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Journal of Hematology & Oncology May 2023Gastric cancer (GC) is one of the most common malignancies worldwide. Most patients are diagnosed at advanced stages due to the subtle symptoms of earlier disease and... (Review)
Review
Gastric cancer (GC) is one of the most common malignancies worldwide. Most patients are diagnosed at advanced stages due to the subtle symptoms of earlier disease and the low rate of regular screening. Systemic therapies for GC, including chemotherapy, targeted therapy and immunotherapy, have evolved significantly in the past few years. For resectable GC, perioperative chemotherapy has become the standard treatment. Ongoing investigations are exploring the potential benefits of targeted therapy or immunotherapy in the perioperative or adjuvant setting. For metastatic disease, there have been notable advancements in immunotherapy and biomarker-directed therapies recently. Classification based on molecular biomarkers, such as programmed cell death ligand 1 (PD-L1), microsatellite instability (MSI), and human epidermal growth factor receptor 2 (HER2), provides an opportunity to differentiate patients who may benefit from immunotherapy or targeted therapy. Molecular diagnostic techniques have facilitated the characterization of GC genetic profiles and the identification of new potential molecular targets. This review systematically summarizes the main research progress in systemic treatment for GC, discusses current individualized strategies and presents future perspectives.
Topics: Humans; Stomach Neoplasms; Immunotherapy; B7-H1 Antigen
PubMed: 37245017
DOI: 10.1186/s13045-023-01451-3 -
Journal of Investigative Surgery : the... Dec 2023Pancreatic cancer is one of the leading causes for cancer-related deaths in the United States. Majority of patients present with unresectable or metastatic disease. For... (Review)
Review
Pancreatic cancer is one of the leading causes for cancer-related deaths in the United States. Majority of patients present with unresectable or metastatic disease. For those that present with localized disease, a multidisciplinary approach is necessary to maximize survival and optimize outcomes. The quality and safety of surgery for pancreatic cancer have improved in recent years with increasing adoption of minimally invasive techniques and surgical adjuncts. Systemic chemotherapy has also evolved to impact survival. It is now increasingly being utilized in the neoadjuvant setting, often with concomitant radiation. Increased utilization of genomic testing in metastatic pancreatic cancer has led to better understanding of their biology, thereby allowing clinicians to consider potential targeted therapies. Similarly, targeted agents such as PARP inhibitors and immune checkpoint- inhibitors have emerged with promising results. In summary, pancreatic cancer remains a disease with poor long-term survival. However, recent developments have led to improved outcomes and have changed practice in the past decade. This review summarizes current practices in pancreatic cancer treatment and the milestones that brought us to where we are today, along with emerging therapies.
Topics: Humans; United States; Pancreatic Neoplasms; Combined Modality Therapy; Neoadjuvant Therapy; Antineoplastic Agents
PubMed: 36191926
DOI: 10.1080/08941939.2022.2129884 -
Nature Reviews. Nephrology Jul 2023Kidney disease is a leading cause of morbidity and mortality across the globe. Current interventions for kidney disease include dialysis and renal transplantation, which... (Review)
Review
Kidney disease is a leading cause of morbidity and mortality across the globe. Current interventions for kidney disease include dialysis and renal transplantation, which have limited efficacy or availability and are often associated with complications such as cardiovascular disease and immunosuppression. There is therefore a pressing need for novel therapies for kidney disease. Notably, as many as 30% of kidney disease cases are caused by monogenic disease and are thus potentially amenable to genetic medicine, such as cell and gene therapy. Systemic disease that affects the kidney, such as diabetes and hypertension, might also be targetable by cell and gene therapy. However, although there are now several approved gene and cell therapies for inherited diseases that affect other organs, none targets the kidney. Promising recent advances in cell and gene therapy have been made, including in the kidney research field, suggesting that this form of therapy might represent a potential solution for kidney disease in the future. In this Review, we describe the potential for cell and gene therapy in treating kidney disease, focusing on recent genetic studies, key advances and emerging technologies, and we describe several crucial considerations for renal genetic and cell therapies.
Topics: Humans; Renal Dialysis; Kidney Diseases; Kidney; Kidney Transplantation; Genetic Therapy
PubMed: 36973494
DOI: 10.1038/s41581-023-00702-3 -
Nature Reviews. Clinical Oncology Jun 2023Chimeric antigen receptors (CAR) are engineered fusion proteins designed to target T cells to antigens expressed on cancer cells. CAR T cells are now an established... (Review)
Review
Chimeric antigen receptors (CAR) are engineered fusion proteins designed to target T cells to antigens expressed on cancer cells. CAR T cells are now an established treatment for patients with relapsed and/or refractory B cell lymphomas, B cell acute lymphoblastic leukaemia and multiple myeloma. At the time of this writing, over a decade of follow-up data are available from the initial patients who received CD19-targeted CAR T cells for B cell malignancies. Data on the outcomes of patients who received B cell maturation antigen (BCMA)-targeted CAR T cells for multiple myeloma are more limited owing to the more recent development of these constructs. In this Review, we summarize long-term follow-up data on efficacy and toxicities from patients treated with CAR T cells targeting CD19 or BCMA. Overall, the data demonstrate that CD19-targeted CAR T cells can induce prolonged remissions in patients with B cell malignancies, often with minimal long-term toxicities, and are probably curative for a subset of patients. By contrast, remissions induced by BCMA-targeted CAR T cells are typically more short-lived but also generally have only limited long-term toxicities. We discuss factors associated with long-term remissions, including the depth of initial response, malignancy characteristics predictive of response, peak circulating CAR levels and the role of lymphodepleting chemotherapy. We also discuss ongoing investigational strategies designed to improve the length of remission following CAR T cell therapy.
Topics: Humans; Immunotherapy, Adoptive; Multiple Myeloma; Receptors, Antigen, T-Cell; B-Cell Maturation Antigen; T-Lymphocytes; Receptors, Chimeric Antigen; Antigens, CD19
PubMed: 37055515
DOI: 10.1038/s41571-023-00754-1 -
Molecular Cancer Jul 2023Breast cancer is the second leading cause of death for women worldwide. The heterogeneity of this disease presents a big challenge in its therapeutic management.... (Review)
Review
Breast cancer is the second leading cause of death for women worldwide. The heterogeneity of this disease presents a big challenge in its therapeutic management. However, recent advances in molecular biology and immunology enable to develop highly targeted therapies for many forms of breast cancer. The primary objective of targeted therapy is to inhibit a specific target/molecule that supports tumor progression. Ak strain transforming, cyclin-dependent kinases, poly (ADP-ribose) polymerase, and different growth factors have emerged as potential therapeutic targets for specific breast cancer subtypes. Many targeted drugs are currently undergoing clinical trials, and some have already received the FDA approval as monotherapy or in combination with other drugs for the treatment of different forms of breast cancer. However, the targeted drugs have yet to achieve therapeutic promise against triple-negative breast cancer (TNBC). In this aspect, immune therapy has come up as a promising therapeutic approach specifically for TNBC patients. Different immunotherapeutic modalities including immune-checkpoint blockade, vaccination, and adoptive cell transfer have been extensively studied in the clinical setting of breast cancer, especially in TNBC patients. The FDA has already approved some immune-checkpoint blockers in combination with chemotherapeutic drugs to treat TNBC and several trials are ongoing. This review provides an overview of clinical developments and recent advancements in targeted therapies and immunotherapies for breast cancer treatment. The successes, challenges, and prospects were critically discussed to portray their profound prospects.
Topics: Humans; Female; Triple Negative Breast Neoplasms; Immunotherapy; Combined Modality Therapy; Molecular Targeted Therapy
PubMed: 37415164
DOI: 10.1186/s12943-023-01805-y -
Signal Transduction and Targeted Therapy May 2023Macrophages exist in various tissues, several body cavities, and around mucosal surfaces and are a vital part of the innate immune system for host defense against many... (Review)
Review
Macrophages exist in various tissues, several body cavities, and around mucosal surfaces and are a vital part of the innate immune system for host defense against many pathogens and cancers. Macrophages possess binary M1/M2 macrophage polarization settings, which perform a central role in an array of immune tasks via intrinsic signal cascades and, therefore, must be precisely regulated. Many crucial questions about macrophage signaling and immune modulation are yet to be uncovered. In addition, the clinical importance of tumor-associated macrophages is becoming more widely recognized as significant progress has been made in understanding their biology. Moreover, they are an integral part of the tumor microenvironment, playing a part in the regulation of a wide variety of processes including angiogenesis, extracellular matrix transformation, cancer cell proliferation, metastasis, immunosuppression, and resistance to chemotherapeutic and checkpoint blockade immunotherapies. Herein, we discuss immune regulation in macrophage polarization and signaling, mechanical stresses and modulation, metabolic signaling pathways, mitochondrial and transcriptional, and epigenetic regulation. Furthermore, we have broadly extended the understanding of macrophages in extracellular traps and the essential roles of autophagy and aging in regulating macrophage functions. Moreover, we discussed recent advances in macrophages-mediated immune regulation of autoimmune diseases and tumorigenesis. Lastly, we discussed targeted macrophage therapy to portray prospective targets for therapeutic strategies in health and diseases.
Topics: Humans; Epigenesis, Genetic; Macrophages; Neoplasms; Immunotherapy; Signal Transduction; Tumor Microenvironment
PubMed: 37211559
DOI: 10.1038/s41392-023-01452-1 -
Critical Reviews in Oncology/hematology Oct 2023Non-small cell lung cancer (NSCLC) stages I-III were previously predominantly treated with surgery and chemotherapy. With the advent of Checkmate-816, neoadjuvant... (Review)
Review
Non-small cell lung cancer (NSCLC) stages I-III were previously predominantly treated with surgery and chemotherapy. With the advent of Checkmate-816, neoadjuvant nivolumab and chemotherapy was FDA approved for the treatment of resectable NSCLC. There are several ongoing trials evaluating other neoadjuvant combinations of chemotherapy and immunotherapy as well as targeted therapies towards driver mutations. Here, we review previous clinical trials and discuss current ongoing trials' potential benefits and challenges.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Neoadjuvant Therapy; Nivolumab; Immunotherapy
PubMed: 37532102
DOI: 10.1016/j.critrevonc.2023.104080 -
Biomolecules & Biomedicine Sep 2023Prostate cancer is one of the most significant causes of morbidity and mortality in male patients. The incidence increases with age, and it is higher among African... (Review)
Review
Prostate cancer is one of the most significant causes of morbidity and mortality in male patients. The incidence increases with age, and it is higher among African Americans. The occurrence of prostate cancer is associated with many risk factors, including genetic and hereditary predisposition. The most common genetic syndromes associated with prostate cancer risk are BRCA-associated hereditary breast and ovarian cancer (HBOC) and Lynch syndrome. Local-regional therapy, i.e., surgery is beneficial in early-stage prostate cancer management. Advanced and metastatic prostate cancers require systemic therapies, including hormonal inhibition, chemotherapy, and targeted agents. Most prostate cancers can be treated by targeting the androgen-receptor pathway and decreasing androgen production or binding to androgen receptors (AR). Castration-resistant prostate cancer (CRPC) usually involves the PI3K/AKT/mTOR pathway and requires targeted therapy. Specific molecular therapy can target mutated cell lines in which DNA defect repair is altered, caused by mutations of BRCA2, partner and localizer of BRCA2 (PALB2), and phosphatase and tensin homolog (PTEN) or the transmembrane protease serine 2-ERG (TMPRSS2-ERG) fusion. Most benefits were demonstrated in cyclin dependent-kinase 12 (CDK12) mutated cell lines when treated with anti-programmed cell death protein 1 (PD1) therapy. Therapies targeting p53 and AKT are the subject of ongoing clinical trials. Many genetic defects are listed as diagnostic, prognostic, and clinically actionable markers in prostate cancer. Androgen receptor splice variant 7 (AR-V7) is an important oncogenic driver and an early diagnostic and prognostic marker, as well as a therapeutic target in hormone-resistant CRPC. This review summarizes the pathophysiological mechanisms and available targeted therapies for prostate cancer.
Topics: Humans; Male; Prostatic Neoplasms, Castration-Resistant; Androgens; Proto-Oncogene Proteins c-akt; Phosphatidylinositol 3-Kinases; Antineoplastic Agents
PubMed: 37021836
DOI: 10.17305/bb.2023.8782 -
Journal of Hematology & Oncology Jun 2023Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma with a poor prognosis. Initial responses to standard-of-care chemo-immunotherapy are,... (Review)
Review
Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma with a poor prognosis. Initial responses to standard-of-care chemo-immunotherapy are, unfortunately, followed by rapid disease recurrence in most patients. Current treatment options are limited, with no therapies specifically approved as third-line or beyond. Delta-like ligand 3 (DLL3), a Notch inhibitory ligand, is an attractive therapeutic target because it is overexpressed on the surface of SCLC cells with minimal to no expression on normal cells. Several DLL3-targeted therapies are being developed for the treatment of SCLC and other neuroendocrine carcinomas, including antibody-drug conjugates (ADCs), T-cell engager (TCE) molecules, and chimeric antigen receptor (CAR) therapies. First, we discuss the clinical experience with rovalpituzumab tesirine (Rova-T), a DLL3-targeting ADC, the development of which was halted due to a lack of efficacy in phase 3 studies, with a view to understanding the lessons that can be garnered for the rapidly evolving therapeutic landscape in SCLC. We then review preclinical and clinical data for several DLL3-targeting agents that are currently in development, including the TCE molecules-tarlatamab (formerly known as AMG 757), BI 764532, and HPN328-and the CAR T-cell therapy AMG 119. We conclude with a discussion of the future challenges and opportunities for DLL3-targeting therapies, including the utility of DLL3 as a biomarker for patient selection and disease progression, and the potential of rational combinatorial approaches that can enhance efficacy.
Topics: Humans; Small Cell Lung Carcinoma; Lung Neoplasms; Ligands; Neoplasm Recurrence, Local; Membrane Proteins; Intracellular Signaling Peptides and Proteins
PubMed: 37355629
DOI: 10.1186/s13045-023-01464-y -
Journal of Hematology & Oncology Sep 2023In one decade, immunotherapy based on immune checkpoint blockades (ICBs) has become a new pillar of cancer treatment following surgery, radiation, chemotherapy, and... (Review)
Review
In one decade, immunotherapy based on immune checkpoint blockades (ICBs) has become a new pillar of cancer treatment following surgery, radiation, chemotherapy, and targeted therapies. However, not all cancer patients benefit from single or combination therapy with anti-CTLA-4 and anti-PD-1/PD-L1 monoclonal antibodies. Thus, an increasing number of immune checkpoint proteins (ICPs) have been screened and their effectiveness evaluated in preclinical and clinical trials. Lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin and mucin-domain-containing-3 (TIM-3), and T cell immunoreceptor with immunoglobulin and tyrosine-based inhibitory motif (ITIM) domain (TIGIT) constitute the second wave of immunotherapy targets that show great promise for use in the treatment of solid tumors and leukemia. To promote the research and clinical application of ICBs directed at these targets, we summarize their discovery, immunotherapy mechanism, preclinical efficiency, and clinical trial results in this review.
Topics: Humans; Hepatitis A Virus Cellular Receptor 2; Immunotherapy; Receptors, Immunologic; Immune Checkpoint Proteins; Antibodies, Monoclonal; Immune Checkpoint Inhibitors; Neoplasms
PubMed: 37670328
DOI: 10.1186/s13045-023-01499-1