sydney, Camperdown 2050, Australia; Li Ka Shing Cell & Gene Therapy Program, The University of Sydney, Camperdown 2050, Australia; Gene and Stem Cell Therapy Program Centenary Institute, The University of Sydney, Camperdown 2050, Australia.
| |
Collapse
|
36
|
Nguyen DT, Ogando-Rivas E, Liu R, Wang T, Rubin J, Jin L, Tao H, Sawyer WW, Mendez-Gomez HR, Cascio M, Mitchell DA, Huang J, Sawyer WG, Sayour EJ, Castillo P. CAR T Cell Locomotion in Solid Tumor Microenvironment. Cells 2022; 11:1974. [PMID: 35741103 PMCID: PMC9221866 DOI: 10.3390/cells11121974] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 06/14/2022] [Accepted: 06/15/2022] [Indexed: 01/25/2023] Open
Abstract
The promising outcomes of chimeric antigen receptor (CAR) T cell therapy in hematologic malignancies potentiates its capability in the fight against many cancers. Nevertheless, this immunotherapy modality needs significant improvements for the treatment of solid tumors. Researchers have incrementally identified limitations and constantly pursued better CAR designs. However, even if CAR T cells are armed with optimal killer functions, they must overcome and survive suppressive barriers imposed by the tumor microenvironment (TME). In this review, we will discuss in detail the important role of TME in CAR T cell trafficking and how the intrinsic barriers contribute to an immunosuppressive phenotype and cancer progression. It is of critical importance that preclinical models can closely recapitulate the in vivo TME to better predict CAR T activity. Animal models have contributed immensely to our understanding of human diseases, but the intensive care for the animals and unreliable representation of human biology suggest in vivo models cannot be the sole approach to CAR T cell therapy. On the other hand, in vitro models for CAR T cytotoxic assessment offer valuable insights to mechanistic studies at the single cell level, but they often lack in vivo complexities, inter-individual heterogeneity, or physiologically relevant spatial dimension. Understanding the advantages and limitations of preclinical models and their applications would enable more reliable prediction of better clinical outcomes.
Collapse
Affiliation(s)
- Duy T. Nguyen
- Department of Mechanical and Aerospace Engineering, University of Florida, Gainesville, FL 32611, USA; (D.T.N.); (W.W.S.); (W.G.S.)
| | - Elizabeth Ogando-Rivas
- Department of Neurosurgery, University of Florida, Gainesville, FL 32608, USA; (E.O.-R.); (R.L.); (L.J.); (H.T.); (H.R.M.-G.); (D.A.M.); (J.H.); (E.J.S.)
| | - Ruixuan Liu
- Department of Neurosurgery, University of Florida, Gainesville, FL 32608, USA; (E.O.-R.); (R.L.); (L.J.); (H.T.); (H.R.M.-G.); (D.A.M.); (J.H.); (E.J.S.)
| | - Theodore Wang
- College of Medicine, University of Florida, Gainesville, FL 32610, USA;
| | - Jacob Rubin
- Warrington College of Business, University of Florida, Gainesville, FL 32610, USA;
| | - Linchun Jin
- Department of Neurosurgery, University of Florida, Gainesville, FL 32608, USA; (E.O.-R.); (R.L.); (L.J.); (H.T.); (H.R.M.-G.); (D.A.M.); (J.H.); (E.J.S.)
| | - Haipeng Tao
- Department of Neurosurgery, University of Florida, Gainesville, FL 32608, USA; (E.O.-R.); (R.L.); (L.J.); (H.T.); (H.R.M.-G.); (D.A.M.); (J.H.); (E.J.S.)
| | - William W. Sawyer
- Department of Mechanical and Aerospace Engineering, University of Florida, Gainesville, FL 32611, USA; (D.T.N.); (W.W.S.); (W.G.S.)
- Department of Pediatrics, Division of Pediatric Hematology Oncology, University of Florida, Gainesville, FL 32610, USA;
| | - Hector R. Mendez-Gomez
- Department of Neurosurgery, University of Florida, Gainesville, FL 32608, USA; (E.O.-R.); (R.L.); (L.J.); (H.T.); (H.R.M.-G.); (D.A.M.); (J.H.); (E.J.S.)
| | - Matthew Cascio
- Department of Pediatrics, Division of Pediatric Hematology Oncology, University of Florida, Gainesville, FL 32610, USA;
| | - Duane A. Mitchell
- Department of Neurosurgery, University of Florida, Gainesville, FL 32608, USA; (E.O.-R.); (R.L.); (L.J.); (H.T.); (H.R.M.-G.); (D.A.M.); (J.H.); (E.J.S.)
| | - Jianping Huang
- Department of Neurosurgery, University of Florida, Gainesville, FL 32608, USA; (E.O.-R.); (R.L.); (L.J.); (H.T.); (H.R.M.-G.); (D.A.M.); (J.H.); (E.J.S.)
| | - W. Gregory Sawyer
- Department of Mechanical and Aerospace Engineering, University of Florida, Gainesville, FL 32611, USA; (D.T.N.); (W.W.S.); (W.G.S.)
| | - Elias J. Sayour
- Department of Neurosurgery, University of Florida, Gainesville, FL 32608, USA; (E.O.-R.); (R.L.); (L.J.); (H.T.); (H.R.M.-G.); (D.A.M.); (J.H.); (E.J.S.)
- Department of Pediatrics, Division of Pediatric Hematology Oncology, University of Florida, Gainesville, FL 32610, USA;
| | - Paul Castillo
- Department of Pediatrics, Division of Pediatric Hematology Oncology, University of Florida, Gainesville, FL 32610, USA;
| |
Collapse
|
37
|
Liu C, Li L, Gao F, Zhou J, Qin Y, Yuan X, Yang G, Zhu Y. Reforming the Chimeric Antigen Receptor by Peptide Towards Optimized CAR T Cells With Enhanced Anti-Cancer Potency and Safety. Front Bioeng Biotechnol 2022; 10:928169. [PMID: 35782491 PMCID: PMC9247402 DOI: 10.3389/fbioe.2022.928169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 05/25/2022] [Indexed: 11/29/2022] Open
Abstract
The emerging chimeric antigen receptor (CAR) T cell revolutionized the clinic treatment of hematological cancers, but meet its Waterloo in solid tumor therapy. Although there exist many reasons for this limitation, one of the largest challenges is the scarcity of recognition for tumor cells, resulting in the undesirable side effects and the subsequent ineffectiveness. To overcome it, a lung-cancer-cell-targeting peptide termed A1 was used in this work to reform the scFv domain of CAR by genetic manipulation. As a result, this modified A1CAR T exhibited the optimized cancer-cell targeting and cytotoxicity in vitro and in vivo. More importantly, by tuning the sensitivity of CAR to antigen, peptide-based A1CAR T cells could distinguish tumors from normal tissue, thereby eliminating the off-tumor toxicity in healthy organs. Collectively, we herein constructed a genetic peptide-engineered CAR T cells by inserting A1 peptide into the scFv domain. Profitted from the optimized recognition pattern and sensitivity, A1CAR T cells showed the ascendancy in solid tumor treatment. Our findings demonstrate that peptide-based CAR T holds great potential in solid tumor therapy due to an excellent targeting ability towards tumor cells.
Collapse
Affiliation(s)
- Cuijuan Liu
- School of Nano Technology and Nano Bionics, University of Science and Technology of China, Hefei, China
- CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, China
| | - Lin Li
- CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, China
| | - Fan Gao
- School of Nano Technology and Nano Bionics, University of Science and Technology of China, Hefei, China
- CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, China
| | - Jundong Zhou
- Nanjing Medical University, Affiliated Suzhou Hospital, Department Radio Oncology, Suzhou, China
| | - Yingzhou Qin
- School of Nano Technology and Nano Bionics, University of Science and Technology of China, Hefei, China
- CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, China
| | - Xin Yuan
- School of Nano Technology and Nano Bionics, University of Science and Technology of China, Hefei, China
- CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, China
| | - Guang Yang
- Department of Oncology, Suzhou BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Suzhou, China
- *Correspondence: Guang Yang, ; Yimin Zhu,
| | - Yimin Zhu
- CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, China
- *Correspondence: Guang Yang, ; Yimin Zhu,
| |
Collapse
|
38
|
Dubois VP, Sehl OC, Foster PJ, Ronald JA. Visualizing CAR-T cell Immunotherapy Using 3 Tesla Fluorine-19 MRI. Mol Imaging Biol 2022; 24:298-308. [PMID: 34786668 PMCID: PMC8983548 DOI: 10.1007/s11307-021-01672-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 09/02/2021] [Accepted: 10/20/2021] [Indexed: 01/19/2023]
Abstract
PURPOSE Chimeric antigen receptor (CAR) T cell cancer immunotherapies have shown remarkable results in patients with hematological malignancies and represent the first approved genetically modified cellular therapies. However, not all blood cancer patients respond favorably, serious side effects have been reported, and the treatment of solid tumors has been a challenge. An imaging tool for visualizing the variety of CAR-T cell products in use and being explored could provide important patient-specific data on CAR-T cell location to inform on potential success or failure of treatment as well as off-target toxicities. Fluorine-19 (19F) magnetic resonance imaging (MRI) allows for the noninvasive detection of 19F perfluorocarbon (PFC) labeled cells. Our objective was to visualize PFC-labeled (PFC +) CAR-T cells in a mouse model of leukemia using clinical field strength (3 Tesla) 19F MRI and compare the cytotoxicity of PFC + versus unlabeled CAR-T cells. PROCEDURES NSG mice (n = 17) received subcutaneous injections of CD19 + human B cell leukemia cells (NALM6) expressing firefly luciferase in their left hind flank (1 × 106). Twenty-one days later, each mouse received an intratumoral injection of 10 × 106 PFC + CD19-targeted CAR-T cells (n = 6), unlabeled CD19-targeted CAR-T cells (n = 3), PFC + untransduced T cells (n = 5), or an equivalent volume of saline (n = 3). 19F MRI was performed on mice treated with PFC + CAR-T cells days 1, 3, and 7 post-treatment. Bioluminescence imaging (BLI) was performed on all mice days - 1, 5, 10, and 14 post-treatment to monitor tumor response. RESULTS PFC + CAR-T cells were successfully detected in tumors using 19F MRI on days 1, 3, and 7 post-injection. In vivo BLI data revealed that mice treated with PFC + or PFC - CAR-T cells had significantly lower tumor burden by day 14 compared to untreated mice and mice treated with PFC + untransduced T cells (p < 0.05). Importantly, mice treated with PFC + CAR-T cells showed equivalent cytotoxicity compared to mice receiving PFC - CAR-T cells. CONCLUSIONS Our studies demonstrate that clinical field strength 19F MRI can be used to visualize PFC + CAR-T cells for up to 7 days post-intratumoral injection. Importantly, PFC labeling did not significantly affect in vivo CAR-T cell cytotoxicity. These imaging tools may have broad applications for tracking emerging CAR-T cell therapies in preclinical models and may eventually be useful for the detection of CAR-T cells in patients where localized injection of CAR-T cells is being pursued.
Collapse
Affiliation(s)
- Veronica P Dubois
- Robarts Research Institute, London, ON, Canada
- The Department of Medical Biophysics, Western University, London, ON, Canada
| | - Olivia C Sehl
- Robarts Research Institute, London, ON, Canada
- The Department of Medical Biophysics, Western University, London, ON, Canada
| | - Paula J Foster
- Robarts Research Institute, London, ON, Canada
- The Department of Medical Biophysics, Western University, London, ON, Canada
| | - John A Ronald
- Robarts Research Institute, London, ON, Canada.
- The Department of Medical Biophysics, Western University, London, ON, Canada.
- Lawson Health Research Institute, London, ON, Canada.
| |
Collapse
|
39
|
Qian S, Villarejo-Campos P, Guijo I, Hernández-Villafranca S, García-Olmo D, González-Soares S, Guadalajara H, Jiménez-Galanes S, Qian C. Update for Advance CAR-T Therapy in Solid Tumors, Clinical Application in Peritoneal Carcinomatosis From Colorectal Cancer and Future Prospects. Front Immunol 2022; 13:841425. [PMID: 35401510 PMCID: PMC8990899 DOI: 10.3389/fimmu.2022.841425] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 03/02/2022] [Indexed: 12/24/2022] Open
Abstract
Latest advances in the field of cancer immunotherapy have developed the (Chimeric Antigen Receptor) CAR-T cell therapy. This therapy was first used in hematological malignancies which obtained promising results; therefore, the use of CAR-T cells has become a popular approach for treating non-solid tumors. CAR-T cells consist of T-lymphocytes that are engineered to express an artificial receptor against any surface antigen of our choice giving us the capacity of offering precise and personalized treatment. This leaded to the development of CAR-T cells for treating solid tumors with the hope of obtaining the same result; however, their use in solid tumor and their efficacy have not achieved the expected results. The reason of these results is because solid tumors have some peculiarities that are not present in hematological malignancies. In this review we explain how CAR-T cells are made, their mechanism of action, adverse effect and how solid tumors can evade their action, and also we summarize their use in colorectal cancer and peritoneal carcinomatosis.
Collapse
Affiliation(s)
- Siyuan Qian
- Department of Surgery, Fundación Jimenez Diaz University Hospital, Madrid, Spain
| | | | - Ismael Guijo
- Department of Surgery, Fundación Jimenez Diaz University Hospital, Madrid, Spain
| | | | - Damián García-Olmo
- Department of Surgery, Fundación Jimenez Diaz University Hospital, Madrid, Spain
- Department of Surgery, Universidad Autónoma de Madrid, Madrid, Spain
| | - Sara González-Soares
- Department of Surgery, Fundación Jimenez Diaz University Hospital, Madrid, Spain
| | - Héctor Guadalajara
- Department of Surgery, Fundación Jimenez Diaz University Hospital, Madrid, Spain
| | | | - Cheng Qian
- Chongqing Precision Biotechnology Co. Ltd, Chongqing, China
| |
Collapse
|
40
|
Preclinical Evaluation of CAR T Cell Function: In Vitro and In Vivo Models. Int J Mol Sci 2022; 23:ijms23063154. [PMID: 35328572 PMCID: PMC8955360 DOI: 10.3390/ijms23063154] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 03/11/2022] [Accepted: 03/11/2022] [Indexed: 01/12/2023] Open
Abstract
Immunotherapy using chimeric antigen receptor (CAR) T cells is a rapidly emerging modality that engineers T cells to redirect tumor-specific cytotoxicity. CAR T cells have been well characterized for their efficacy against B cell malignancies, and rigorously studied in other types of tumors. Preclinical evaluation of CAR T cell function, including direct tumor killing, cytokine production, and memory responses, is crucial to the development and optimization of CAR T cell therapies. Such comprehensive examinations are usually performed in different types of models. Model establishment should focus on key challenges in the clinical setting and the capability to generate reliable data to indicate CAR T cell therapeutic potency in the clinic. Further, modeling the interaction between CAR T cells and tumor microenvironment provides additional insight for the future endeavors to enhance efficacy, especially against solid tumors. This review will summarize both in vitro and in vivo models for CAR T cell functional evaluation, including how they have evolved with the needs of CAR T cell research, the information they can provide for preclinical assessment of CAR T cell products, and recent technology advances to test CAR T cells in more clinically relevant models.
Collapse
|
41
|
Wang SW, Gao C, Zheng YM, Yi L, Lu JC, Huang XY, Cai JB, Zhang PF, Cui YH, Ke AW. Current applications and future perspective of CRISPR/Cas9 gene editing in cancer. Mol Cancer 2022; 21:57. [PMID: 35189910 PMCID: PMC8862238 DOI: 10.1186/s12943-022-01518-8] [Citation(s) in RCA: 166] [Impact Index Per Article: 55.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 01/24/2022] [Indexed: 02/08/2023] Open
Abstract
Clustered regularly interspaced short palindromic repeats (CRISPR) system provides adaptive immunity against plasmids and phages in prokaryotes. This system inspires the development of a powerful genome engineering tool, the CRISPR/CRISPR-associated nuclease 9 (CRISPR/Cas9) genome editing system. Due to its high efficiency and precision, the CRISPR/Cas9 technique has been employed to explore the functions of cancer-related genes, establish tumor-bearing animal models and probe drug targets, vastly increasing our understanding of cancer genomics. Here, we review current status of CRISPR/Cas9 gene editing technology in oncological research. We first explain the basic principles of CRISPR/Cas9 gene editing and introduce several new CRISPR-based gene editing modes. We next detail the rapid progress of CRISPR screening in revealing tumorigenesis, metastasis, and drug resistance mechanisms. In addition, we introduce CRISPR/Cas9 system delivery vectors and finally demonstrate the potential of CRISPR/Cas9 engineering to enhance the effect of adoptive T cell therapy (ACT) and reduce adverse reactions.
Collapse
Affiliation(s)
- Si-Wei Wang
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Chao Gao
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
- Institute of Biomedical Sciences, Fudan University, 138 Medical School Road, Shanghai, 200032, People's Republic of China
| | - Yi-Min Zheng
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Li Yi
- Institute of Biomedical Sciences, Fudan University, 138 Medical School Road, Shanghai, 200032, People's Republic of China
| | - Jia-Cheng Lu
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Xiao-Yong Huang
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Jia-Bin Cai
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Peng-Fei Zhang
- Department of Oncology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China
| | - Yue-Hong Cui
- Department of Oncology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China.
| | - Ai-Wu Ke
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People's Republic of China.
| |
Collapse
|
42
|
Griffith AA, Callahan KP, King NG, Xiao Q, Su X, Salomon AR. SILAC Phosphoproteomics Reveals Unique Signaling Circuits in CAR-T Cells and the Inhibition of B Cell-Activating Phosphorylation in Target Cells. J Proteome Res 2022; 21:395-409. [PMID: 35014847 PMCID: PMC8830406 DOI: 10.1021/acs.jproteome.1c00735] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Chimeric antigen receptor (CAR) is a single-pass transmembrane receptor designed to specifically target and eliminate cancers. While CARs prove highly efficacious against B cell malignancies, the intracellular signaling events which promote CAR T cell activity remain elusive. To gain further insight into both CAR T cell signaling and the potential signaling response of cells targeted by CAR, we analyzed phosphopeptides captured by two separate phosphoenrichment strategies from third generation CD19-CAR T cells cocultured with SILAC labeled Raji B cells by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Here, we report that CD19-CAR T cells upregulated several key phosphorylation events also observed in canonical T cell receptor (TCR) signaling, while Raji B cells exhibited a significant decrease in B cell receptor-signaling related phosphorylation events in response to coculture. Our data suggest that CD19-CAR stimulation activates a mixture of unique CD19-CAR-specific signaling pathways and canonical TCR signaling, while global phosphorylation in Raji B cells is reduced after association with the CD19-CAR T cells.
Collapse
Affiliation(s)
- Alijah A. Griffith
- Department of Molecular Biology, Cell Biology & Biochemistry, Brown University, Providence, RI, 02912
| | - Kenneth P. Callahan
- Department of Molecular Biology, Cell Biology & Biochemistry, Brown University, Providence, RI, 02912
| | - Nathan Gordo King
- Department of Molecular Biology, Cell Biology & Biochemistry, Brown University, Providence, RI, 02912
| | - Qian Xiao
- Department of Cell Biology, Yale School of Medicine, Yale University, New Haven, CT, 06520
| | - Xiaolei Su
- Department of Cell Biology, Yale School of Medicine, Yale University, New Haven, CT, 06520
| | - Arthur R. Salomon
- Department of Molecular Biology, Cell Biology & Biochemistry, Brown University, Providence, RI, 02912,
| |
Collapse
|
43
|
A cell-based phenotypic library selection and screening approach for the de novo discovery of novel functional chimeric antigen receptors. Sci Rep 2022; 12:1136. [PMID: 35064152 PMCID: PMC8782825 DOI: 10.1038/s41598-022-05058-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 01/03/2022] [Indexed: 11/16/2022] Open
Abstract
Anti-tumor therapies that seek to exploit and redirect the cytotoxic killing and effector potential of autologous or syngeneic T cells have shown extraordinary promise and efficacy in certain clinical settings. Such cells, when engineered to express synthetic chimeric antigen receptors (CARs) acquire novel targeting and activation properties which are governed and orchestrated by, typically, antibody fragments specific for a tumor antigen of interest. However, it is becoming increasingly apparent that not all antibodies are equal in this regard, with a growing appreciation that ‘optimal’ CAR performance requires a consideration of multiple structural and contextual parameters. Thus, antibodies raised by classical approaches and intended for other applications often perform poorly or not at all when repurposed as CARs. With this in mind, we have explored the potential of an in vitro phenotypic CAR library discovery approach that tightly associates antibody-driven bridging of tumor and effector T cells with an informative and functionally relevant CAR activation reporter signal. Critically, we demonstrate the utility of this enrichment methodology for ‘real world’ de novo discovery by isolating several novel anti-mesothelin CAR-active scFv candidates.
Collapse
|
44
|
Targeting PTPN22 does not enhance the efficacy of CAR T cells in solid tumours. Mol Cell Biol 2022; 42:e0044921. [PMID: 35041491 DOI: 10.1128/mcb.00449-21] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Adoptive cell therapy with chimeric antigen receptor (CAR) T cells has revolutionised the treatment of certain B cell malignancies, but has been in ineffective against solid tumours. Recent studies have highlighted the potential of targeting negative regulators of T cell signalling to enhance the efficacy and extend the utility of CAR T cells to solid tumours. Autoimmunity-linked protein tyrosine phosphatase N22 (PTPN22) has been proposed as a target for cancer immunotherapy. Here we have used CRISPR/Cas9 gene-editing to generate PTPN22-deficient (Ptpn22Δ/Δ) mice (C57BL/6) and assessed the impact of PTPN22 deficiency on the cytotoxicity and efficacy of CAR T cells in vitro and in vivo. As reported previously, PTPN22 deficiency was accompanied by the promotion of effector T cell responses ex vivo and the repression of syngeneic tumour growth in vivo. However, PTPN22-deficiency did not enhance the cytotoxic activity of murine CAR T cells targeting the extracellular domain of the human oncoprotein HER2 in vitro. Moreover, PTPN22-deficient α-HER2 CAR T cells or ovalbumin-specific OT-I CD8+ T cells adoptively transferred into mice bearing HER2+ mammary tumours or ovalbumin-expressing mammary or colorectal tumours respectively were no more effective than their wild type counterparts in suppressing tumour growth. The deletion of PTPN22 using CRISPR/Cas9 gene-editing also did not affect the cytotoxic activity of human CAR T cells targeting the Lewis Y antigen that is expressed by many human solid tumours. Therefore, PTPN22-deficiency does not enhance the anti-tumour activity of CAR T cells in solid organ malignancies.
Collapse
|
45
|
Mirzaee Godarzee M, Mahmud Hussen B, Razmara E, Hakak‐Zargar B, Mohajerani F, Dabiri H, Fatih Rasul M, Ghazimoradi MH, Babashah S, Sadeghizadeh M. Strategies to overcome the side effects of chimeric antigen receptor T cell therapy. Ann N Y Acad Sci 2022; 1510:18-35. [DOI: 10.1111/nyas.14724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 10/05/2021] [Accepted: 10/22/2021] [Indexed: 11/26/2022]
Affiliation(s)
| | - Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy Hawler Medical University Erbil Iraq
| | - Ehsan Razmara
- Australian Regenerative Medicine Institute Monash University, Clayton, Victoria, Australia, 3800
| | | | - Fatemeh Mohajerani
- Department of Molecular Genetics, Faculty of Biological Sciences Tarbiat Modares University Tehran Iran
| | - Hamed Dabiri
- Department of Molecular Genetics, Faculty of Biological Sciences Tarbiat Modares University Tehran Iran
| | - Mohammed Fatih Rasul
- Department of Medical Analysis, Faculty of Sciences Tishk International University Erbil Iraq
| | | | - Sadegh Babashah
- Department of Molecular Genetics, Faculty of Biological Sciences Tarbiat Modares University Tehran Iran
| | - Majid Sadeghizadeh
- Department of Molecular Genetics, Faculty of Biological Sciences Tarbiat Modares University Tehran Iran
| |
Collapse
|
46
|
Network Biology and Artificial Intelligence Drive the Understanding of the Multidrug Resistance Phenotype in Cancer. Drug Resist Updat 2022; 60:100811. [DOI: 10.1016/j.drup.2022.100811] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 01/22/2022] [Accepted: 01/24/2022] [Indexed: 02/07/2023]
|
47
|
Lisby AN, Carlson RD, Baybutt TR, Weindorfer M, Snook AE. Evaluation of CAR-T cell cytotoxicity: Real-time impedance-based analysis. Methods Cell Biol 2022; 167:81-98. [DOI: 10.1016/bs.mcb.2021.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
|
48
|
Guerra E, Di Pietro R, Basile M, Trerotola M, Alberti S. Cancer-Homing CAR-T Cells and Endogenous Immune Population Dynamics. Int J Mol Sci 2021; 23:405. [PMID: 35008832 PMCID: PMC8745734 DOI: 10.3390/ijms23010405] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Revised: 12/27/2021] [Accepted: 12/28/2021] [Indexed: 02/08/2023] Open
Abstract
Chimeric antigen receptor (CAR) therapy is based on patient blood-derived T cells and natural killer cells, which are engineered in vitro to recognize a target antigen in cancer cells. Most CAR-T recognize target antigens through immunoglobulin antigen-binding regions. Hence, CAR-T cells do not require the major histocompatibility complex presentation of a target peptide. CAR-T therapy has been tremendously successful in the treatment of leukemias. On the other hand, the clinical efficacy of CAR-T cells is rarely detected against solid tumors. CAR-T-cell therapy of cancer faces many hurdles, starting from the administration of engineered cells, wherein CAR-T cells must encounter the correct chemotactic signals to traffic to the tumor in sufficient numbers. Additional obstacles arise from the hostile environment that cancers provide to CAR-T cells. Intense efforts have gone into tackling these pitfalls. However, we argue that some CAR-engineering strategies may risk missing the bigger picture, i.e., that a successful CAR-T-cell therapy must efficiently intertwine with the complex and heterogeneous responses that the body has already mounted against the tumor. Recent findings lend support to this model.
Collapse
Affiliation(s)
- Emanuela Guerra
- Center for Advanced Studies and Technology (CAST), Laboratory of Cancer Pathology, University “G. d’Annunzio”, 66100 Chieti, Italy; (E.G.); (M.T.)
- Department of Medical, Oral and Biotechnological Sciences, University “G. d’Annunzio”, 66100 Chieti, Italy
| | - Roberta Di Pietro
- Department of Medicine and Aging Sciences, Section of Biomorphology, University “G. d’Annunzio”, 66100 Chieti, Italy; (R.D.P.); (M.B.)
| | - Mariangela Basile
- Department of Medicine and Aging Sciences, Section of Biomorphology, University “G. d’Annunzio”, 66100 Chieti, Italy; (R.D.P.); (M.B.)
| | - Marco Trerotola
- Center for Advanced Studies and Technology (CAST), Laboratory of Cancer Pathology, University “G. d’Annunzio”, 66100 Chieti, Italy; (E.G.); (M.T.)
- Department of Medical, Oral and Biotechnological Sciences, University “G. d’Annunzio”, 66100 Chieti, Italy
| | - Saverio Alberti
- Unit of Medical Genetics, Department of Biomedical Sciences, University of Messina, 98122 Messina, Italy
| |
Collapse
|
49
|
A Comprehensive Review of Recent Advancements in Cancer Immunotherapy and Generation of CAR T Cell by CRISPR-Cas9. Processes (Basel) 2021. [DOI: 10.3390/pr10010016] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The mechanisms involved in immune responses to cancer have been extensively studied for several decades, and considerable attention has been paid to harnessing the immune system’s therapeutic potential. Cancer immunotherapy has established itself as a promising new treatment option for a variety of cancer types. Various strategies including cancer vaccines, monoclonal antibodies (mAbs), adoptive T-cell cancer therapy and CAR T-cell therapy have gained prominence through immunotherapy. However, the full potential of cancer immunotherapy remains to be accomplished. In spite of having startling aspects, cancer immunotherapies have some difficulties including the inability to effectively target cancer antigens and the abnormalities in patients’ responses. With the advancement in technology, this system has changed the genome-based immunotherapy process in the human body including the generation of engineered T cells. Due to its high specificity, CRISPR-Cas9 has become a simple and flexible genome editing tool to target nearly any genomic locus. Recently, the CD19-mediated CAR T-cell (chimeric antigen receptor T cell) therapy has opened a new avenue for the treatment of human cancer, though low efficiency is a major drawback of this process. Thus, increasing the efficiency of the CAR T cell (engineered T cells that induce the chimeric antigen receptor) by using CRISPR-Cas9 technology could be a better weapon to fight against cancer. In this review, we have broadly focused on recent immunotherapeutic techniques against cancer and the use of CRISPR-Cas9 technology for the modification of the T cell, which can specifically recognize cancer cells and be used as immune-therapeutics against cancer.
Collapse
|
50
|
The Immunotherapy for Colorectal Cancer, Lung Cancer and Pancreatic Cancer. Int J Mol Sci 2021; 22:ijms222312836. [PMID: 34884642 PMCID: PMC8657810 DOI: 10.3390/ijms222312836] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 11/24/2021] [Accepted: 11/26/2021] [Indexed: 12/12/2022] Open
Abstract
Immunotherapy is a novel anti-cancer method which employs a different mechanism to conventional treatment. It has become a significant strategy because it provides a better or an alternative option for cancer patients. Recently, immunotherapy has been increasingly approved for the treatment of cancer; however, it has various limitations; for instance, it is only suitable for specific patients, the response rate is still low in most cases, etc. Colorectal cancer, lung cancer and pancreatic cancer are known as three major death-causing cancers in most countries. In this review, we discuss immunotherapeutic treatment for these three cancers, and consider the option, prospects and limitations of immunotherapy. The development of immunotherapy should focus on the discovery of biomarkers to screen suitable patients, new targets on tumors, neoadjuvant immunotherapy and the combination of immunotherapy with conventional therapeutic methods. We can expect that immunotherapy potentially will develop as one of the best therapies for patients with advanced cancer or poor responses to traditional methods.
Collapse
|