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Medicina (Kaunas, Lithuania) Dec 2023In 1968, Jean Berger first introduced the medical world to IgA nephropathy (IgAN). Fifty-five years later, its pathogenesis is still unclear, but treatments such as... (Review)
Review
In 1968, Jean Berger first introduced the medical world to IgA nephropathy (IgAN). Fifty-five years later, its pathogenesis is still unclear, but treatments such as renin-angiotensin-aldosterone system inhibitors (RAAS-Is), tonsillectomies, and glucocorticoids are currently used worldwide. There have been great strides in the past 20 years since the discoveries of the specific dysregulation of mucosal immunity, galactose-deficient IgA1 (Gd-IgA1), and Gd-IgA1 immune complexes in patients with IgAN. According to these findings, a multi-hit hypothesis was developed, and this multi-hit hypothesis has provided several putative therapeutic targets. A number of novel agents, including molecularly targeted drugs for targets such as APRIL, plasma cells, complement systems, and endothelin, are undergoing clinical trials. Some candidate drugs have been found to be effective, with minimal side effects. Over half a century after the discovery of IgAN, these therapies will soon be available for clinical use.
Topics: Humans; Glomerulonephritis, IGA; Drug Delivery Systems; Glucocorticoids; Plasma Cells
PubMed: 38256315
DOI: 10.3390/medicina60010054 -
Biochimica Et Biophysica Acta.... Aug 2023Cellular and stromal components including tumor cells, immune cells, mesenchymal cells, cancer-linked fibroblasts, and extracellular matrix, constituent tumor... (Review)
Review
Cellular and stromal components including tumor cells, immune cells, mesenchymal cells, cancer-linked fibroblasts, and extracellular matrix, constituent tumor microenvironment (TME). TME plays a crucial role in reprogramming tumor initiation, uncontrolled proliferation, invasion and metastasis as well as response to therapeutic modalities. In recent years targeting the TME has developed as a potential strategy for treatment of cancer because of its life-threatening functions in restricting tumor development and modulating responses to standard-of-care medicines. Cold atmospheric plasma, oncolytic viral therapy, bacterial therapy, nano-vaccine, and repurposed pharmaceuticals with combination therapy, antiangiogenic drugs, and immunotherapies are among the most effective therapies directed by TME that have either been clinically authorized or are currently being studied. This article discusses above-mentioned therapies in light of targeting TME. We also cover problems related to the TME-targeted therapies, as well as future insights and practical uses in this rapidly growing field.
Topics: Humans; Neoplasms; Immunotherapy; Fibroblasts; Tumor Microenvironment
PubMed: 37160171
DOI: 10.1016/j.bbadis.2023.166746 -
International Journal of Molecular... Feb 2024Glioblastoma (GB) stands out as the most prevalent and lethal form of brain cancer. Although great efforts have been made by clinicians and researchers, no significant... (Review)
Review
Glioblastoma (GB) stands out as the most prevalent and lethal form of brain cancer. Although great efforts have been made by clinicians and researchers, no significant improvement in survival has been achieved since the Stupp protocol became the standard of care (SOC) in 2005. Despite multimodality treatments, recurrence is almost universal with survival rates under 2 years after diagnosis. Here, we discuss the recent progress in our understanding of GB pathophysiology, in particular, the importance of glioma stem cells (GSCs), the tumor microenvironment conditions, and epigenetic mechanisms involved in GB growth, aggressiveness and recurrence. The discussion on therapeutic strategies first covers the SOC treatment and targeted therapies that have been shown to interfere with different signaling pathways (pRB/CDK4/RB1/P16, TP53/MDM2/P14, PI3k/Akt-PTEN, RAS/RAF/MEK, PARP) involved in GB tumorigenesis, pathophysiology, and treatment resistance acquisition. Below, we analyze several immunotherapeutic approaches (i.e., checkpoint inhibitors, vaccines, CAR-modified NK or T cells, oncolytic virotherapy) that have been used in an attempt to enhance the immune response against GB, and thereby avoid recidivism or increase survival of GB patients. Finally, we present treatment attempts made using nanotherapies (nanometric structures having active anti-GB agents such as antibodies, chemotherapeutic/anti-angiogenic drugs or sensitizers, radionuclides, and molecules that target GB cellular receptors or open the blood-brain barrier) and non-ionizing energies (laser interstitial thermal therapy, high/low intensity focused ultrasounds, photodynamic/sonodynamic therapies and electroporation). The aim of this review is to discuss the advances and limitations of the current therapies and to present novel approaches that are under development or following clinical trials.
Topics: Humans; Glioblastoma; Phosphatidylinositol 3-Kinases; Glioma; Hyperthermia, Induced; Combined Modality Therapy; Tumor Microenvironment
PubMed: 38473776
DOI: 10.3390/ijms25052529 -
Oncoimmunology 2023The traditional picture of cancer patients as weak individuals requiring maximum rest and protection is beginning to dissolve. Too much focus on the medical side and... (Review)
Review
The traditional picture of cancer patients as weak individuals requiring maximum rest and protection is beginning to dissolve. Too much focus on the medical side and one's own vulnerability and mortality might be counterproductive and not doing justice to the complexity of human nature. Unlike cytotoxic and lympho-depleting treatments, immune-engaging therapies strengthen the immune system and are typically less harmful for patients. Thus, cancer patients receiving checkpoint inhibitors are not viewed as being vulnerable , at least not in immunological and physical terms. This perspective article advocates a holistic approach to cancer immunotherapy, with an empowered patient in the center, focusing on personal resources and receiving domain-specific support from healthcare professionals. It summarizes recent evidence on non-pharmaceutical interventions to enhance the efficacy of immune checkpoint blockade and improve quality of life. These interventions target behavioral factors such as diet, physical activity, stress management, circadian timing of checkpoint inhibitor infusion, and waiving unnecessary co-medication curtailing immunotherapy efficacy. Non-pharmaceutical interventions are universally accessible, broadly applicable, instantly actionable, scalable, and economically sustainable, creating value for all stakeholders involved. Most importantly, this holistic framework re-emphasizes the patient as a whole and harnesses the full potential of anticancer immunity and checkpoint blockade, potentially leading to survival benefits. Digital therapeutics are proposed to accompany the patients on their mission toward change in lifestyle-related behaviors for creating optimal conditions for treatment efficacy and personal growth.
Topics: Humans; Quality of Life; Neoplasms; Antineoplastic Agents; Immunotherapy
PubMed: 37791231
DOI: 10.1080/2162402X.2023.2255459 -
Molecular Therapy : the Journal of the... Jul 2023Lung cancer causes the most cancer-related deaths worldwide. In recent years, molecular and immunohistochemical techniques have rapidly developed, further inaugurating... (Review)
Review
Lung cancer causes the most cancer-related deaths worldwide. In recent years, molecular and immunohistochemical techniques have rapidly developed, further inaugurating an era of personalized medicine for lung cancer. The rare subset of lung cancers accounts for approximately 10%, each displaying distinct clinical characteristics. Treatments for rare lung cancers are mainly based on evidence from common counterparts, which may lead to unsolid clinical benefits considering intertumoral heterogeneity. The increasing knowledge of molecular profiling of rare lung cancers has made targeting genetic alterations and immune checkpoints a powerful strategy. Additionally, cellular therapy has emerged as a promising way to target tumor cells. In this review, we first discuss the current status of targeted therapy and preclinical models for rare lung cancers, as well as provide mutational profiles by integrating the results of existing cohorts. Finally, we point out the challenges and future directions for developing targeted agents for rare lung cancer.
Topics: Humans; Immunotherapy; Lung Neoplasms; Antineoplastic Agents; Precision Medicine; Molecular Targeted Therapy
PubMed: 37179456
DOI: 10.1016/j.ymthe.2023.05.007 -
Molecular Therapy : the Journal of the... Dec 2023Recombinant adeno-associated viral (AAV) vectors are the current benchmark for systemic delivery of gene therapies to multiple organs in vivo. Despite clinical... (Review)
Review
Recombinant adeno-associated viral (AAV) vectors are the current benchmark for systemic delivery of gene therapies to multiple organs in vivo. Despite clinical successes, safe and effective gene delivery to extrahepatic tissues has proven challenging due to dose limiting toxicity arising from high liver uptake of AAV vectors. Deeper understanding of AAV structure, receptor biology, and pharmacology has enabled the design and engineering of liver-de-targeted capsids ushering in several new vector candidates. This next generation of AAVs offers significant promise for extrahepatic gene delivery to cardiovascular, musculoskeletal, and neurological tissues with improved safety profiles.
Topics: Dependovirus; Gene Transfer Techniques; Genetic Therapy; Capsid; Liver; Genetic Vectors
PubMed: 37805712
DOI: 10.1016/j.ymthe.2023.10.005 -
Frontiers in Medicine 2023Despite the putatively targetable genomic landscape of high-grade gliomas, the long-term survival benefit of genomically-tailored targeted therapies remains discouraging.
BACKGROUND
Despite the putatively targetable genomic landscape of high-grade gliomas, the long-term survival benefit of genomically-tailored targeted therapies remains discouraging.
METHODS
Using glioblastoma (GBM) as a representative example of high-grade gliomas, we evaluated the clonal architecture and distribution of hotspot mutations in 388 GBMs from the Cancer Genome Atlas (TCGA). Mutations were matched with 54 targeted therapies, followed by a comprehensive evaluation of drug biochemical properties in reference to the drug's clinical efficacy in high-grade gliomas. We then assessed clinical outcomes of a cohort of patients with high-grade gliomas with targetable mutations reviewed at the Johns Hopkins Molecular Tumor Board (JH MTB; = 50).
RESULTS
Among 1,156 sequence alterations evaluated, 28.6% represented hotspots. While the frequency of hotspot mutations in GBM was comparable to cancer types with actionable hotspot alterations, GBMs harbored a higher fraction of subclonal mutations that affected hotspots (7.0%), compared to breast cancer (4.9%), lung cancer (4.4%), and melanoma (1.4%). In investigating the biochemical features of targeted therapies paired with recurring alterations, we identified a trend toward higher lipid solubility and lower IC in GBM cell lines among drugs with clinical efficacy. The drugs' half-life, molecular weight, surface area and binding to efflux transporters were not associated with clinical efficacy. Among the JH MTB cohort of patients with wild-type high-grade gliomas who received targeted therapies, trametinib monotherapy or in combination with dabrafenib conferred radiographic partial response in 75% of patients harboring or actionable mutations. Cabozantinib conferred radiographic partial response in two patients harboring a and a amplification. Patients with wild-type gliomas that harbored actionable alterations who received genotype-matched targeted therapy had longer progression-free (PFS) and overall survival (OS; 7.37 and 14.72 respectively) than patients whose actionable alterations were not targeted (2.83 and 4.2 months respectively).
CONCLUSION
While multiple host, tumor and drug-related features may limit the delivery and efficacy of targeted therapies for patients with high-grade gliomas, genotype-matched targeted therapies confer favorable clinical outcomes. Further studies are needed to generate more data on the impact of biochemical features of targeted therapies on their clinical efficacy for high-grade gliomas.
PubMed: 38143440
DOI: 10.3389/fmed.2023.1254955 -
Cells Mar 2024Lung cancer remains a formidable global health challenge that necessitates inventive strategies to improve its therapeutic outcomes. The conventional treatments,... (Review)
Review
Lung cancer remains a formidable global health challenge that necessitates inventive strategies to improve its therapeutic outcomes. The conventional treatments, including surgery, chemotherapy, and radiation, have demonstrated limitations in achieving sustained responses. Therefore, exploring novel approaches encompasses a range of interventions that show promise in enhancing the outcomes for patients with advanced or refractory cases of lung cancer. These groundbreaking interventions can potentially overcome cancer resistance and offer personalized solutions. Despite the rapid evolution of emerging lung cancer therapies, persistent challenges such as resistance, toxicity, and patient selection underscore the need for continued development. Consequently, the landscape of lung cancer therapy is transforming with the introduction of precision medicine, immunotherapy, and innovative therapeutic modalities. Additionally, a multifaceted approach involving combination therapies integrating targeted agents, immunotherapies, or traditional cytotoxic treatments addresses the heterogeneity of lung cancer while minimizing its adverse effects. This review provides a brief overview of the latest emerging therapies that are reshaping the landscape of lung cancer treatment. As these novel treatments progress through clinical trials are integrated into standard care, the potential for more effective, targeted, and personalized lung cancer therapies comes into focus, instilling renewed hope for patients facing challenging diagnoses.
Topics: Humans; Lung Neoplasms; Antineoplastic Agents; Immunotherapy; Combined Modality Therapy; Precision Medicine
PubMed: 38474400
DOI: 10.3390/cells13050436 -
Viruses Oct 2023Shrimp aquaculture has become a vital industry, meeting the growing global demand for seafood. Shrimp viral diseases have posed significant challenges to the aquaculture... (Review)
Review
Shrimp aquaculture has become a vital industry, meeting the growing global demand for seafood. Shrimp viral diseases have posed significant challenges to the aquaculture industry, causing major economic losses worldwide. Conventional treatment methods have proven to be ineffective in controlling these diseases. However, recent advances in RNA interference (RNAi) technology have opened new possibilities for combating shrimp viral diseases. This cutting-edge technology uses cellular machinery to silence specific viral genes, preventing viral replication and spread. Numerous studies have shown the effectiveness of RNAi-based therapies in various model organisms, paving the way for their use in shrimp health. By precisely targeting viral pathogens, RNAi has the potential to provide a sustainable and environmentally friendly solution to combat viral diseases in shrimp aquaculture. This review paper provides an overview of RNAi-based therapy and its potential as a game-changer for shrimp viral diseases. We discuss the principles of RNAi, its application in combating viral infections, and the current progress made in RNAi-based therapy for shrimp viral diseases. We also address the challenges and prospects of this innovative approach.
Topics: Animals; RNAi Therapeutics; RNA Interference; Virus Diseases; Crustacea; Aquaculture
PubMed: 37896827
DOI: 10.3390/v15102050 -
Nature Medicine Apr 2024Chimeric antigen receptor T cell (CAR-T) therapy is an emerging strategy to improve treatment outcomes for recurrent high-grade glioma, a cancer that responds poorly to...
Chimeric antigen receptor T cell (CAR-T) therapy is an emerging strategy to improve treatment outcomes for recurrent high-grade glioma, a cancer that responds poorly to current therapies. Here we report a completed phase I trial evaluating IL-13Rα2-targeted CAR-T cells in 65 patients with recurrent high-grade glioma, the majority being recurrent glioblastoma (rGBM). Primary objectives were safety and feasibility, maximum tolerated dose/maximum feasible dose and a recommended phase 2 dose plan. Secondary objectives included overall survival, disease response, cytokine dynamics and tumor immune contexture biomarkers. This trial evolved to evaluate three routes of locoregional T cell administration (intratumoral (ICT), intraventricular (ICV) and dual ICT/ICV) and two manufacturing platforms, culminating in arm 5, which utilized dual ICT/ICV delivery and an optimized manufacturing process. Locoregional CAR-T cell administration was feasible and well tolerated, and as there were no dose-limiting toxicities across all arms, a maximum tolerated dose was not determined. Probable treatment-related grade 3+ toxicities were one grade 3 encephalopathy and one grade 3 ataxia. A clinical maximum feasible dose of 200 × 10 CAR-T cells per infusion cycle was achieved for arm 5; however, other arms either did not test or achieve this dose due to manufacturing feasibility. A recommended phase 2 dose will be refined in future studies based on data from this trial. Stable disease or better was achieved in 50% (29/58) of patients, with two partial responses, one complete response and a second complete response after additional CAR-T cycles off protocol. For rGBM, median overall survival for all patients was 7.7 months and for arm 5 was 10.2 months. Central nervous system increases in inflammatory cytokines, including IFNγ, CXCL9 and CXCL10, were associated with CAR-T cell administration and bioactivity. Pretreatment intratumoral CD3 T cell levels were positively associated with survival. These findings demonstrate that locoregional IL-13Rα2-targeted CAR-T therapy is safe with promising clinical activity in a subset of patients. ClinicalTrials.gov Identifier: NCT02208362 .
Topics: Humans; Receptors, Chimeric Antigen; Neoplasm Recurrence, Local; Glioma; T-Lymphocytes; Glioblastoma; Immunotherapy, Adoptive
PubMed: 38454126
DOI: 10.1038/s41591-024-02875-1