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Signal Transduction and Targeted Therapy Jan 2023Recent advances in neoantigen research have accelerated the development and regulatory approval of tumor immunotherapies, including cancer vaccines, adoptive cell... (Review)
Review
Recent advances in neoantigen research have accelerated the development and regulatory approval of tumor immunotherapies, including cancer vaccines, adoptive cell therapy and antibody-based therapies, especially for solid tumors. Neoantigens are newly formed antigens generated by tumor cells as a result of various tumor-specific alterations, such as genomic mutation, dysregulated RNA splicing, disordered post-translational modification, and integrated viral open reading frames. Neoantigens are recognized as non-self and trigger an immune response that is not subject to central and peripheral tolerance. The quick identification and prediction of tumor-specific neoantigens have been made possible by the advanced development of next-generation sequencing and bioinformatic technologies. Compared to tumor-associated antigens, the highly immunogenic and tumor-specific neoantigens provide emerging targets for personalized cancer immunotherapies, and serve as prospective predictors for tumor survival prognosis and immune checkpoint blockade responses. The development of cancer therapies will be aided by understanding the mechanism underlying neoantigen-induced anti-tumor immune response and by streamlining the process of neoantigen-based immunotherapies. This review provides an overview on the identification and characterization of neoantigens and outlines the clinical applications of prospective immunotherapeutic strategies based on neoantigens. We also explore their current status, inherent challenges, and clinical translation potential.
Topics: Humans; Neoplasms; Antigens, Neoplasm; Immunotherapy; Cancer Vaccines
PubMed: 36604431
DOI: 10.1038/s41392-022-01270-x -
Cancer Letters Oct 2022Compared with conventional chemotherapy and targeted therapy, immunotherapy has changed the treatment prospects of various solid tumors and has recently become the main... (Review)
Review
Compared with conventional chemotherapy and targeted therapy, immunotherapy has changed the treatment prospects of various solid tumors and has recently become the main treatment method for metastatic or recurrent solid tumors, including malignant melanoma, non-small-cell lung cancer, and renal cell carcinoma. The application of immune checkpoint inhibitor (ICI)-based immunotherapy in patients with colorectal cancer (CRC) has yielded satisfactory results in terms of safety and efficacy, and several immunotherapeutic agents, including pembrolizumab, nivolumab, and ipilimumab, have been approved for the treatment of advanced CRC. The advent of other immunotherapies, such as chimeric antigen receptor-modified T (CAR-T) cells or cancer vaccines, have also contributed to the development of immunotherapy for CRC. Here, we summarize the findings of recent clinical trials on the efficacy of immunotherapy in CRC and briefly describe the mechanisms associated with tumor-intrinsic resistance to ICIs. We then discuss potential biomarkers for predicting the efficacy of immunotherapy.
Topics: Antibodies, Monoclonal; Carcinoma, Non-Small-Cell Lung; Colorectal Neoplasms; Humans; Immunologic Factors; Immunotherapy; Lung Neoplasms; Neoplasm Recurrence, Local
PubMed: 35810989
DOI: 10.1016/j.canlet.2022.215816 -
Clinical and Experimental Immunology May 2020T cell immunoglobulin and ITIM domain (TIGIT) is an inhibitory receptor expressed on lymphocytes that was recently propelled under the spotlight as a major emerging... (Review)
Review
T cell immunoglobulin and ITIM domain (TIGIT) is an inhibitory receptor expressed on lymphocytes that was recently propelled under the spotlight as a major emerging target in cancer immunotherapy. TIGIT interacts with CD155 expressed on antigen-presenting cells or tumour cells to down-regulate T cell and natural killer (NK) cell functions. TIGIT has emerged as a key inhibitor of anti-tumour responses that can hinder multiple steps of the cancer immunity cycle. Pre-clinical studies indicated that TIGIT blockade may protect against various solid and haematological cancers. Several monoclonal antibodies (mAbs) that block the inhibitory activity of human TIGIT have been developed. Clinical trials are ongoing, investigating TIGIT blockade as a monotherapy or in combination with anti-PD1/PD-L1 mAbs for the treatment of patients with advanced solid malignancies. In this review, we cover our current knowledge on TIGIT, from its discovery in 2009 to its current status as a clinical target.
Topics: Antineoplastic Agents, Immunological; Humans; Killer Cells, Natural; Neoplasm Proteins; Neoplasms; Receptors, Immunologic; Receptors, Virus; T-Lymphocytes
PubMed: 31828774
DOI: 10.1111/cei.13407 -
Nature Reviews. Disease Primers Oct 2020Bone is the most frequent site for metastasis for many cancers, notably for tumours originating in the breast and the prostate. Tumour cells can escape from the primary... (Review)
Review
Bone is the most frequent site for metastasis for many cancers, notably for tumours originating in the breast and the prostate. Tumour cells can escape from the primary tumour site and colonize the bone microenvironment. Within the bone, these disseminated tumour cells, as well as those arising in the context of multiple myeloma, may assume a state of dormancy, remaining quiescent for years before resuming proliferation and causing overt metastasis, which causes bone destruction via activation of osteoclast-mediated osteolysis. This structural damage can lead to considerable morbidity, including pain, fractures and impaired quality of life. Although treatment of bone metastases and myeloma bone disease is rarely curative, disease control is often possible for many years through the use of systemic anticancer treatments on a background of multidisciplinary supportive care. This care should include bone-targeted agents to inhibit tumour-associated osteolysis and prevent skeletal morbidity as well as use of appropriate local treatments such as radiation therapy, orthopaedic surgery and specialist palliative care to minimize the impact of metastatic bone disease on physical functioning. In this Primer, we provide an overview of the clinical features, the pathophysiology and the specific treatment approaches to prevent and treat bone metastases from solid tumours as well as myeloma bone disease.
Topics: Bone Neoplasms; Humans; Neoplasm Metastasis; Neoplasms
PubMed: 33060614
DOI: 10.1038/s41572-020-00216-3 -
Nature Reviews. Clinical Oncology Feb 2021Tumour budding is an emerging prognostic biomarker in colorectal cancer (CRC) and other solid cancers. Tumour buds are usually defined as isolated single cancer cells or... (Review)
Review
Tumour budding is an emerging prognostic biomarker in colorectal cancer (CRC) and other solid cancers. Tumour buds are usually defined as isolated single cancer cells or clusters of up to four cancer cells located at the invasive tumour front. The prognostic value of tumour budding is now supported by a large body of evidence, whereas the utility of this phenotype as a predictive biomarker remains under investigation. The application of tumour budding indices in clinical practice requires a standardized scoring system that can be tailored to specific tumour types and clinical scenarios. In the context of CRC, tumour budding can be assessed according to the method agreed at the International Tumour Budding Consensus Conference (ITBCC) in 2016. Using the ITBCC scoring system, tumour budding is an independent predictor of lymph node metastasis in patients with pT1 CRC and of unfavourable survival in patients with stage II colon cancer. Regardless of the clinical scenario or tumour type, the assertion that 'the more tumour buds, the worse the clinical outcome' applies. In this Review, we provide an overview of tumour budding in solid cancers, highlighting the molecular and biological aspects of this phenomenon, including its associations with epithelial-mesenchymal transition and features of the tumour microenvironment. We also describe the available evidence demonstrating the value of tumour budding as a biomarker across various solid cancers.
Topics: Biomarkers, Tumor; Colorectal Neoplasms; Epithelial-Mesenchymal Transition; Female; Humans; Immunohistochemistry; Lymphatic Metastasis; Neoplasm Staging; Neoplasms; Prognosis; Tumor Microenvironment
PubMed: 32901132
DOI: 10.1038/s41571-020-0422-y -
Journal of Neuro-oncology Jan 2021Glioblastoma is a very aggressive cancer with dismal prognosis despite standard of care including surgical resection, radiation therapy, and chemotherapy. There is... (Review)
Review
INTRODUCTION
Glioblastoma is a very aggressive cancer with dismal prognosis despite standard of care including surgical resection, radiation therapy, and chemotherapy. There is interest in applying immunotherapy to glioblastoma as this modality has demonstrated remarkable improvements in the management of several solid tumors including melanoma, renal cell carcinoma, and non-small cell lung cancer. This review aims to provide an overview of the current state of glioblastoma immunotherapy.
METHODS
Literature search was performed on PubMed between 1961 and 2020.
RESULTS
Initial clinical trials of checkpoint inhibitors and vaccine therapy for glioblastoma have largely been disappointing for both primary and recurrent glioblastoma. This failure has been attributed to glioblastoma's highly immunosuppressive environment and multiple mechanisms of therapy resistance including high tumor heterogeneity, low mutational burden, systemic immunosuppression, and local immune dysfunction.
CONCLUSIONS
Current clinical trials are exploring combination therapy and novel treatment strategies beyond immune checkpoint therapies and vaccine therapy such as CAR T cells. There is also an effort to establish synergy between immunotherapy and current standard of care. Furthermore, recent advances in personalized neoantigen vaccines suggest a shift towards personalized, patient-specific GBM treatment.
Topics: Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Glioblastoma; Humans; Immunotherapy; Lung Neoplasms; Neoplasm Recurrence, Local
PubMed: 32253714
DOI: 10.1007/s11060-020-03448-1 -
World Journal of Gastroenterology Sep 2021Incidental pancreatic cysts are commonly encountered with some cysts having malignant potential. The most common pancreatic cystic neoplasms include serous cystadenoma,... (Review)
Review
Incidental pancreatic cysts are commonly encountered with some cysts having malignant potential. The most common pancreatic cystic neoplasms include serous cystadenoma, mucinous cystic neoplasm and intraductal papillary mucinous neoplasm. Risk stratifying pancreatic cysts is important in deciding whether patients may benefit from endoscopic ultrasound (EUS) or surgical resection. Surgery should be reserved for patients with malignant cysts or cysts at high risk for developing malignancy as suggested by various risk features including solid mass, nodule and dilated main pancreatic duct. EUS may supplement magnetic resonance imaging findings for cysts that remain indeterminate or have concerning features on imaging. Various cyst fluid markers including carcinoembryonic antigen, glucose, amylase, cytology, and DNA markers help distinguish mucinous from nonmucinous cysts. This review will guide the practicing gastroenterologist in how to evaluate incidental pancreatic cysts and when to consider referral for EUS or surgery. For presumed low risk cysts, surveillance strategies will be discussed. Managing pancreatic cysts requires an individualized approach that is directed by the various guidelines.
Topics: Cyst Fluid; Endoscopic Ultrasound-Guided Fine Needle Aspiration; Endosonography; Humans; Pancreatic Cyst; Pancreatic Neoplasms
PubMed: 34629795
DOI: 10.3748/wjg.v27.i34.5700 -
Cancer Cell Apr 2020Immune checkpoint inhibitors (ICIs) have rapidly altered the treatment landscape for multiple tumor types, providing unprecedented survival in some patients. Despite the... (Review)
Review
Immune checkpoint inhibitors (ICIs) have rapidly altered the treatment landscape for multiple tumor types, providing unprecedented survival in some patients. Despite the characteristic durability of response to ICI, unfortunately many patients with initial response will later develop acquired resistance. The current understanding of mechanisms of acquired resistance to ICIs is remarkably limited, perhaps restraining effective development of next-generation immunotherapies. Here, we examine the barriers to progress and emerging clinical reports interrogating acquired resistance with the goal to facilitate efforts to overcome acquired resistance to ICIs in the future.
Topics: Antineoplastic Agents, Immunological; Disease Management; Drug Resistance, Neoplasm; Humans; Immunologic Factors; Immunotherapy; Neoplasms
PubMed: 32289269
DOI: 10.1016/j.ccell.2020.03.017 -
Trends in Cancer Jul 2022The view of cancer as a tumor cell-centric disease is now replaced by our understanding of the interconnection and dependency of tumor stroma. Cancer-associated... (Review)
Review
The view of cancer as a tumor cell-centric disease is now replaced by our understanding of the interconnection and dependency of tumor stroma. Cancer-associated fibroblasts (CAFs), the most abundant stromal cells in the tumor microenvironment (TME), are involved in anticancer therapeutic resistance. As we unearth more solid evidence on the link between CAFs and tumor progression, we gain insight into the role of CAFs in establishing resistance to cancer therapies. Herein, we review the origin, heterogeneity, and function of CAFs, with a focus on how CAF subsets can be used as biomarkers and can contribute to therapeutic resistance in cancer. We also depict current breakthroughs in targeting CAFs to overcome anticancer therapeutic resistance and discuss emerging CAF-targeting modalities.
Topics: Cancer-Associated Fibroblasts; Drug Resistance, Neoplasm; Humans; Neoplasms; Stromal Cells; Tumor Microenvironment
PubMed: 35331673
DOI: 10.1016/j.trecan.2022.03.001 -
Nature Nov 2019Metastatic cancer is a major cause of death and is associated with poor treatment efficacy. A better understanding of the characteristics of late-stage cancer is...
Metastatic cancer is a major cause of death and is associated with poor treatment efficacy. A better understanding of the characteristics of late-stage cancer is required to help adapt personalized treatments, reduce overtreatment and improve outcomes. Here we describe the largest, to our knowledge, pan-cancer study of metastatic solid tumour genomes, including whole-genome sequencing data for 2,520 pairs of tumour and normal tissue, analysed at median depths of 106× and 38×, respectively, and surveying more than 70 million somatic variants. The characteristic mutations of metastatic lesions varied widely, with mutations that reflect those of the primary tumour types, and with high rates of whole-genome duplication events (56%). Individual metastatic lesions were relatively homogeneous, with the vast majority (96%) of driver mutations being clonal and up to 80% of tumour-suppressor genes being inactivated bi-allelically by different mutational mechanisms. Although metastatic tumour genomes showed similar mutational landscape and driver genes to primary tumours, we find characteristics that could contribute to responsiveness to therapy or resistance in individual patients. We implement an approach for the review of clinically relevant associations and their potential for actionability. For 62% of patients, we identify genetic variants that may be used to stratify patients towards therapies that either have been approved or are in clinical trials. This demonstrates the importance of comprehensive genomic tumour profiling for precision medicine in cancer.
Topics: Clone Cells; DNA Copy Number Variations; Female; Humans; INDEL Mutation; Information Dissemination; Male; Mutation; Neoplasm Metastasis; Neoplasms; Precision Medicine; Whole Genome Sequencing
PubMed: 31645765
DOI: 10.1038/s41586-019-1689-y