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1
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Anderson R, Mkhize NM, Kgokolo MMC, Steel HC, Rossouw TM, Anderson L, Rapoport BL. Current and Emerging Insights into the Causes, Immunopathogenesis, and Treatment of Cutaneous Squamous Cell Carcinoma. Cancers (Basel) 2025; 17:1702. [PMID: 40427199 DOI: 10.3390/cancers17101702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2025] [Revised: 05/06/2025] [Accepted: 05/12/2025] [Indexed: 05/29/2025] Open
Abstract
The increasing incidence of cutaneous squamous cell carcinoma (cSCC), together with the ominous risks of metastasis and recurrence, underscores the importance of identifying novel therapies and validated biomarkers to augment patient management, particularly in the context of well-established and advanced disease. Following a brief overview of the well-recognized epidemiology, clinical features, and diagnosis of cSCC, the current review is focused on risk factors, most prominently excessive exposure to ultraviolet radiation (UVR) as a cause of persistent, pro-tumorigenic mutagenesis, and immune suppression. The next phase of the review encompasses an evaluation of the search for key driver mutations in the pathogenesis of cSCC, including the role of these and other mutations in the formation of immunologically reactive neoepitopes. With respect to additional mechanisms of tumorigenesis, immune evasion is prioritized, specifically the involvement of cell-free and infiltrating cellular mediators of immune suppression. Prominent amongst the former are the cytokine, transforming growth factor-β1 (TGF-β1), the prostanoid, prostaglandin E2, and the emerging immune suppressive nucleoside adenosine. In the case of the latter, tumor-infiltrating and circulating regulatory T cells have been implicated as being key players. The final sections of the review are focused on an update of the immunotherapy of established and advanced disease, as well as on the search for novel, reliable lesional and systemic biomarkers with the potential to guide patient management.
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Affiliation(s)
- Ronald Anderson
- The Clinical and Translational Research Unit, The Medical Oncology Centre of Rosebank, Saxonwold, Johannesburg 2196, Gauteng, South Africa
| | - Nomzamo M Mkhize
- Department of Dermatology, Faculty of Health Sciences, University of Pretoria, Prinshof, Pretoria 0084, Gauteng, South Africa
| | - Mahlatse M C Kgokolo
- Department of Dermatology, Faculty of Health Sciences, University of Pretoria, Prinshof, Pretoria 0084, Gauteng, South Africa
| | - Helen C Steel
- Department of Immunology, Faculty of Health Sciences, University of Pretoria, Prinshof, Pretoria 0084, Gauteng, South Africa
| | - Theresa M Rossouw
- Department of Immunology, Faculty of Health Sciences, University of Pretoria, Prinshof, Pretoria 0084, Gauteng, South Africa
| | | | - Bernardo L Rapoport
- The Clinical and Translational Research Unit, The Medical Oncology Centre of Rosebank, Saxonwold, Johannesburg 2196, Gauteng, South Africa
- Department of Immunology, Faculty of Health Sciences, University of Pretoria, Prinshof, Pretoria 0084, Gauteng, South Africa
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2
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Aden D, Zaheer S, Sureka N, Trisal M, Chaurasia JK, Zaheer S. Exploring immune checkpoint inhibitors: Focus on PD-1/PD-L1 axis and beyond. Pathol Res Pract 2025; 269:155864. [PMID: 40068282 DOI: 10.1016/j.prp.2025.155864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Revised: 01/20/2025] [Accepted: 02/25/2025] [Indexed: 04/19/2025]
Abstract
Immunotherapy emerges as a promising approach, marked by recent substantial progress in elucidating how the host immune response impacts tumor development and its sensitivity to various treatments. Immune checkpoint inhibitors have revolutionized cancer therapy by unleashing the power of the immune system to recognize and eradicate tumor cells. Among these, inhibitors targeting the programmed cell death protein 1 (PD-1) and its ligand (PD-L1) have garnered significant attention due to their remarkable clinical efficacy across various malignancies. This review delves into the mechanisms of action, clinical applications, and emerging therapeutic strategies surrounding PD-1/PD-L1 blockade. We explore the intricate interactions between PD-1/PD-L1 and other immune checkpoints, shedding light on combinatorial approaches to enhance treatment outcomes and overcome resistance mechanisms. Furthermore, we discuss the expanding landscape of immune checkpoint inhibitors beyond PD-1/PD-L1, including novel targets such as CTLA-4, LAG-3, TIM-3, and TIGIT. Through a comprehensive analysis of preclinical and clinical studies, we highlight the promise and challenges of immune checkpoint blockade in cancer immunotherapy, paving the way for future advancements in the field.
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Affiliation(s)
- Durre Aden
- Department of Pathology, Hamdard Institute of Medical science and research, Jamia Hamdard, New Delhi, India.
| | - Samreen Zaheer
- Department of Radiotherapy, Jawaharlal Nehru Medical College, AMU, Aligarh, India.
| | - Niti Sureka
- Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India.
| | - Monal Trisal
- Department of Pathology, Hamdard Institute of Medical science and research, Jamia Hamdard, New Delhi, India.
| | | | - Sufian Zaheer
- Department of Pathology, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India.
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3
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Uniyal P, Kashyap VK, Behl T, Parashar D, Rawat R. KRAS Mutations in Cancer: Understanding Signaling Pathways to Immune Regulation and the Potential of Immunotherapy. Cancers (Basel) 2025; 17:785. [PMID: 40075634 PMCID: PMC11899378 DOI: 10.3390/cancers17050785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 02/15/2025] [Accepted: 02/19/2025] [Indexed: 03/14/2025] Open
Abstract
The Kirsten rat sarcoma viral oncogene homologue (KRAS) mutation is one of the most prevailing mutations in various tumors and is difficult to cure. Long-term proliferation in carcinogenesis is primarily initiated by oncogenic KRAS-downstream signaling. Recent research suggests that it also activates the autocrine effect and interplays the tumor microenvironment (TME). Here, we discuss the emerging research, including KRAS mutations to immune evasion in TME, which induce immunological modulation that promotes tumor development. This review gives an overview of the existing knowledge of the underlying connection between KRAS mutations and tumor immune modulation. It also addresses the mechanisms to reduce the effect of oncogenes on the immune system and recent advances in clinical trials for immunotherapy in KRAS-mutated cancers.
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Affiliation(s)
- Priyanka Uniyal
- Department of Pharmaceutical Technology, School of Health Sciences and Technology, UPES, Dehradun 248007, India;
| | - Vivek Kumar Kashyap
- Division of Cancer Immunology and Microbiology, Medicine, and Oncology Integrated Service Unit, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA;
- South Texas Center of Excellence in Cancer Research (ST-CECR), School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA
| | - Tapan Behl
- Amity School of Pharmaceutical Sciences, Amity University, Mohali 140306, India;
| | - Deepak Parashar
- Division of Hematology & Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Ravi Rawat
- Department of Pharmaceutical Technology, School of Health Sciences and Technology, UPES, Dehradun 248007, India;
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4
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Aboul-Ella H, Gohar A, Ali AA, Ismail LM, Mahmoud AEER, Elkhatib WF, Aboul-Ella H. Monoclonal antibodies: From magic bullet to precision weapon. MOLECULAR BIOMEDICINE 2024; 5:47. [PMID: 39390211 PMCID: PMC11467159 DOI: 10.1186/s43556-024-00210-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Accepted: 09/19/2024] [Indexed: 10/12/2024] Open
Abstract
Monoclonal antibodies (mAbs) are used to prevent, detect, and treat a broad spectrum of non-communicable and communicable diseases. Over the past few years, the market for mAbs has grown exponentially with an expected compound annual growth rate (CAGR) of 11.07% from 2024 (237.64 billion USD estimated at the end of 2023) to 2033 (679.03 billion USD expected by the end of 2033). Ever since the advent of hybridoma technology introduced in 1975, antibody-based therapeutics were realized using murine antibodies which further progressed into humanized and fully human antibodies, reducing the risk of immunogenicity. Some benefits of using mAbs over conventional drugs include a drastic reduction in the chances of adverse reactions, interactions between drugs, and targeting specific proteins. While antibodies are very efficient, their higher production costs impede the process of commercialization. However, their cost factor has been improved by developing biosimilar antibodies as affordable versions of therapeutic antibodies. Along with the recent advancements and innovations in antibody engineering have helped and will furtherly help to design bio-better antibodies with improved efficacy than the conventional ones. These novel mAb-based therapeutics are set to revolutionize existing drug therapies targeting a wide spectrum of diseases, thereby meeting several unmet medical needs. This review provides comprehensive insights into the current fundamental landscape of mAbs development and applications and the key factors influencing the future projections, advancement, and incorporation of such promising immunotherapeutic candidates as a confrontation approach against a wide list of diseases, with a rationalistic mentioning of any limitations facing this field.
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Affiliation(s)
- Hassan Aboul-Ella
- Department of Microbiology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt.
| | - Asmaa Gohar
- Department of Microbiology and Immunology, Faculty of Pharmacy, Galala University, Suez, Egypt
- Department of Microbiology and Immunology, Faculty of Pharmacy, Ahram Canadian University (ACU), Giza, Egypt
- Egyptian Drug Authority (EDA), Giza, Egypt
| | - Aya Ahmed Ali
- Department of Microbiology and Immunology, Faculty of Pharmacy, Sinai University, Sinai, Egypt
| | - Lina M Ismail
- Department of Biotechnology and Molecular Chemistry, Faculty of Science, Cairo University, Giza, Egypt
- Creative Egyptian Biotechnologists (CEB), Giza, Egypt
| | | | - Walid F Elkhatib
- Department of Microbiology and Immunology, Faculty of Pharmacy, Galala University, Suez, Egypt
- Department of Microbiology and Immunology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Heba Aboul-Ella
- Department of Pharmacognosy, Faculty of Pharmacy and Drug Technology, Egyptian Chinese University (ECU), Cairo, Egypt
- Scientific Research Group in Egypt (SRGE), Cairo, Egypt
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5
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Jaing TH, Wang YL, Chiu CC. Immune Checkpoint Inhibitors for Pediatric Cancers: Is It Still a Stalemate? Pharmaceuticals (Basel) 2024; 17:991. [PMID: 39204096 PMCID: PMC11357301 DOI: 10.3390/ph17080991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Revised: 07/11/2024] [Accepted: 07/24/2024] [Indexed: 09/03/2024] Open
Abstract
The knowledge surrounding the application of immune checkpoint inhibitors (ICIs) in the treatment of pediatric cancers is continuously expanding and evolving. These therapies work by enhancing the body's natural immune response against tumors, which may have been suppressed by certain pathways. The effectiveness of ICIs in treating adult cancers has been widely acknowledged. However, the results of early phase I/II clinical trials that exclusively targeted the use of ICIs for treating different pediatric cancers have been underwhelming. The response rates to ICIs have generally been modest, except for cases of pediatric classic Hodgkin lymphoma. There seems to be a notable disparity in the immunogenicity of childhood cancers compared to adult cancers, potentially accounting for this phenomenon. On average, childhood cancers tend to have significantly fewer neoantigens. In recent times, there has been a renewed sense of optimism regarding the potential benefits of ICI therapies for specific groups of children with cancer. In initial research, individuals diagnosed with pediatric hypermutated and SMARCB1-deficient cancers have shown remarkable positive outcomes when treated with ICI therapies. This is likely due to the underlying biological factors that promote the expression of neoantigens and inflammation within the tumor. Ongoing trials are diligently assessing the effectiveness of ICIs for pediatric cancer patients in these specific subsets. This review aimed to analyze the safety and effectiveness of ICIs in pediatric patients with different types of highly advanced malignancies.
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Affiliation(s)
- Tang-Her Jaing
- Division of Hematology and Oncology, Department of Pediatrics, Chang Gung Memorial Hospital, 5 Fu-Shin Street, Kwei-Shan, Taoyuan 33315, Taiwan, China;
| | - Yi-Lun Wang
- Division of Hematology and Oncology, Department of Pediatrics, Chang Gung Memorial Hospital, 5 Fu-Shin Street, Kwei-Shan, Taoyuan 33315, Taiwan, China;
| | - Chia-Chi Chiu
- Division of Nursing, Chang Gung Memorial Hospital, 5 Fu-Shin Street, Kwei-Shan, Taoyuan 33315, Taiwan, China;
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6
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Tao J, Dhanjee HH, Gribble MW, Kottisch V, Rodriguez J, Brown JS, Schmidt H, Juneja J, Denhez F, Lee PS, Lipovšek D, Krystek S, Zhang Y, Bousquet P, Zhang Y, Pentelute BL, Buchwald SL. Site-Specific Antibody Prodrugs via S-Arylation: a Bioconjugation Approach Toward Masked Tyrosine Analogues. J Am Chem Soc 2024; 146:20080-20085. [PMID: 39001844 DOI: 10.1021/jacs.4c04035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/15/2024]
Abstract
The utility of antibody therapeutics is hampered by potential cross-reactivity with healthy tissue. Over the past decade, significant advances have been made in the design of activatable antibodies, which increase, or create altogether, the therapeutic window of a parent antibody. Of these, antibody prodrugs (pro-antibodies) are masked antibodies that have advanced the most for therapeutic use. They are designed to reveal the active, parent antibody only when encountering proteases upregulated in the microenvironment of the targeted disease tissue, thereby minimizing off-target activity. However, current pro-antibody designs are relegated to fusion proteins that append masking groups restricted to the use of only canonical amino acids, offering excellent control of the site of introduction, but with no authority over where the masking group is installed other than the N-terminus of the antibody. Here, we present a palladium-based bioconjugation approach for the site-specific introduction of a masked tyrosine mimic in the complementary determining region of the FDA approved antibody therapeutic ipilimumab used as a model system. The approach enables the introduction of a protease cleavable group tethered to noncanonical polymers (polyethylene glycol (PEG)) resulting in 47-fold weaker binding to cells expressing CTLA-4, the target antigen of ipilimumab. Upon exposure to tumor-associated proteases, the masking group is cleaved, unveiling a tyrosine-mimic (dubbed hydroxyphenyl cysteine (HPC)) that restores (>90% restoration) binding affinity to its target antigen.
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Affiliation(s)
- Jason Tao
- Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Heemal H Dhanjee
- Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Michael W Gribble
- Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Veronika Kottisch
- Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Jacob Rodriguez
- Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Joseph S Brown
- Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
| | - Holly Schmidt
- Research and Early Development, Bristol Myers Squibb, P.O. Box 4000, Princeton, New Jersey 08544, United States
| | - Juhi Juneja
- Research and Early Development, Bristol Myers Squibb, P.O. Box 4000, Princeton, New Jersey 08544, United States
| | - Fabienne Denhez
- Research and Early Development, Bristol Myers Squibb, P.O. Box 4000, Princeton, New Jersey 08544, United States
| | - Peter S Lee
- Research and Early Development, Bristol Myers Squibb, P.O. Box 4000, Princeton, New Jersey 08544, United States
| | - Daša Lipovšek
- Research and Early Development, Bristol Myers Squibb, P.O. Box 4000, Princeton, New Jersey 08544, United States
| | - Stanley Krystek
- Research and Early Development, Bristol Myers Squibb, P.O. Box 4000, Princeton, New Jersey 08544, United States
| | - Yihong Zhang
- Research and Early Development, Bristol Myers Squibb, P.O. Box 4000, Princeton, New Jersey 08544, United States
| | - Patrick Bousquet
- Research and Early Development, Bristol Myers Squibb, P.O. Box 4000, Princeton, New Jersey 08544, United States
| | - Yong Zhang
- Research and Early Development, Bristol Myers Squibb, P.O. Box 4000, Princeton, New Jersey 08544, United States
| | - Bradley L Pentelute
- Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
- The Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, Massachusetts 02142, United States
- Center for Environmental Health Sciences, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
- Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, Massachusetts 02142, United States
| | - Stephen L Buchwald
- Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States
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7
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Yuan C, Wang Y, Guo ZS. Editorial: Recent advances in gene modified immune cells and oncolytic virus for cancer immunotherapy. Front Immunol 2024; 15:1454183. [PMID: 39026671 PMCID: PMC11254808 DOI: 10.3389/fimmu.2024.1454183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Accepted: 06/25/2024] [Indexed: 07/20/2024] Open
Affiliation(s)
- Cunzhong Yuan
- Gynecologic Oncology Key Laboratory of Shandong Province, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Yao Wang
- Department of Bio-therapeutic, the First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Zong Sheng Guo
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
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Liu W, Li N, Hou J, Cao R, Jia L, Guo Y, Xu J. Structure and antitumor activity of a polysaccharide from Rosa roxburghii. Int J Biol Macromol 2024; 273:132807. [PMID: 38825289 DOI: 10.1016/j.ijbiomac.2024.132807] [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: 03/11/2024] [Revised: 05/14/2024] [Accepted: 05/30/2024] [Indexed: 06/04/2024]
Abstract
It is well known that Rosa roxburghii, as a homology of both medicine and food, is rich in polysaccharides. To discover bioactive macromolecules for combating cancer, the polysaccharides in R. roxburghii were investigated, leading to the purification of a polysaccharide (RRTP80-1). RRTP80-1 was measured to have an average molecular weight of 8.65 × 103 g/mol. Monosaccharide composition analysis revealed that RRTP80-1 was formed from three types of monosaccharides including arabinose, glucose, and galactose. Methylation and GC-MS analysis suggested that the backbone of RRTP80-1 consisted of →5)-α-l-Araf-(1→, →6)-α-d-Glcp-(1→, →2,5)-α-l-Araf-(1→, →4,6)-β-d-Galp-(1→, and →3)-α-l-Araf-(1→, with branch chains composed of α-l-Araf-(1→. In vivo studies indicated that RRTP80-1 exhibited inhibitory activity against the growth and proliferation of neoplasms in the zebrafish tumor xenograft model by suppressing angiogenesis. Additionally, RRTP80-1 was found to upregulate reactive oxygen species (ROS) and nitric oxide (NO) production levels in zebrafish models. All these studies suggest that RRTP80-1 activates the immune system to inhibit tumors. The potential role of the newly discovered homogeneous polysaccharide RRTP80-1 in cancer treatment was preliminarily clarified in this study.
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Affiliation(s)
- Wenhui Liu
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, People's Republic of China
| | - Na Li
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, People's Republic of China
| | - Jiantong Hou
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, People's Republic of China
| | - Ruyu Cao
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, People's Republic of China
| | - Lingyun Jia
- School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China.
| | - Yuanqiang Guo
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, People's Republic of China.
| | - Jing Xu
- State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, People's Republic of China.
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Chuang L, Qifeng J, Shaolei Y. The tumor immune microenvironment and T-cell-related immunotherapies in colorectal cancer. Discov Oncol 2024; 15:244. [PMID: 38918278 PMCID: PMC11199466 DOI: 10.1007/s12672-024-01117-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Accepted: 06/21/2024] [Indexed: 06/27/2024] Open
Abstract
The tumor microenvironment includes a complex network of immune T-cell subsets that play important roles in colorectal cancer (CRC) progression and are key elements of CRC immunotherapy. T cells develop and migrate within tumors, recognizing tumor-specific antigens to regulate immune surveillance. Current immunotherapies are divided into the following main categories based on the regulatory role of T-cell subsets in the tumor immune microenvironment (TIME): cytokines, monoclonal antibodies, peptide vaccines, CAR-T cells and more. This review describes the composition of the tumor immune microenvironment in colorectal cancer and the involvement of T cells in the pathogenesis and progression of CRC as well as current T-cell-related immunotherapies. Further studies on CRC-specific tumor antigens, the gene regulation of T cells, and the regulation of immune activity are needed.
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Affiliation(s)
- Liu Chuang
- Hanan Branch of the Second Affiliated Hospital of Heilongjiang University of Chinese Medicine, Guogoli Street, Nangang District, Harbin, China
| | - Ju Qifeng
- The First Affiliated Hospital Heilongjiang University of Chinese Medicine, Harbin, China
| | - Yu Shaolei
- Hanan Branch of the Second Affiliated Hospital of Heilongjiang University of Chinese Medicine, Guogoli Street, Nangang District, Harbin, China.
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Lin J, Wu Y, Liu G, Cui R, Xu Y. Advances of ultrasound in tumor immunotherapy. Int Immunopharmacol 2024; 134:112233. [PMID: 38735256 DOI: 10.1016/j.intimp.2024.112233] [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: 01/09/2024] [Revised: 04/11/2024] [Accepted: 05/07/2024] [Indexed: 05/14/2024]
Abstract
Immunotherapy has become a revolutionary method for treating tumors, offering new hope to cancer patients worldwide. Immunotherapy strategies such as checkpoint inhibitors, chimeric antigen receptor T-cell (CAR-T) therapy, and cancer vaccines have shown significant potential in clinical trials. Despite the promising results, there are still limitations that impede the overall effectiveness of immunotherapy; the response to immunotherapy is uneven, the response rate of patients is still low, and systemic immune toxicity accompanied with tumor cell immune evasion is common. Ultrasound technology has evolved rapidly in recent years and has become a significant player in tumor immunotherapy. The introductions of high intensity focused ultrasound and ultrasound-stimulated microbubbles have opened doors for new therapeutic strategies in the fight against tumor. This paper explores the revolutionary advancements of ultrasound combined with immunotherapy in this particular field.
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Affiliation(s)
- Jing Lin
- Department of Ultrasound, Guangdong Provincial Hospital of Chinese Medicine-Zhuhai Hospital, Zhuhai, PR China.
| | - Yuwei Wu
- Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Taipa, Macao, PR China
| | - Guangde Liu
- Department of Ultrasound, Guangdong Provincial Hospital of Chinese Medicine-Zhuhai Hospital, Zhuhai, PR China
| | - Rui Cui
- Department of Ultrasonography, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, PR China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, PR China
| | - Youhua Xu
- Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Taipa, Macao, PR China; Macau University of Science and Technology Zhuhai MUST Science and Technology Research Institute, Hengqin, Zhuhai, PR China.
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11
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Kim SM, Park N, Park HB, Lee J, Chun C, Kim KH, Choi JS, Kim HJ, Choi S, Lee JH. Exploring novel immunotherapy biomarker candidates induced by cancer deformation. PLoS One 2024; 19:e0303433. [PMID: 38743676 PMCID: PMC11093347 DOI: 10.1371/journal.pone.0303433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 04/24/2024] [Indexed: 05/16/2024] Open
Abstract
Triple-negative breast cancer (TNBC) demands urgent attention for the development of effective treatment strategies due to its aggressiveness and limited therapeutic options [1]. This research is primarily focused on identifying new biomarkers vital for immunotherapy, with the aim of developing tailored treatments specifically for TNBC, such as those targeting the PD-1/PD-L1 pathway. To achieve this, the study places a strong emphasis on investigating Ig genes, a characteristic of immune checkpoint inhibitors, particularly genes expressing Ig-like domains with altered expression levels induced by "cancer deformation," a condition associated with cancer malignancy. Human cells can express approximately 800 Ig family genes, yet only a few Ig genes, including PD-1 and PD-L1, have been developed into immunotherapy drugs thus far. Therefore, we investigated the Ig genes that were either upregulated or downregulated by the artificial metastatic environment in TNBC cell line. As a result, we confirmed the upregulation of approximately 13 Ig genes and validated them using qPCR. In summary, our study proposes an approach for identifying new biomarkers applicable to future immunotherapies aimed at addressing challenging cases of TNBC where conventional treatments fall short.
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Affiliation(s)
- Se Min Kim
- Life Science and Biotechnology Department (LSBT), Underwood Division (UD), Underwood International College, Yonsei University, Sinchon, Seoul, Korea
| | - Namu Park
- Department of Biomedical Informatics & Medical Education, University of Washington, Seattle, Washington, United States of America
| | - Hye Bin Park
- Digital Health Care Research Center, Gumi Electronics and Information Technology Research Institute (GERI), Gumidaero, Gumi, Gyeongbuk, South Korea
| | - JuKyung Lee
- Digital Health Care Research Center, Gumi Electronics and Information Technology Research Institute (GERI), Gumidaero, Gumi, Gyeongbuk, South Korea
| | - Changho Chun
- Department of Bioengineering, University of Washington, Seattle, Washington, United States of America
- Department of Rehabilitation Medicine, University of Washington, Seattle, Washington, United States of America
| | - Kyung Hoon Kim
- Department of Bioengineering, University of Washington, Seattle, Washington, United States of America
| | - Jong Seob Choi
- Division of Advanced Materials Engineering, Kongju National University, Chungnam, South Korea
| | - Hyung Jin Kim
- School of Electrical & Electronic Engineerin, Ulsan College, Ulsan, Korea
| | - Sekyu Choi
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
| | - Jung Hyun Lee
- Department of Dermatology, School of Medicine, University of Washington, Seattle, Washington, United States of America
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, United States of America
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12
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Jou E. Clinical and basic science aspects of innate lymphoid cells as novel immunotherapeutic targets in cancer treatment. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2024; 209:1-60. [PMID: 39461748 DOI: 10.1016/bs.pmbts.2024.03.036] [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: 10/29/2024]
Abstract
Immunotherapy has revolutionised cancer treatment over the past decade, demonstrating remarkable efficacy across a broad range of cancer types. However, not all patients or cancer types respond to contemporary clinically-utilised immunotherapeutic strategies, which largely focus on harnessing adaptive immune T cells for cancer treatment. Accordingly, it is increasingly recognised that upstream innate immune pathways, which govern and orchestrate the downstream adaptive immune response, may prove critical in overcoming cancer immunotherapeutic resistance. Innate lymphoid cells (ILCs) are the most recently discovered major innate immune cell population. They have overarching roles in homeostasis and orchestrating protective immunity against pathogens. As innate immune counterparts of adaptive immune T cells, ILCs exert effector functions through the secretion of cytokines and direct cell-to-cell contact, with broad influence on the overall immune response. Importantly, dysregulation of ILC subsets have been associated with a range of diseases, including immunodeficiency disorders, allergy, autoimmunity, and more recently, cancer. ILCs may either promote or inhibit cancer initiation and progression depending on the cancer type and the specific ILC subsets involved. Critically, therapeutic targeting of ILCs and their associated cytokines shows promise against a wide range of cancer types in both preclinical models and early phase oncology clinical trials. This chapter provides a comprehensive overview of the current understanding of ILC subsets and the associated cytokines they produce in cancer pathogenesis, with specific focus on how these innate pathways are, or can be targeted, therapeutically to overcome therapeutic resistance and ultimately improve patient care.
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Affiliation(s)
- Eric Jou
- Department of Oncology, Oxford University Hospitals, University of Oxford, Oxford, United Kingdom; Kellogg College, University of Oxford, Oxford, United Kingdom.
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13
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Khorasani M, Alaei M. cGAS-STING and PD1/PDL-1 pathway in breast cancer: a window to new therapies. J Recept Signal Transduct Res 2024; 44:1-7. [PMID: 38470108 DOI: 10.1080/10799893.2024.2325353] [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: 10/30/2023] [Accepted: 02/23/2024] [Indexed: 03/13/2024]
Abstract
Breast cancer is a complex malignancy with diverse molecular and cellular subtypes and clinical outcomes. Despite advances in treatment, breast cancer remains a significant health challenge. However, recent advances in cancer immunotherapy have shown promising results in the treatment of breast cancer, particularly the use of inhibitors that target the immune checkpoint PD1/PDL1. Also, the cGAS-STING pathway, an important part of the innate immune response, has been considered as a major potential therapeutic target for breast cancer. In this narrative review, we provide an overview of the cGAS-STING and PD1/PDL-1 pathway in breast cancer, including their role in tumor development, progression, and response to treatment. We also discuss potential future directions for research.
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Affiliation(s)
- Milad Khorasani
- Healthy Ageing Research Centre, Neyshabur University of Medical Sciences, Neyshabur, Iran
- Department of Clinical Biochemistry, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | - Maryam Alaei
- Department of Clinical Biochemistry, Mashhad University of Medical Sciences, Mashhad, Iran
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14
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Rivera J, Digklia A, Christou AS, Anibal J, Vallis KA, Wood BJ, Stride E. A Review of Ultrasound-Mediated Checkpoint Inhibitor Immunotherapy. ULTRASOUND IN MEDICINE & BIOLOGY 2024; 50:1-7. [PMID: 37798210 DOI: 10.1016/j.ultrasmedbio.2023.08.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Revised: 08/11/2023] [Accepted: 08/26/2023] [Indexed: 10/07/2023]
Abstract
Over the past decade, immunotherapy has emerged as a major modality in cancer medicine. However, despite its unprecedented success, immunotherapy currently benefits only a subgroup of patients, may induce responses of limited duration and is associated with potentially treatment-limiting side effects. In addition, responses to immunotherapeutics are sometimes diminished by the emergence of a complex array of resistance mechanisms. The efficacy of immunotherapy depends on dynamic interactions between tumour cells and the immune landscape in the tumour microenvironment. Ultrasound, especially in conjunction with cavitation-promoting agents such as microbubbles, can assist in the uptake and/or local release of immunotherapeutic agents at specific target sites, thereby increasing treatment efficacy and reducing systemic toxicity. There is also increasing evidence that ultrasound and/or cavitation may themselves directly stimulate a beneficial immune response. In this review, we summarize the latest developments in the use of ultrasound and cavitation agents to promote checkpoint inhibitor immunotherapy.
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Affiliation(s)
- Jocelyne Rivera
- Center for Interventional Oncology, Interventional Radiology, National Institutes of Health Clinical Center, National Cancer Institute, Bethesda, MD, USA; Botnar Research Centre, Institute of Biomedical Engineering, University of Oxford, Oxford, UK
| | - Antonia Digklia
- Department of Oncology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Anna S Christou
- Center for Interventional Oncology, Interventional Radiology, National Institutes of Health Clinical Center, National Cancer Institute, Bethesda, MD, USA
| | - James Anibal
- Center for Interventional Oncology, Interventional Radiology, National Institutes of Health Clinical Center, National Cancer Institute, Bethesda, MD, USA; Computational Health Informatics Lab, Institute of Biomedical Engineering, University of Oxford, Oxford, UK
| | | | - Bradford J Wood
- Center for Interventional Oncology, Interventional Radiology, National Institutes of Health Clinical Center, National Cancer Institute, Bethesda, MD, USA
| | - Eleanor Stride
- Botnar Research Centre, Institute of Biomedical Engineering, University of Oxford, Oxford, UK.
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15
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Wang J, Ma J, Tai Z, Li L, Zhang T, Cheng T, Yu J, Zhu Q, Bao L, Chen Z. Nanocarrier-Mediated Immunogenic Cell Death for Melanoma Treatment. Int J Nanomedicine 2023; 18:7149-7172. [PMID: 38059000 PMCID: PMC10697015 DOI: 10.2147/ijn.s434582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 11/20/2023] [Indexed: 12/08/2023] Open
Abstract
Melanoma, a highly aggressive skin tumor, exhibits notable features including heterogeneity, a high mutational load, and innate immune escape. Despite advancements in melanoma treatment, current immunotherapies fail to fully exploit the immune system's maximum potential. Activating immunogenic cell death (ICD) holds promise in enhancing tumor cell immunogenicity, stimulating immune amplification response, improving drug sensitivity, and eliminating tumors. Nanotechnology-enabled ICD has emerged as a compelling therapeutic strategy for augmenting cancer immunotherapy. Nanoparticles possess versatile attributes, such as prolonged blood circulation, stability, and tumor-targeting capabilities, rendering them ideal for drug delivery. In this review, we elucidate the mechanisms underlying ICD induction and associated therapeutic strategies. Additionally, we provide a concise overview of the immune stress response associated with ICD and explore the potential synergistic benefits of combining ICD induction methods with the utilization of nanocarriers.
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Affiliation(s)
- Jiandong Wang
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200443, People’s Republic of China
- Department of Pharmacy, Third Affiliated Hospital of Naval Medical University, Shanghai, People’s Republic of China
- School of Pharmacy, Bengbu Medical College, Bengbu, Anhui, People’s Republic of China
| | - Jinyuan Ma
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200443, People’s Republic of China
- Shanghai Engineering Research Center of External Chinese Medicine, Shanghai, 200443, People’s Republic of China
| | - Zongguang Tai
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200443, People’s Republic of China
- Shanghai Engineering Research Center of External Chinese Medicine, Shanghai, 200443, People’s Republic of China
| | - Lisha Li
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200443, People’s Republic of China
- Shanghai Engineering Research Center of External Chinese Medicine, Shanghai, 200443, People’s Republic of China
| | - Tingrui Zhang
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200443, People’s Republic of China
- Shanghai Engineering Research Center of External Chinese Medicine, Shanghai, 200443, People’s Republic of China
| | - Tingting Cheng
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200443, People’s Republic of China
- Department of Pharmacy, Third Affiliated Hospital of Naval Medical University, Shanghai, People’s Republic of China
- School of Pharmacy, Bengbu Medical College, Bengbu, Anhui, People’s Republic of China
| | - Junxia Yu
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200443, People’s Republic of China
- Department of Pharmacy, Third Affiliated Hospital of Naval Medical University, Shanghai, People’s Republic of China
- School of Pharmacy, Bengbu Medical College, Bengbu, Anhui, People’s Republic of China
| | - Quangang Zhu
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200443, People’s Republic of China
- Shanghai Engineering Research Center of External Chinese Medicine, Shanghai, 200443, People’s Republic of China
| | - Leilei Bao
- Department of Pharmacy, Third Affiliated Hospital of Naval Medical University, Shanghai, People’s Republic of China
| | - Zhongjian Chen
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200443, People’s Republic of China
- Shanghai Engineering Research Center of External Chinese Medicine, Shanghai, 200443, People’s Republic of China
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16
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Li Y, Yang B, Miao H, Liu L, Wang Z, Jiang C, Yang Y, Qiu S, Li X, Geng Y, Zhang Y, Liu Y. Nicotinamide N -methyltransferase promotes M2 macrophage polarization by IL6 and MDSC conversion by GM-CSF in gallbladder carcinoma. Hepatology 2023; 78:1352-1367. [PMID: 36633260 DOI: 10.1097/hep.0000000000000028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 10/14/2022] [Indexed: 01/13/2023]
Abstract
BACKGROUND AND AIMS Nicotinamide N -methyltransferase (NNMT), an enzyme responsible for the methylation of nicotinamide, is involved in many metabolic pathways in adipose tissue and the liver. However, the role of NNMT in editing the tumor immune microenvironment is not well understood. APPROACH AND RESULTS Here, we identified that NNMT can promote IL6 and granulocyte-macrophage colony-stimulating factor (GM-CSF) expression by decreasing the tri-methyl-histone H3 levels on the promoters of IL6 and CSF2 (encoding GM-CSF) and CCAAT/Enhancer Binding Protein, an essential transcription factor for IL6 expression, thus promoting differentiation of macrophages into M2 type tumor-associated macrophages and generation of myeloid-derived suppressor cells from peripheral blood mononuclear cells. Treatment of xenografted tumor models overexpressing NNMT gallbladder carcinoma (GBC) cells with the NNMT inhibitor JBSNF-000088 resulted in compromised tumor development and decreased expression levels of IL6, GM-CSF, tumor-associated macrophage marker CD206, and myeloid-derived suppressor cell marker CD33 but increased expression levels of CD8. In addition, elevated expression of NNMT in tumors of patients with GBC was correlated with increased expression levels of CD206 and CD33 but with decreased levels of CD8 and survival of patients. CONCLUSIONS These data highlight the critical role of NNMT in GBC progression. Inhibition of NNMT by JBSNF-000088 is a potential molecular target for GBC immunotherapy.
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Affiliation(s)
- Yang Li
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China
| | - Bo Yang
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China
| | - Huijie Miao
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Liguo Liu
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China
| | - Ziyi Wang
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chengkai Jiang
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yang Yang
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shimei Qiu
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Xuechuan Li
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yajun Geng
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yijian Zhang
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yingbin Liu
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai, China
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17
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Liu D, Hu L, Shao H. Therapeutic drug monitoring of immune checkpoint inhibitors: based on their pharmacokinetic properties and biomarkers. Cancer Chemother Pharmacol 2023:10.1007/s00280-023-04541-8. [PMID: 37410155 DOI: 10.1007/s00280-023-04541-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 05/03/2023] [Indexed: 07/07/2023]
Abstract
As a new means of oncology treatment, immune checkpoint inhibitors (ICIs) can improve survival rates in patients with resistant or refractory tumors. However, there are obvious inter-individual differences in the unsatisfactory response rate, drug resistance rate and the occurrence of immune-related adverse events (irAE). These questions have sparked interest in researchers looking for a way to screen sensitive populations and predict efficacy and safety. Therapeutic drug monitoring (TDM) is a way to ensure the safety and effectiveness of medication by measuring the concentration of drugs in body fluids and adjusting the medication regimen. It has the potential to be an adjunctive means of predicting the safety and efficacy of ICIs treatment. In this review, the author outlined the pharmacokinetic (PK) characteristics of ICIs in patients. The feasibility and limitations of TDM of ICIs were discussed by summarizing the relationships between the pharmacokinetic parameters and the efficacy, toxicity and biomarkers.
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Affiliation(s)
- Dongxue Liu
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Linlin Hu
- Department of Pharmacy, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
- Office of Medication Clinical Institution, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Hua Shao
- Office of Medication Clinical Institution, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
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18
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Li M, Zheng K, Liu X. Mitochondria‐Targeting Phthalocyanines and Porphyrins for Enhanced Photodynamic Tumor Therapy. ChemistrySelect 2023. [DOI: 10.1002/slct.202205022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/11/2023]
Affiliation(s)
- Mengyuan Li
- Qingdao University of Science and Technology Qingdao 266042 China
| | - Ke Zheng
- Qingdao University of Science and Technology Qingdao 266042 China
| | - Xinxin Liu
- Qingdao University of Science and Technology Qingdao 266042 China
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19
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Avila JP, Carvalho BM, Coimbra EC. A Comprehensive View of the Cancer-Immunity Cycle (CIC) in HPV-Mediated Cervical Cancer and Prospects for Emerging Therapeutic Opportunities. Cancers (Basel) 2023; 15:1333. [PMID: 36831674 PMCID: PMC9954575 DOI: 10.3390/cancers15041333] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 02/13/2023] [Accepted: 02/17/2023] [Indexed: 02/22/2023] Open
Abstract
Cervical cancer (CC) is the fourth most common cancer in women worldwide, with more than 500,000 new cases each year and a mortality rate of around 55%. Over 80% of these deaths occur in developing countries. The most important risk factor for CC is persistent infection by a sexually transmitted virus, the human papillomavirus (HPV). Conventional treatments to eradicate this type of cancer are accompanied by high rates of resistance and a large number of side effects. Hence, it is crucial to devise novel effective therapeutic strategies. In recent years, an increasing number of studies have aimed to develop immunotherapeutic methods for treating cancer. However, these strategies have not proven to be effective enough to combat CC. This means there is a need to investigate immune molecular targets. An adaptive immune response against cancer has been described in seven key stages or steps defined as the cancer-immunity cycle (CIC). The CIC begins with the release of antigens by tumor cells and ends with their destruction by cytotoxic T-cells. In this paper, we discuss several molecular alterations found in each stage of the CIC of CC. In addition, we analyze the evidence discovered, the molecular mechanisms and their relationship with variables such as histological subtype and HPV infection, as well as their potential impact for adopting novel immunotherapeutic approaches.
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Affiliation(s)
| | | | - Eliane Campos Coimbra
- Institute of Biological Sciences, University of Pernambuco (ICB/UPE), Rua Arnóbio Marques, 310, Santo Amaro, Recife 50100-130, PE, Brazil
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20
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The role of immune checkpoint inhibitors in patients with intracranial metastatic disease. J Neurooncol 2023; 161:469-478. [PMID: 36790654 DOI: 10.1007/s11060-023-04263-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 02/08/2023] [Indexed: 02/16/2023]
Abstract
Intracranial metastatic disease (IMD) complicates the course of nearly 2-4% of patients with systemic cancer. The prevalence of IMD has been increasing over the past few decades. Historically, definitive treatment for brain metastases (BM) has been limited to radiation therapy or surgical resection. Chemotherapies have not typically proven valuable in the treatment of IMD, with the exception of highly chemotherapy-sensitive lesions. Recent data have supported a role for systemic targeted therapies and immune checkpoint inhibitors (ICIs) in the treatment of select patients with IMD. There remains, however, a clear clinical need for further investigation to delineate the role of ICIs in patients with BM. In this review, we outline and describe recent and current efforts to identify the efficacy of ICI therapy in patients with IMD.
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21
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Raza A, Rossi GR, Janjua TI, Souza-Fonseca-Guimaraes F, Popat A. Nanobiomaterials to modulate natural killer cell responses for effective cancer immunotherapy. Trends Biotechnol 2023; 41:77-92. [PMID: 35840426 DOI: 10.1016/j.tibtech.2022.06.011] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 06/08/2022] [Accepted: 06/17/2022] [Indexed: 02/06/2023]
Abstract
Natural killer (NK) cells have emerged as a major target for cancer immunotherapies, particularly as cellular therapy modalities because they have relatively less toxicity than T lymphocytes. However, NK cell-based therapy suffers from many challenges, including problems with its activation, resistance to genetic engineering, and large-scale expansion needed for therapeutic purposes. Recently, nanobiomaterials have emerged as a promising solution to control the challenges associated with NK cells. This focused review summarises the recent advances in the field and highlights current and future perspectives of using nanobiomaterials to maximise anticancer responses of NK cells for safe and effective immunotherapy. Finally, we provide our opinion on the role of smart materials in activating NK cells as a potential cellular therapy of the future.
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Affiliation(s)
- Aun Raza
- School of Pharmacy, The University of Queensland, Woolloongabba, QLD 4102, Australia
| | - Gustavo Rodrigues Rossi
- University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia
| | - Taskeen Iqbal Janjua
- School of Pharmacy, The University of Queensland, Woolloongabba, QLD 4102, Australia
| | | | - Amirali Popat
- School of Pharmacy, The University of Queensland, Woolloongabba, QLD 4102, Australia.
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22
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Diep YN, Kim TJ, Cho H, Lee LP. Nanomedicine for advanced cancer immunotherapy. J Control Release 2022; 351:1017-1037. [DOI: 10.1016/j.jconrel.2022.10.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 09/30/2022] [Accepted: 10/01/2022] [Indexed: 11/09/2022]
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23
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Zhu Z, McGray AJR, Jiang W, Lu B, Kalinski P, Guo ZS. Improving cancer immunotherapy by rationally combining oncolytic virus with modulators targeting key signaling pathways. Mol Cancer 2022; 21:196. [PMID: 36221123 PMCID: PMC9554963 DOI: 10.1186/s12943-022-01664-z] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 09/26/2022] [Indexed: 11/10/2022] Open
Abstract
Oncolytic viruses (OVs) represent a new class of multi-modal immunotherapies for cancer, with OV-elicited antitumor immunity being key to their overall therapeutic efficacy. Currently, the clinical effectiveness of OV as monotherapy remains limited, and thus investigators have been exploring various combinations with other anti-cancer agents and demonstrated improved therapeutic efficacy. As cancer cells have evolved to alter key signaling pathways for enhanced cell proliferation, cancer progression and metastasis, these cellular and molecular changes offer promising targets for rational cancer therapy design. In this regard, key molecules in relevant signaling pathways for cancer cells or/and immune cells, such as EGFR-KRAS (e.g., KRASG12C), PI3K-AKT-mTOR, ERK-MEK, JAK-STAT, p53, PD-1-PD-L1, and epigenetic, or immune pathways (e.g., histone deacetylases, cGAS-STING) are currently under investigation and have the potential to synergize with OV to modulate the immune milieu of the tumor microenvironment (TME), thereby improving and sustaining antitumor immunity. As many small molecule modulators of these signaling pathways have been developed and have shown strong therapeutic potential, here we review key findings related to both OV-mediated immunotherapy and the utility of small molecule modulators of signaling pathways in immuno-oncology. Then, we focus on discussion of the rationales and potential strategies for combining OV with selected modulators targeting key cellular signaling pathways in cancer or/and immune cells to modulate the TME and enhance antitumor immunity and therapeutic efficacy. Finally, we provide perspectives and viewpoints on the application of novel experimental systems and technologies that can propel this exciting branch of medicine into a bright future.
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Affiliation(s)
- Zhi Zhu
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA.,Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.,Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - A J Robert McGray
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Weijian Jiang
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Binfeng Lu
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA.,Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Pawel Kalinski
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
| | - Zong Sheng Guo
- UPMC Hillman Cancer Center, Pittsburgh, PA, USA. .,Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
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24
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Ding Y, Wang Z, Zhou F, Chen C, Qin Y. Associating resistance to immune checkpoint inhibitors with immunological escape in colorectal cancer. Front Oncol 2022; 12:987302. [PMID: 36248998 PMCID: PMC9561929 DOI: 10.3389/fonc.2022.987302] [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: 07/06/2022] [Accepted: 09/13/2022] [Indexed: 11/13/2022] Open
Abstract
Colorectal cancer is a common malignant tumor that ranks third in incidence and second in mortality worldwide, and surgery in conjunction with chemotherapy and radiotherapy remains the most common treatment option. As a result of radiotherapy’s severe side effects and dismal survival rates, it is anticipated that more alternatives may emerge. Immunotherapy, a breakthrough treatment, has made significant strides in colorectal cancer over the past few years, overcoming specialized therapy, which has more selectivity and a higher survival prognosis than chemoradiotherapy. Among these, immune checkpoint inhibitor therapy has emerged as the primary immunotherapy for colorectal cancer nowadays. Nonetheless, as the use of immune checkpoint inhibitor has expanded, resistance has arisen inevitably. Immune escape is the primary cause of non-response and resistance to immune checkpoint inhibitors. That is the development of primary and secondary drug resistance. In this article, we cover the immune therapy-related colorectal cancer staging, the specific immune checkpoint inhibitors treatment mechanism, and the tumor microenvironment and immune escape routes of immunosuppressive cells that may be associated with immune checkpoint inhibitors resistance reversal. The objective is to provide better therapeutic concepts for clinical results and to increase the number of individuals who can benefit from colorectal cancer immunotherapy.
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Affiliation(s)
- Yi Ding
- Department of Oncology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zehua Wang
- Department of Oncology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Fengmei Zhou
- Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Chen Chen
- Department of Oncology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yanru Qin
- Department of Oncology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- *Correspondence: Yanru Qin,
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25
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Nteli P, Bajwa DE, Politakis D, Michalopoulos C, Kefala-Narin A, Efstathopoulos EP, Gazouli M. Nanomedicine approaches for treatment of hematologic and oncologic malignancies. World J Clin Oncol 2022; 13:553-566. [PMID: 36157164 PMCID: PMC9346428 DOI: 10.5306/wjco.v13.i7.553] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 05/10/2022] [Accepted: 06/27/2022] [Indexed: 02/06/2023] Open
Abstract
Cancer is a leading cause of death worldwide. Nowadays, the therapies are inadequate and spur demand for improved technologies. Rapid growth in nanotechnology and novel nanomedicine products represents an opportunity to achieve sophisticated targeting strategies and multi-functionality. Nanomedicine is increasingly used to develop new cancer diagnosis and treatment methods since this technology can modulate the biodistribution and the target site accumulation of chemotherapeutic drugs, thereby reducing their toxicity. Cancer nanotechnology and cancer immunotherapy are two parallel themes that have emerged over the last few decades while searching for a cure for cancer. Immunotherapy is revolutionizing cancer treatment, as it can achieve unprecedented responses in advanced-stage patients, including complete cures and long-term survival. A deeper understanding of the human immune system allows the establishment of combination regimens in which immunotherapy is combined with other treatment modalities (as in the case of the nanodrug Ferumoxytol). Furthermore, the combination of gene therapy approaches with nanotechnology that aims to silence or express cancer-relevant genes via one-time treatment is gradually progressing from bench to bedside. The most common example includes lipid-based nanoparticles that target VEGF-Α and KRAS pathways. This review focuses on nanoparticle-based platforms utilized in recent advances aiming to increase the efficacy of currently available cancer therapies. The insights provided and the evidence obtained in this paper indicate a bright future ahead for immuno-oncology applications of engineering nanomedicines.
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Affiliation(s)
- Polyxeni Nteli
- Department of Basic Medical Sciences, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Danae Efremia Bajwa
- Department of Basic Medical Sciences, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Dimitrios Politakis
- Department of Basic Medical Sciences, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Charalampos Michalopoulos
- Department of Basic Medical Sciences, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Anastasia Kefala-Narin
- Department of Basic Medical Sciences, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Efstathios P Efstathopoulos
- 2nd Department of Radiology, Medical School, National and Kapodistrian University of Athens, General University Hospital Attikon, Athens12462, Greece
| | - Maria Gazouli
- Department of Basic Medical Sciences, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
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26
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Sitta J, Claudio PP, Howard CM. Virus-Based Immuno-Oncology Models. Biomedicines 2022; 10:biomedicines10061441. [PMID: 35740462 PMCID: PMC9220907 DOI: 10.3390/biomedicines10061441] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 06/04/2022] [Accepted: 06/15/2022] [Indexed: 12/12/2022] Open
Abstract
Immunotherapy has been extensively explored in recent years with encouraging results in selected types of cancer. Such success aroused interest in the expansion of such indications, requiring a deep understanding of the complex role of the immune system in carcinogenesis. The definition of hot vs. cold tumors and the role of the tumor microenvironment enlightened the once obscure understanding of low response rates of solid tumors to immune check point inhibitors. Although the major scope found in the literature focuses on the T cell modulation, the innate immune system is also a promising oncolytic tool. The unveiling of the tumor immunosuppressive pathways, lead to the development of combined targeted therapies in an attempt to increase immune infiltration capability. Oncolytic viruses have been explored in different scenarios, in combination with various chemotherapeutic drugs and, more recently, with immune check point inhibitors. Moreover, oncolytic viruses may be engineered to express tumor specific pro-inflammatory cytokines, antibodies, and antigens to enhance immunologic response or block immunosuppressive mechanisms. Development of preclinical models capable to replicate the human immunologic response is one of the major challenges faced by these studies. A thorough understanding of immunotherapy and oncolytic viruses’ mechanics is paramount to develop reliable preclinical models with higher chances of successful clinical therapy application. Thus, in this article, we review current concepts in cancer immunotherapy including the inherent and synthetic mechanisms of immunologic enhancement utilizing oncolytic viruses, immune targeting, and available preclinical animal models, their advantages, and limitations.
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Affiliation(s)
- Juliana Sitta
- Department of Radiology, University of Mississippi Medical Center, Jackson, MS 39216, USA;
| | - Pier Paolo Claudio
- Department of BioMolecular Sciences, Department of Radiation Oncology, Cancer Center & Research Institute, University of Mississippi Medical Center, Jackson, MS 39216, USA;
| | - Candace M. Howard
- Department of Radiology, University of Mississippi Medical Center, Jackson, MS 39216, USA;
- Correspondence:
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27
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Fruhwirth GO, Weigelin B, Daldrup-Link HE, Ponomarev V. Editorial to the Special Issue Entitled "Imaging in Immunooncology". Mol Imaging Biol 2022; 24:177-180. [PMID: 35303206 PMCID: PMC8983534 DOI: 10.1007/s11307-022-01719-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Gilbert O. Fruhwirth
- Comprehensive Cancer Centre, School of Cancer and Pharmaceutical Studies, King’s College London, London, UK
| | - Bettina Weigelin
- Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, Tübingen, Germany
- Cluster of Excellence iFIT (EXC 2180) “Image-Guided and Functionally Instructed Tumor Therapies,”, University of Tuebingen, Tübingen, Germany
| | | | - Vladimir Ponomarev
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY USA
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28
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Makuku R, Seyedmirzaei H, Tantuoyir MM, Rodríguez-Román E, Albahash A, Mohamed K, Moyo E, Ahmed AO, Razi S, Rezaei N. Exploring the application of immunotherapy against HIV infection in the setting of malignancy: A detailed review article. Int Immunopharmacol 2022; 105:108580. [PMID: 35121225 DOI: 10.1016/j.intimp.2022.108580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 01/17/2022] [Accepted: 01/24/2022] [Indexed: 11/27/2022]
Abstract
According to the Joint United Nations Programme on HIV/AIDS (UNAIDS), as of 2019, approximately 42.2 million people have died from acquired immunodeficiency syndrome (AIDS)-related illnesses since the start of the epidemic. Antiretroviral therapy (ART) has significantly reduced mortality, morbidity, and incidence of the human immunodeficiency virus (HIV)/AIDS-defining cancers, taming once-dreaded disease into a benign chronic infection. Although the treatment has prolonged the patients' survival, general HIV prevalence has increased and this increase has dovetailed with an increasing incidence of Non-AIDS-defining cancers (NADCs) among people living with HIV (PLWH). This is happening when new promising approaches in both oncology and HIV infection are being developed. This review focuses on recent progress witnessed in immunotherapy approaches against HIV-related, Non-AIDS-defining cancers (NADCs), and HIV infection.
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Affiliation(s)
- Rangarirai Makuku
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Universal Scientific Education and Research Network (USERN), Harare, Zimbabwe
| | - Homa Seyedmirzaei
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Marcarious M Tantuoyir
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Network of Immunity in Infection, Malignancy, and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Accra, Ghana; Biomedical Engineering Unit, University of Ghana Medical Center (UGMC), Accra, Ghana
| | - Eduardo Rodríguez-Román
- Center for Microbiology and Cell Biology, Instituto Venezolano de Investigaciones Científicas, Caracas 1020A, Venezuela; Universal Scientific Education and Research Network (USERN), Caracas, Venezuela
| | - Assil Albahash
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Kawthar Mohamed
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Universal Scientific Education and Research Network (USERN), Manama, Bahrain
| | - Ernest Moyo
- Universal Scientific Education and Research Network (USERN), Harare, Zimbabwe; Department of Mathematics and Statistics, Midlands State University, Zimbabwe
| | | | - Sepideh Razi
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran; School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Stockholm, Sweden.
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29
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Nash A, Aghlara-Fotovat S, Hernandez A, Scull C, Veiseh O. Clinical translation of immunomodulatory therapeutics. Adv Drug Deliv Rev 2021; 176:113896. [PMID: 34324885 PMCID: PMC8567306 DOI: 10.1016/j.addr.2021.113896] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 07/21/2021] [Accepted: 07/22/2021] [Indexed: 02/07/2023]
Abstract
Immunomodulatory therapeutics represent a unique class of drug products that have tremendous potential to rebalance malfunctioning immune systems and are quickly becoming one of the fastest-growing areas in the pharmaceutical industry. For these drugs to become mainstream medicines, they must provide greater therapeutic benefit than the currently used treatments without causing severe toxicities. Immunomodulators, cell-based therapies, antibodies, and viral therapies have all achieved varying amounts of success in the treatment of cancers and/or autoimmune diseases. However, many challenges related to precision dosing, off-target effects, and manufacturing hurdles will need to be addressed before we see widespread adoption of these therapies in the clinic. This review provides a perspective on the progress of immunostimulatory and immunosuppressive therapies to date and discusses the opportunities and challenges for clinical translation of the next generation of immunomodulatory therapeutics.
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Affiliation(s)
- Amanda Nash
- Rice University, Department of Bioengineering, Houston TX, United States
| | | | - Andrea Hernandez
- Rice University, Department of Bioengineering, Houston TX, United States
| | | | - Omid Veiseh
- Rice University, Department of Bioengineering, Houston TX, United States.
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30
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Ferreira M, Secher T, Heuze-Vourc’H N, Reckamp KL. Immune Checkpoint and Anti-Angiogenic Antibodies for the Treatment of Non-Small Cell Lung Cancer in the European Union and United States. Pharmaceutics 2021; 13:pharmaceutics13060912. [PMID: 34205484 PMCID: PMC8234109 DOI: 10.3390/pharmaceutics13060912] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 06/05/2021] [Accepted: 06/16/2021] [Indexed: 12/26/2022] Open
Abstract
Several types of antibodies (Abs) are currently used in non-small cell lung cancer (NSCLC). Anti-angiogenic and immune checkpoint inhibitor (ICI) Abs are the most frequent treatments used alone or with chemotherapy in metastatic NSCLC, for the front line and beyond. Considering the many therapeutic options for locally advanced and metastatic lung cancer and differences in use according to geographic area, we present here a comprehensive review of the marketed ICI and anti-angiogenic Abs approved in the European Union (EU) and the US to treat locally advanced and metastatic NSCLC patients. We briefly describe the different molecules and their development in thoracic oncology and compare pharmacokinetic data, processing decision algorithms and marketing authorizations by the EMA and US Food and Drug Administration (FDA).
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Affiliation(s)
- Marion Ferreira
- INSERM, Centre d’Etude des Pathologies Respiratoires, U1100, Boulevard Tonnellé, F-37032 Tours, France; (T.S.); (N.H.-V.)
- Faculté de Médecine, Université de Tours, F-37032 Tours, France
- CHRU de Tours, Département de Pneumologie et Explorations fonctionnelles Respiratoires, F-37032 Tours, France
- Correspondence:
| | - Thomas Secher
- INSERM, Centre d’Etude des Pathologies Respiratoires, U1100, Boulevard Tonnellé, F-37032 Tours, France; (T.S.); (N.H.-V.)
- Faculté de Médecine, Université de Tours, F-37032 Tours, France
| | - Nathalie Heuze-Vourc’H
- INSERM, Centre d’Etude des Pathologies Respiratoires, U1100, Boulevard Tonnellé, F-37032 Tours, France; (T.S.); (N.H.-V.)
- Faculté de Médecine, Université de Tours, F-37032 Tours, France
| | - Karen L Reckamp
- Department of Medicine, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA;
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31
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Guo ZS. Oncolytic Virus Immunotherapy: Showcasing Impressive Progress in Special Issue II. Biomedicines 2021; 9:biomedicines9060663. [PMID: 34200560 PMCID: PMC8226691 DOI: 10.3390/biomedicines9060663] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Accepted: 06/09/2021] [Indexed: 12/19/2022] Open
Affiliation(s)
- Zong-Sheng Guo
- UPMC Hillman Cancer Center and Departments of Surgery, Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
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32
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Mehanny M, Lehr CM, Fuhrmann G. Extracellular vesicles as antigen carriers for novel vaccination avenues. Adv Drug Deliv Rev 2021; 173:164-180. [PMID: 33775707 DOI: 10.1016/j.addr.2021.03.016] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 03/01/2021] [Accepted: 03/23/2021] [Indexed: 02/07/2023]
Abstract
Antigen delivery has always been a challenge in scientific practice of vaccine formulation. Yet, mammalian extracellular vesicles (EVs) or bacterial membrane vesicles (MVs) provide an innovative avenue for safe and effective delivery of antigenic material. They include intrinsically loaded antigens from EV-secreting cells or extrinsically loaded antigens onto pre-formed vesicles. Interestingly, many studies shed light on potential novel anti-cancer vaccination immunotherapy for therapeutic applications from mammalian cell host-derived EVs, as well as conventional vaccination for prophylactic applications using bacterial cell-derived MVs against infectious diseases. Here, we discuss the rationale, status quo and potential for both vaccine applications using EVs.
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33
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Lobinger D, Gempt J, Sievert W, Barz M, Schmitt S, Nguyen HT, Stangl S, Werner C, Wang F, Wu Z, Fan H, Zanth H, Shevtsov M, Pilz M, Riederer I, Schwab M, Schlegel J, Multhoff G. Potential Role of Hsp70 and Activated NK Cells for Prediction of Prognosis in Glioblastoma Patients. Front Mol Biosci 2021; 8:669366. [PMID: 34079819 PMCID: PMC8165168 DOI: 10.3389/fmolb.2021.669366] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 05/04/2021] [Indexed: 11/13/2022] Open
Abstract
Despite rapid progress in the treatment of many cancers, glioblastoma remains a devastating disease with dismal prognosis. The aim of this study was to identify chaperone- and immune-related biomarkers to improve prediction of outcome in glioblastoma. Depending on its intra- or extracellular localization the major stress-inducible heat shock protein 70 (Hsp70) fulfills different tasks. In the cytosol Hsp70 interferes with pro-apoptotic signaling pathways and thereby protects tumor cells from programmed cell death. Extracellular Hsp70 together with pro-inflammatory cytokines are reported to stimulate the expression of activatory NK cell receptors, recognizing highly aggressive human tumor cells that present Hsp70 on their cell surface. Therefore, intra-, extracellular and membrane-bound Hsp70 levels were assessed in gliomas together with activatory NK cell receptors. All gliomas were found to be membrane Hsp70-positive and high grade gliomas more frequently show an overexpression of Hsp70 in the nucleus and cytosol. Significantly elevated extracellular Hsp70 levels are detected in glioblastomas with large necrotic areas. Overall survival (OS) is more favorable in patients with low Hsp70 serum levels indicating that a high Hsp70 expression is associated with an unfavorable prognosis. The data provide a first hint that elevated frequencies of activated NK cells at diagnosis might be associated with a better clinical outcome.
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Affiliation(s)
- Dominik Lobinger
- Department of Radiation Oncology, School of Medicine, Technical University Munich (TUM), Munich, Germany.,Central Institute for Translational Cancer Research, School of Medicine, Technical University Munich, Munich, Germany
| | - Jens Gempt
- Department of Neurosurgery, School of Medicine, Technical University Munich (TUM), School of Medicine, Munich, Germany
| | - Wolfgang Sievert
- Department of Radiation Oncology, School of Medicine, Technical University Munich (TUM), Munich, Germany.,Central Institute for Translational Cancer Research, School of Medicine, Technical University Munich, Munich, Germany
| | - Melanie Barz
- Department of Neurosurgery, School of Medicine, Technical University Munich (TUM), School of Medicine, Munich, Germany
| | - Sven Schmitt
- Department of Radiation Oncology, School of Medicine, Technical University Munich (TUM), Munich, Germany.,Central Institute for Translational Cancer Research, School of Medicine, Technical University Munich, Munich, Germany
| | - Huyen Thie Nguyen
- Department of Radiation Oncology, School of Medicine, Technical University Munich (TUM), Munich, Germany.,Central Institute for Translational Cancer Research, School of Medicine, Technical University Munich, Munich, Germany
| | - Stefan Stangl
- Department of Radiation Oncology, School of Medicine, Technical University Munich (TUM), Munich, Germany.,Central Institute for Translational Cancer Research, School of Medicine, Technical University Munich, Munich, Germany
| | - Caroline Werner
- Department of Radiation Oncology, School of Medicine, Technical University Munich (TUM), Munich, Germany.,Central Institute for Translational Cancer Research, School of Medicine, Technical University Munich, Munich, Germany
| | - Fei Wang
- Department of Radiation Oncology, School of Medicine, Technical University Munich (TUM), Munich, Germany.,Central Institute for Translational Cancer Research, School of Medicine, Technical University Munich, Munich, Germany
| | - Zhiyuan Wu
- Department of Radiation Oncology, School of Medicine, Technical University Munich (TUM), Munich, Germany.,Central Institute for Translational Cancer Research, School of Medicine, Technical University Munich, Munich, Germany
| | - Hengyi Fan
- Department of Radiation Oncology, School of Medicine, Technical University Munich (TUM), Munich, Germany.,Central Institute for Translational Cancer Research, School of Medicine, Technical University Munich, Munich, Germany
| | - Hannah Zanth
- Department of Radiation Oncology, School of Medicine, Technical University Munich (TUM), Munich, Germany.,Central Institute for Translational Cancer Research, School of Medicine, Technical University Munich, Munich, Germany
| | - Maxim Shevtsov
- Department of Radiation Oncology, School of Medicine, Technical University Munich (TUM), Munich, Germany.,Central Institute for Translational Cancer Research, School of Medicine, Technical University Munich, Munich, Germany.,Institute of Cytology of the Russian Academy of Sciences, St. Petersburg, Russia
| | - Mathias Pilz
- Department of Radiation Oncology, School of Medicine, Technical University Munich (TUM), Munich, Germany.,Central Institute for Translational Cancer Research, School of Medicine, Technical University Munich, Munich, Germany
| | - Isabelle Riederer
- Department of Neuroradiology, School of Medicine, Technical University Munich (TUM), Munich, Germany
| | - Melissa Schwab
- Department of Radiation Oncology, School of Medicine, Technical University Munich (TUM), Munich, Germany.,Central Institute for Translational Cancer Research, School of Medicine, Technical University Munich, Munich, Germany
| | - Jürgen Schlegel
- Department of Neuropathology, Technical University Munich (TUM), Munich, Germany
| | - Gabriele Multhoff
- Department of Radiation Oncology, School of Medicine, Technical University Munich (TUM), Munich, Germany.,Central Institute for Translational Cancer Research, School of Medicine, Technical University Munich, Munich, Germany
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34
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Kwon N, Kim H, Li X, Yoon J. Supramolecular agents for combination of photodynamic therapy and other treatments. Chem Sci 2021; 12:7248-7268. [PMID: 34163818 PMCID: PMC8171357 DOI: 10.1039/d1sc01125a] [Citation(s) in RCA: 82] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 04/04/2021] [Indexed: 12/17/2022] Open
Abstract
Photodynamic therapy (PDT) is a promising treatment for cancers such as superficial skin cancers, esophageal cancer, and cervical cancer. Unfortunately, PDT often does not have sufficient therapeutic benefits due to its intrinsic oxygen dependence and the limited permeability of irradiating light. Side effects from "always on" photosensitizers (PSs) can be problematic, and PDT cannot treat tumor metastases or recurrences. In recent years, supramolecular approaches using non-covalent interactions have attracted attention due to their potential in PS development. A supramolecular PS assembly could be built to maximize photodynamic effects and minimize side effects. A combination of two or more therapies can effectively address shortcomings while maximizing the benefits of each treatment regimen. Using the supramolecular assembly, it is possible to design a multifunctional supramolecular PS to exert synergistic effects by combining PDT with other treatment methods. This review provides a summary of important research progress on supramolecular systems that can be used to combine PDT with photothermal therapy, chemotherapy, and immunotherapy to compensate for the shortcomings of PDT, and it provides an overview of the prospects for future cancer treatment advances and clinical applications.
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Affiliation(s)
- Nahyun Kwon
- Department of Chemistry and Nanoscience, Ewha Womans University Seoul 03760 Korea
| | - Heejeong Kim
- Department of Chemistry and Nanoscience, Ewha Womans University Seoul 03760 Korea
| | - Xingshu Li
- College of Chemistry, State Key Laboratory of Photocatalysis on Energy and Environment, Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University Fuzhou 350116 China
| | - Juyoung Yoon
- Department of Chemistry and Nanoscience, Ewha Womans University Seoul 03760 Korea
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35
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Pietrobon V, Cesano A, Marincola F, Kather JN. Next Generation Imaging Techniques to Define Immune Topographies in Solid Tumors. Front Immunol 2021; 11:604967. [PMID: 33584676 PMCID: PMC7873485 DOI: 10.3389/fimmu.2020.604967] [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: 09/10/2020] [Accepted: 12/03/2020] [Indexed: 12/12/2022] Open
Abstract
In recent years, cancer immunotherapy experienced remarkable developments and it is nowadays considered a promising therapeutic frontier against many types of cancer, especially hematological malignancies. However, in most types of solid tumors, immunotherapy efficacy is modest, partly because of the limited accessibility of lymphocytes to the tumor core. This immune exclusion is mediated by a variety of physical, functional and dynamic barriers, which play a role in shaping the immune infiltrate in the tumor microenvironment. At present there is no unified and integrated understanding about the role played by different postulated models of immune exclusion in human solid tumors. Systematically mapping immune landscapes or "topographies" in cancers of different histology is of pivotal importance to characterize spatial and temporal distribution of lymphocytes in the tumor microenvironment, providing insights into mechanisms of immune exclusion. Spatially mapping immune cells also provides quantitative information, which could be informative in clinical settings, for example for the discovery of new biomarkers that could guide the design of patient-specific immunotherapies. In this review, we aim to summarize current standard and next generation approaches to define Cancer Immune Topographies based on published studies and propose future perspectives.
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Affiliation(s)
| | | | | | - Jakob Nikolas Kather
- Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
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36
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Nicoś M, Krawczyk P, Crosetto N, Milanowski J. The Role of Intratumor Heterogeneity in the Response of Metastatic Non-Small Cell Lung Cancer to Immune Checkpoint Inhibitors. Front Oncol 2020; 10:569202. [PMID: 33344229 PMCID: PMC7746867 DOI: 10.3389/fonc.2020.569202] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 11/09/2020] [Indexed: 12/12/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs) represent one of the most promising therapeutic approaches in metastatic non-small cell lung cancer (M-NSCLC). Unfortunately, approximately 50–75% of patients do not respond to this treatment modality. Intratumor heterogeneity (ITH) at the genetic and phenotypic level is considered as a major cause of anticancer therapy failure, including resistance to ICIs. Recent observations suggest that spatial heterogeneity in the composition and spatial organization of the tumor microenvironment plays a major role in the response of M-NSCLC patients to ICIs. In this mini review, we first present a brief overview of the use of ICIs in M-NSCLC. We then discuss the role of genetic and non-genetic ITH on the efficacy of ICIs in patients with M-NSCLC.
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Affiliation(s)
- Marcin Nicoś
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Lublin, Poland.,Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Paweł Krawczyk
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Lublin, Poland
| | - Nicola Crosetto
- Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Janusz Milanowski
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Lublin, Poland
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37
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Gulliver C, Hoffmann R, Baillie GS. The enigmatic helicase DHX9 and its association with the hallmarks of cancer. Future Sci OA 2020; 7:FSO650. [PMID: 33437516 PMCID: PMC7787180 DOI: 10.2144/fsoa-2020-0140] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 10/20/2020] [Indexed: 12/16/2022] Open
Abstract
Much interest has been expended lately in characterizing the association between DExH-Box helicase 9 (DHX9) dysregulation and malignant development, however, the enigmatic nature of DHX9 has caused conflict as to whether it regularly functions as an oncogene or tumor suppressor. The impact of DHX9 on malignancy appears to be cell-type specific, dependent upon the availability of binding partners and activation of inter-connected signaling pathways. Realization of DHX9's pivotal role in the development of several hallmarks of cancer has boosted the enzyme's potential as a cancer biomarker and therapeutic target, opening up novel avenues for exploring DHX9 in precision medicine applications. Our review discusses the ascribed functions of DHX9 in cancer, explores its enigmatic nature and potential as an antineoplastic target.
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Affiliation(s)
- Chloe Gulliver
- Institute of Cardiovascular & Medical Science, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow, UK
| | - Ralf Hoffmann
- Institute of Cardiovascular & Medical Science, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow, UK
- Philips Research Europe, High Tech Campus, Eindhoven, The Netherlands
| | - George S Baillie
- Institute of Cardiovascular & Medical Science, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow, UK
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38
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Liu W, Jin H, Chen T, Zhang G, Lai S, Liu G. Investigating the Role of the N-Terminal Loop of PD-1 in Binding Process Between PD-1 and Nivolumab via Molecular Dynamics Simulation. Front Mol Biosci 2020; 7:574759. [PMID: 33102523 PMCID: PMC7522605 DOI: 10.3389/fmolb.2020.574759] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Accepted: 08/14/2020] [Indexed: 12/16/2022] Open
Abstract
The blockade of immune checkpoints, such as programmed death receptor 1 (PD-1) and programmed death ligand 1 protein (PD-L1), is a promising therapeutic approach in cancer immunotherapy. Nivolumab, a humanized IgG4 antibody targeting PD-1, was approved by the US Food and Drug Administration for several cancers in 2014. Crystal structures of the nivolumab/PD-1 complex show that the epitope of PD-1 locates at the IgV domain (including the FG and BC loops) and the N-terminal loop. Although the N-terminal loop of PD-1 has been shown to play a dominant role in the complex interface of the static structure, its role in the dynamic binding process has not been illustrated clearly. Here, eight molecular systems were established for nivolumab/PD-1 complex, and long-time molecular dynamics simulations were performed for each. Results showed that the N-terminal loop of PD-1 prefers to bind with nivolumab to stabilize the interface between IgV and nivolumab. Furthermore, the binding of the N-terminal loop with nivolumab induces the rebinding between the IgV domain and nivolumab. Thus, we proposed a two-step binding model for the nivolumab/PD-1 binding, where the interface switches to a high-affinity state with the help of the N-terminal loop. This finding suggests that the N-terminal loop of PD-1 might be a potential target for anti-PD-1 antibody design, which could serve as an important gatekeeper for the anti-PD-1 antibody binding.
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Affiliation(s)
- Wenping Liu
- Guangdong Food and Drug Vocational College, Guangzhou, China
| | - Haoyu Jin
- Guangdong Food and Drug Vocational College, Guangzhou, China
| | - Ting Chen
- Guangdong Food and Drug Vocational College, Guangzhou, China
| | - Gangping Zhang
- Guangdong Food and Drug Vocational College, Guangzhou, China
| | - Shengsheng Lai
- Guangdong Food and Drug Vocational College, Guangzhou, China
| | - Guangjian Liu
- Clinical Data Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
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Tanriverdi O, Tasar M, Yilmaz M, Durak MF, Sezer SB, Demir H, Ozcan M. Important milestones for cancer at the Nobel prize. Indian J Cancer 2020; 57:370-375. [PMID: 33078741 DOI: 10.4103/ijc.ijc_983_19] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
The Nobel Prize, which is awarded annually, is open to everyone, regardless of nationality, race, belief or ideology, and winners are announced in October. We evaluated the history of the Nobel prizes for awards that have been awarded in fields related to cancer. The contents of the research and their contribution to oncology were determined and reviewed. There were nine awards directly related to cancer. Only studies thought to be groundbreaking in carcinogenesis and molecular treatment of cancer are included in this review.
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Affiliation(s)
- Ozgur Tanriverdi
- Department of Medical Oncology; Bioethics Practice and Research Center, Mugla, Turkey
| | | | | | | | | | - Hatice Demir
- Bioethics Practice and Research Center; Department of History of Medicine and Ethics, Mugla Sitki Koçman University Faculty of Medicine, Mugla, Turkey
| | - Muesser Ozcan
- Bioethics Practice and Research Center; Department of History of Medicine and Ethics, Mugla Sitki Koçman University Faculty of Medicine, Mugla, Turkey
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Hübbe ML, Jæhger DE, Andresen TL, Andersen MH. Leveraging Endogenous Dendritic Cells to Enhance the Therapeutic Efficacy of Adoptive T-Cell Therapy and Checkpoint Blockade. Front Immunol 2020; 11:578349. [PMID: 33101304 PMCID: PMC7546347 DOI: 10.3389/fimmu.2020.578349] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 08/26/2020] [Indexed: 01/15/2023] Open
Abstract
Adoptive cell therapy (ACT), based on treatment with autologous tumor infiltrating lymphocyte (TIL)-derived or genetically modified chimeric antigen receptor (CAR) T cells, has become a potentially curative therapy for subgroups of patients with melanoma and hematological malignancies. To further improve response rates, and to broaden the applicability of ACT to more types of solid malignancies, it is necessary to explore and define strategies that can be used as adjuvant treatments to ACT. Stimulation of endogenous dendritic cells (DCs) alongside ACT can be used to promote epitope spreading and thereby decrease the risk of tumor escape due to target antigen downregulation, which is a common cause of disease relapse in initially responsive ACT treated patients. Addition of checkpoint blockade to ACT and DC stimulation might further enhance response rates by counteracting an eventual inactivation of infused and endogenously primed tumor-reactive T cells. This review will outline and discuss therapeutic strategies that can be utilized to engage endogenous DCs alongside ACT and checkpoint blockade, to strengthen the anti-tumor immune response.
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Affiliation(s)
- Mie Linder Hübbe
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital Herlev, Copenhagen, Denmark
| | - Ditte Elisabeth Jæhger
- Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Thomas Lars Andresen
- Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Mads Hald Andersen
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital Herlev, Copenhagen, Denmark
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Tomela K, Pietrzak B, Schmidt M, Mackiewicz A. The Tumor and Host Immune Signature, and the Gut Microbiota as Predictive Biomarkers for Immune Checkpoint Inhibitor Response in Melanoma Patients. Life (Basel) 2020; 10:life10100219. [PMID: 32992737 PMCID: PMC7600343 DOI: 10.3390/life10100219] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 09/17/2020] [Accepted: 09/18/2020] [Indexed: 02/07/2023] Open
Abstract
There are various melanoma treatment strategies that are based on immunological responses, among which immune checkpoint inhibitors (ICI) are relatively novel form. Nowadays, anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed death-1 (PD-1) antibodies represent a standard treatment for metastatic melanoma. Although there are remarkable curative effects in responders to ICI therapy, up to 70% of melanoma patients show resistance to this treatment. This low response rate is caused by innate as well as acquired resistance, and some aspects of treatment resistance are still unknown. Growing evidence shows that gut microbiota and bacterial metabolites, such as short-chain fatty acids (SCFAs), affect the efficacy of immunotherapy. Various bacterial species have been indicated as potential biomarkers of anti-PD-1 or anti-CTLA-4 therapy efficacy in melanoma, next to biomarkers related to molecular and genetic tumor characteristics or the host immunological response, which are detected in patients' blood. Here, we review the current status of biomarkers of response to ICI melanoma therapies, their pre-treatment predictive values, and their utility as on-treatment monitoring tools in order to select a relevant personalized therapy on the basis of probability of the best clinical outcome.
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Affiliation(s)
- Katarzyna Tomela
- Department of Cancer Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, 8 Rokietnicka Street, 60-806 Poznan, Poland;
- Correspondence:
| | - Bernadeta Pietrzak
- Department of Food Biotechnology and Microbiology, Poznan University of Life Sciences, 48 Wojska Polskiego Street, 60-627 Poznan, Poland; (B.P.); (M.S.)
| | - Marcin Schmidt
- Department of Food Biotechnology and Microbiology, Poznan University of Life Sciences, 48 Wojska Polskiego Street, 60-627 Poznan, Poland; (B.P.); (M.S.)
| | - Andrzej Mackiewicz
- Department of Cancer Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, 8 Rokietnicka Street, 60-806 Poznan, Poland;
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 15 Garbary Street, 61-866 Poznan, Poland
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Johdi NA, Sukor NF. Colorectal Cancer Immunotherapy: Options and Strategies. Front Immunol 2020; 11:1624. [PMID: 33042104 PMCID: PMC7530194 DOI: 10.3389/fimmu.2020.01624] [Citation(s) in RCA: 286] [Impact Index Per Article: 57.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 06/17/2020] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer is the third most common cancer in the world with increasing incidence and mortality rates globally. Standard treatments for colorectal cancer have always been surgery, chemotherapy and radiotherapy which may be used in combination to treat patients. However, these treatments have many side effects due to their non-specificity and cytotoxicity toward any cells including normal cells that are growing and dividing. Furthermore, many patients succumb to relapse even after a series of treatments. Thus, it is crucial to have more alternative and effective treatments to treat CRC patients. Immunotherapy is one of the new alternatives in cancer treatment. The strategy is to utilize patients' own immune systems in combating the cancer cells. Cancer immunotherapy overcomes the issue of specificity which is the major problem in chemotherapy and radiotherapy. The normal cells with no cancer antigens are not affected. The outcomes of some cancer immunotherapy have been astonishing in some cases, but some which rely on the status of patients' own immune systems are not. Those patients who responded well to cancer immunotherapy have a better prognostic and better quality of life.
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Affiliation(s)
- Nor Adzimah Johdi
- UKM Medical Molecular Biology Institute (UMBI), National University of Malaysia, Bangi, Malaysia
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Macpherson AM, Barry SC, Ricciardelli C, Oehler MK. Epithelial Ovarian Cancer and the Immune System: Biology, Interactions, Challenges and Potential Advances for Immunotherapy. J Clin Med 2020; 9:E2967. [PMID: 32937961 PMCID: PMC7564553 DOI: 10.3390/jcm9092967] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 08/28/2020] [Accepted: 09/03/2020] [Indexed: 12/11/2022] Open
Abstract
Recent advances in the understanding of immune function and the interactions with tumour cells have led to the development of various cancer immunotherapies and strategies for specific cancer types. However, despite some stunning successes with some malignancies such as melanomas and lung cancer, most patients receive little or no benefit from immunotherapy, which has been attributed to the tumour microenvironment and immune evasion. Although the US Food and Drug Administration have approved immunotherapies for some cancers, to date, only the anti-angiogenic antibody bevacizumab is approved for the treatment of epithelial ovarian cancer. Immunotherapeutic strategies for ovarian cancer are still under development and being tested in numerous clinical trials. A detailed understanding of the interactions between cancer and the immune system is vital for optimisation of immunotherapies either alone or when combined with chemotherapy and other therapies. This article, in two main parts, provides an overview of: (1) components of the normal immune system and current knowledge regarding tumour immunology, biology and their interactions; (2) strategies, and targets, together with challenges and potential innovative approaches for cancer immunotherapy, with attention given to epithelial ovarian cancer.
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Affiliation(s)
- Anne M. Macpherson
- Discipline of Obstetrics and Gynaecology, Adelaide Medical School, Robinson Research Institute, University of Adelaide, Adelaide 5000, Australia; (A.M.M.); (C.R.)
| | - Simon C. Barry
- Molecular Immunology, Robinson Research Institute, University of Adelaide, Adelaide 5005, Australia;
| | - Carmela Ricciardelli
- Discipline of Obstetrics and Gynaecology, Adelaide Medical School, Robinson Research Institute, University of Adelaide, Adelaide 5000, Australia; (A.M.M.); (C.R.)
| | - Martin K. Oehler
- Discipline of Obstetrics and Gynaecology, Adelaide Medical School, Robinson Research Institute, University of Adelaide, Adelaide 5000, Australia; (A.M.M.); (C.R.)
- Department of Gynaecological Oncology, Royal Adelaide Hospital, Adelaide 5000, Australia
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Heat Shock Proteins and PD-1/PD-L1 as Potential Therapeutic Targets in Myeloproliferative Neoplasms. Cancers (Basel) 2020; 12:cancers12092592. [PMID: 32932806 PMCID: PMC7563255 DOI: 10.3390/cancers12092592] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Revised: 08/27/2020] [Accepted: 09/04/2020] [Indexed: 12/15/2022] Open
Abstract
Simple Summary Myeloproliferative neoplasms (MPN), which are a heterogeneous group of rare disorders that affect blood cell production in bone marrow, present many significant challenges for clinicians. Though considerable progress has been made, in particular with the JAK1/2 inhibitor ruxolitinib, more effective alternative therapeutic approaches are needed. In the search for new and more efficient therapies, heat shock proteins, also known as stress proteins, and the programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) immune checkpoint axis have been found to be of great interest in hematologic malignancies. Here, we review the therapeutic potential of stress protein inhibitors in the management of patients diagnosed with MPN and summarize the accumulating evidence of the role of the PD-1/PD-L1 axis in MPN in order to provide perspectives on future therapeutic opportunities relative to the inhibition of these targets. Abstract Myeloproliferative neoplasms (MPN) are a group of clonal disorders that affect hematopoietic stem/progenitor cells. These disorders are often caused by oncogenic driver mutations associated with persistent Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling. While JAK inhibitors, such as ruxolitinib, reduce MPN-related symptoms in myelofibrosis, they do not influence the underlying cause of the disease and are not curative. Due to these limitations, there is a need for alternative therapeutic strategies and targets. Heat shock proteins (HSPs) are cytoprotective stress-response chaperones involved in protein homeostasis and in many critical pathways, including inflammation. Over the last decade, several research teams have unraveled the mechanistic connection between STAT signaling and several HSPs, showing that HSPs are potential therapeutic targets for MPN. These HSPs include HSP70, HSP90 (chaperoning JAK2) and both HSP110 and HSP27, which are key factors modulating STAT3 phosphorylation status. Like the HSPs, the PD-1/PD-L1 signaling pathway has been widely studied in cancer, but the importance of PD-L1-mediated immune escape in MPN was only recently reported. In this review, we summarize the role of HSPs and PD-1/PD-L1 signaling, the modalities of their experimental blockade, and the effect in MPN. Finally, we discuss the potential of these emerging targeted approaches in MPN therapy.
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Guo ZS. Oncolytic immunotherapy for metastatic cancer: lessons and future strategies. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1113. [PMID: 33145332 PMCID: PMC7575964 DOI: 10.21037/atm.2020.04.42] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Affiliation(s)
- Zong-Sheng Guo
- UPMC Hillman Cancer Center and Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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Ihrig A, Richter J, Grüllich C, Apostolidis L, Horak P, Villalobos M, Grapp M, Friederich HC, Maatouk I. Patient expectations are better for immunotherapy than traditional chemotherapy for cancer. J Cancer Res Clin Oncol 2020; 146:3189-3198. [PMID: 32813113 PMCID: PMC7679331 DOI: 10.1007/s00432-020-03336-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Accepted: 07/23/2020] [Indexed: 12/12/2022]
Abstract
Purpose The main aim of the study was to explore the expectations and knowledge of advanced-stage cancer patients about immunotherapy. Methods This mixed methods study included 53 cancer patients on immune checkpoint inhibitors (ICIs), 55 cancer patients undergoing chemotherapy (CT), and 53 non-cancer patients. Participants’ expectations about ICIs and CT were compared. Additional qualitative data were derived from semi-structured interviews. Results Among patients who did not receive ICIs, 63 (58%) had never heard of ICIs and 94 (87%) had large gaps in their knowledge of ICIs. Among ICI patients, 33 (62%) simply described ICIs without errors. ICI perception was positive, regardless of whether respondents received or had heard of ICIs, which became particularly evident when compared to CT. ICIs were rated as more promising, and all adverse effects were expected to be significantly lower than those of CT. Knowledge about ICIs was also limited in the interviewed ICI patients. Some patients reported adverse effects of ICIs that were mostly mild and well-tolerated or easily treated. Conclusions The lack of understanding of ICIs should be improved by activities to increase the knowledge of ICI patients and the general population. In contrast to CT, ICIs invoked fewer negative associations with efficacy and toxicity. Therefore, attention should be paid to risk awareness when educating patients. (Clinical trial registration number: DRKS00011868) Trial Registration: German clinical trials register, www.germanctr.de, number DRKS00011868.
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Affiliation(s)
- Andreas Ihrig
- Division of Psychooncology, Department of General Internal Medicine and Psychosomatic, University Hospital Heidelberg, Heidelberg, Germany
| | - Jenniffer Richter
- Division of Psychooncology, Department of General Internal Medicine and Psychosomatic, University Hospital Heidelberg, Heidelberg, Germany
| | - Carsten Grüllich
- Department of Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany
| | - Leonidas Apostolidis
- Department of Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany
| | - Peter Horak
- Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Matthias Villalobos
- Department of Thoracic Oncology, University Hospital Heidelberg and Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Röntgenstr. 1, 69126, Heidelberg, Germany
| | - Miriam Grapp
- Division of Psychooncology, Department of General Internal Medicine and Psychosomatic, University Hospital Heidelberg, Heidelberg, Germany
| | - Hans-Christoph Friederich
- Division of Psychooncology, Department of General Internal Medicine and Psychosomatic, University Hospital Heidelberg, Heidelberg, Germany
| | - Imad Maatouk
- Division of Psychooncology, Department of General Internal Medicine and Psychosomatic, University Hospital Heidelberg, Heidelberg, Germany.
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Yao L, Jia G, Lu L, Bao Y, Ma W. Factors affecting tumor responders and predictive biomarkers of toxicities in cancer patients treated with immune checkpoint inhibitors. Int Immunopharmacol 2020; 85:106628. [PMID: 32474388 DOI: 10.1016/j.intimp.2020.106628] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 04/24/2020] [Accepted: 05/20/2020] [Indexed: 12/20/2022]
Abstract
Cancer immunotherapy has brought a great revolution in the treatment of advanced human cancer. Immune checkpoint inhibitors (ICIs) that target cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death protein 1 pathway (PD-1/PD-L1) have been widely administrated in the past years and demonstrated promising in a variety of malignancies. While some patients show benefit from ICIs, others do not respond or even develop resistance to these therapies. Among the responders, the treatments are consequently accompanied with immune-related adverse effects (irAEs), which are diverse in their effected organs, degree of severity and timing. Some of the toxicities are fatal and result in discontinuance of immunotherapy. The toxicity profile from anti-CTLA-4 to anti-PD-1/PD-L1 immunotherapies is distinct from those caused by conventional anticancer therapies, though their presentation may be similar. In order to better help clinicians recognize, monitor and manage irAEs in a growing population of cancer patients who are receiving ICI therapy, this article summarizes the FDA approved ICIs and focuses on (1) existing toxic evidence related to ICIs, (2) occurrence of irAEs, (3) factors influencing tumor responders treated with ICIs, (4) predictive biomarkers of irAEs, and (5) new potential mechanisms of resistance to ICI therapy.
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Affiliation(s)
- Liqin Yao
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital, Huzhou University School of Medicine, Huzhou, Zhejiang 313000, China
| | - Gang Jia
- Department of Medical Oncology, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, China
| | - Lingeng Lu
- Department of Chronic Disease Epidemiology, Yale School of Public Health, School of Medicine, Center for Biomedical Data Science, Yale Cancer Center, Yale University, 60 College Street, New Haven, CT 06520, USA
| | - Ying Bao
- Department of General Surgery, The First Affiliated Hospital, Huzhou University School of Medicine, Huzhou, Zhejiang 313000, China
| | - Wenxue Ma
- Department of Medicine and Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
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Law AMK, Valdes-Mora F, Gallego-Ortega D. Myeloid-Derived Suppressor Cells as a Therapeutic Target for Cancer. Cells 2020; 9:cells9030561. [PMID: 32121014 PMCID: PMC7140518 DOI: 10.3390/cells9030561] [Citation(s) in RCA: 309] [Impact Index Per Article: 61.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 02/22/2020] [Accepted: 02/24/2020] [Indexed: 12/15/2022] Open
Abstract
The emergence of immunotherapy has been an astounding breakthrough in cancer treatments. In particular, immune checkpoint inhibitors, targeting PD-1 and CTLA-4, have shown remarkable therapeutic outcomes. However, response rates from immunotherapy have been reported to be varied, with some having pronounced success and others with minimal to no clinical benefit. An important aspect associated with this discrepancy in patient response is the immune-suppressive effects elicited by the tumour microenvironment (TME). Immune suppression plays a pivotal role in regulating cancer progression, metastasis, and reducing immunotherapy success. Most notably, myeloid-derived suppressor cells (MDSC), a heterogeneous population of immature myeloid cells, have potent mechanisms to inhibit T-cell and NK-cell activity to promote tumour growth, development of the pre-metastatic niche, and contribute to resistance to immunotherapy. Accumulating research indicates that MDSC can be a therapeutic target to alleviate their pro-tumourigenic functions and immunosuppressive activities to bolster the efficacy of checkpoint inhibitors. In this review, we provide an overview of the general immunotherapeutic approaches and discuss the characterisation, expansion, and activities of MDSCs with the current treatments used to target them either as a single therapeutic target or synergistically in combination with immunotherapy.
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Affiliation(s)
- Andrew M. K. Law
- Tumour Development Group, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
- Correspondence: (A.M.K.L.); (F.V.-M.); (D.G.-O.); Tel.: +61-(0)2-9355-5894 (A.M.K.L); +61-(0)2-9385-0143 (F.V.-M); +61-(0)2-9355-5776 (D.G.-O)
| | - Fatima Valdes-Mora
- Histone Variants Group, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
- St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales Sydney, Sydney, NSW 2052, Australia
- Correspondence: (A.M.K.L.); (F.V.-M.); (D.G.-O.); Tel.: +61-(0)2-9355-5894 (A.M.K.L); +61-(0)2-9385-0143 (F.V.-M); +61-(0)2-9355-5776 (D.G.-O)
| | - David Gallego-Ortega
- Tumour Development Group, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
- St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales Sydney, Sydney, NSW 2052, Australia
- Correspondence: (A.M.K.L.); (F.V.-M.); (D.G.-O.); Tel.: +61-(0)2-9355-5894 (A.M.K.L); +61-(0)2-9385-0143 (F.V.-M); +61-(0)2-9355-5776 (D.G.-O)
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Essa D, Kondiah PPD, Choonara YE, Pillay V. The Design of Poly(lactide-co-glycolide) Nanocarriers for Medical Applications. Front Bioeng Biotechnol 2020; 8:48. [PMID: 32117928 PMCID: PMC7026499 DOI: 10.3389/fbioe.2020.00048] [Citation(s) in RCA: 125] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Accepted: 01/22/2020] [Indexed: 12/19/2022] Open
Abstract
Polymeric biomaterials have found widespread applications in nanomedicine, and poly(lactide-co-glycolide), (PLGA) in particular has been successfully implemented in numerous drug delivery formulations due to its synthetic malleability and biocompatibility. However, the need for preconception in these formulations is increasing, and this can be achieved by selection and elimination of design variables in order for these systems to be tailored for their specific applications. The starting materials and preparation methods have been shown to influence various parameters of PLGA-based nanocarriers and their implementation in drug delivery systems, while the implementation of computational simulations as a component of formulation studies can provide valuable information on their characteristics. This review provides a critical summary of the synthesis and applications of PLGA-based systems in bio-medicine and outlines experimental and computational design considerations of these systems.
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Affiliation(s)
| | | | | | - Viness Pillay
- Wits Advanced Drug Delivery Platform, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
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The Programmed Death Pathway in Ocular Adnexal Sebaceous Carcinoma. Ophthalmic Plast Reconstr Surg 2020; 36:74-79. [DOI: 10.1097/iop.0000000000001472] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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