-
Journal of Hematology & Oncology Jan 2022There is an urgent need for highly efficacious antiviral therapies in immunosuppressed hosts who develop coronavirus disease (COVID-19), with special concern for those...
Plitidepsin as a successful rescue treatment for prolonged viral SARS-CoV-2 replication in a patient with previous anti-CD20 monoclonal antibody-mediated B cell depletion and chronic lymphocytic leukemia.
BACKGROUND
There is an urgent need for highly efficacious antiviral therapies in immunosuppressed hosts who develop coronavirus disease (COVID-19), with special concern for those affected by hematological malignancies.
CASE PRESENTATION
Here, we report the case of a 75-year-old male with chronic lymphocytic leukemia who was deficient in CD19CD20 B-lymphocyte populations due to previous treatment with anti-CD20 monoclonal antibodies. The patient presented with severe COVID-19 pneumonia due to prolonged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and was treated with two courses of the antiviral plitidepsin on a compassionate use basis. The patient subsequently achieved an undetectable viral load, and his pneumonia resolved.
CONCLUSIONS
Treatment with plitidepsin was well-tolerated without any further hematological or cardiovascular toxicities. This case further supports plitidepsin as a potential antiviral drug in SARS-CoV-2 patients affected by immune deficiencies and hematological malignancies.
Topics: Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antigens, CD20; B-Lymphocytes; COVID-19; Depsipeptides; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocyte Depletion; Male; Peptides, Cyclic; SARS-CoV-2; Treatment Outcome; Virus Replication
PubMed: 35012608
DOI: 10.1186/s13045-021-01220-0 -
The Oncologist Jun 2023T-cell receptor (TCR-T) therapies are based on the expression of an introduced TCR targeting a tumor associated antigen (TAA) which has been studied in several trials in... (Meta-Analysis)
Meta-Analysis
BACKGROUND
T-cell receptor (TCR-T) therapies are based on the expression of an introduced TCR targeting a tumor associated antigen (TAA) which has been studied in several trials in cutaneous melanoma. We conducted a systematic review and meta-analysis aiming to assess the primary efficacy of TCR-based adoptive cell therapy in cutaneous melanoma.
METHODS
We searched through PubMed electronic database from its inception until May 21, 2022. Primary endpoints were pooled objective response rate (ORR) and disease control rate (DCR). We conducted logistic regression analyses to identify potential predictive factors for tumor response.
RESULTS
From 187 patients, 50 showed an objective response (pooled ORR 28%; 95% CI, 20%-37%) and a pooled DCR of 38% (95% CI, 27%-50%). Median PFS was 2, 9 months (95% CI, 1.4-3.1). A trend toward higher PFS was demonstrated for patients treated with cancer/testis antigens targeting TCR-T cells (HR 0.91 95% CI, 0.64-1.3, P = .61) among whom, patients treated with NYESO-1 targeting TCR-T showed a significantly higher PFS (HR 0.63 95% CI, 0.64-0.98, P = .03). In addition, the number of infused cells was associated with a significantly higher likelihood of tumor response (OR 6.61; 95% CI, 1.68-21.6; P = .007).
CONCLUSION
TCR-T therapy shows promising results in terms of antitumor activity and survival similar to those reported for TILs with a significantly higher benefit for cancer/testis antigens targeting cells. Since TCR-based therapy shows advantages of great potential over classic ACT strategies, further research in solid cancers is warranted (PROSPERO ID CRD42022328011).
Topics: Male; Humans; Melanoma; Skin Neoplasms; Immunotherapy, Adoptive; Receptors, Antigen, T-Cell; Melanoma, Cutaneous Malignant
PubMed: 37036865
DOI: 10.1093/oncolo/oyad078 -
Frontiers in Pharmacology 2021There is an urgent need to identify therapeutics for the treatment of Coronavirus disease 2019 (COVID-19). Although different antivirals are given for the clinical...
There is an urgent need to identify therapeutics for the treatment of Coronavirus disease 2019 (COVID-19). Although different antivirals are given for the clinical management of SARS-CoV-2 infection, their efficacy is still under evaluation. Here, we have screened existing drugs approved for human use in a variety of diseases, to compare how they counteract SARS-CoV-2-induced cytopathic effect and viral replication Among the potential 72 antivirals tested herein that were previously proposed to inhibit SARS-CoV-2 infection, only 18 % had an IC below 25 µM or 10 IU/ml. These included plitidepsin, novel cathepsin inhibitors, nelfinavir mesylate hydrate, interferon 2-alpha, interferon-gamma, fenofibrate, camostat along the well-known remdesivir and chloroquine derivatives. Plitidepsin was the only clinically approved drug displaying nanomolar efficacy. Four of these families, including novel cathepsin inhibitors, blocked viral entry in a cell-type specific manner. Since the most effective antivirals usually combine therapies that tackle the virus at different steps of infection, we also assessed several drug combinations. Although no particular synergy was found, inhibitory combinations did not reduce their antiviral activity. Thus, these combinations could decrease the potential emergence of resistant viruses. Antivirals prioritized herein identify novel compounds and their mode of action, while independently replicating the activity of a reduced proportion of drugs which are mostly approved for clinical use. Combinations of these drugs should be tested in animal models to inform the design of fast track clinical trials.
PubMed: 33841165
DOI: 10.3389/fphar.2021.646676 -
BioRxiv : the Preprint Server For... Feb 2021Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths worldwide and massive...
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths worldwide and massive societal and economic burden. Recently, a new variant of SARS-CoV-2, known as B.1.1.7, was first detected in the United Kingdom and is spreading in several other countries, heightening public health concern and raising questions as to the resulting effectiveness of vaccines and therapeutic interventions. We and others previously identified host-directed therapies with antiviral efficacy against SARS-CoV-2 infection. Less prone to the development of therapy resistance, host-directed drugs represent promising therapeutic options to combat emerging viral variants as host genes possess a lower propensity to mutate compared to viral genes. Here, in the first study of the full-length B.1.1.7 variant virus , we find two host-directed drugs, plitidepsin (aplidin; inhibits translation elongation factor eEF1A) and ralimetinib (inhibits p38 MAP kinase cascade), as well as remdesivir, to possess similar antiviral activity against both the early-lineage SARS-CoV-2 and the B.1.1.7 variant, evaluated in both human gastrointestinal and lung epithelial cell lines. We find that plitidepsin is over an order of magnitude more potent than remdesivir against both viruses. These results highlight the importance of continued development of host-directed therapeutics to combat current and future coronavirus variant outbreaks.
PubMed: 33501437
DOI: 10.1101/2021.01.24.427991 -
Potential role of marine species-derived bioactive agents in the management of SARS-CoV-2 infection.Future Microbiology Nov 2021COVID-19, caused by the SARS-CoV-2 outbreak, has resulted in a massive global health crisis. Bioactive molecules extracted or synthesized using starting material...
COVID-19, caused by the SARS-CoV-2 outbreak, has resulted in a massive global health crisis. Bioactive molecules extracted or synthesized using starting material obtained from marine species, including griffithsin, plitidepsin and fingolimod are in clinical trials to evaluate their anti-SARS-CoV-2 and anti-HIV efficacies. The current review highlights the anti-SARS-CoV-2 potential of marine-derived phytochemicals explored using , and models. The current literature suggests that these molecules have the potential to bind with various key drug targets of SARS-CoV-2. In addition, many of these agents have anti-inflammatory and immunomodulatory potentials and thus could play a role in the attenuation of COVID-19 complications. Overall, these agents may play a role in the management of COVID-19, but further preclinical and clinical studies are still required to establish their role in the mitigation of the current viral pandemic.
Topics: Alkaloids; Anti-Inflammatory Agents; Antiviral Agents; Depsipeptides; Fingolimod Hydrochloride; Humans; Lectins; Marine Biology; Molecular Docking Simulation; Oceans and Seas; Peptides, Cyclic; Phycocyanin; Phytochemicals; Plant Lectins; Polyphenols; Polysaccharides; SARS-CoV-2; Seaweed; Sesquiterpenes; COVID-19 Drug Treatment
PubMed: 34689597
DOI: 10.2217/fmb-2021-0024 -
Journal of Intensive Care Medicine Nov 2023The occurrence of pneumomediastinum (PM) and/or pneumothorax (PTX) in patients with severe pneumonia due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)... (Observational Study)
Observational Study
INTRODUCTION
The occurrence of pneumomediastinum (PM) and/or pneumothorax (PTX) in patients with severe pneumonia due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was evaluated.
METHODS
This was a prospective observational study conducted in patients admitted to the intermediate respiratory care unit (IRCU) of a COVID-19 monographic hospital in Madrid (Spain) between December 14, 2020 and September 28, 2021. All patients had a diagnosis of severe SARS-CoV-2 pneumonia and required noninvasive respiratory support (NIRS): high-flow nasal cannula (HFNC), continuous positive airway pressure (CPAP), and bilevel positive airway pressure (BiPAP). The incidences of PM and/or PTX, overall and by NIRS, and their impact on the probabilities of invasive mechanical ventilation (IMV) and death were studied.
RESULTS
A total of 1306 patients were included. 4.3% (56/1306) developed PM/PTX, 3.8% (50/1306) PM, 1.6% (21/1306) PTX, and 1.1% (15/1306) PM + PTX. 16.1% (9/56) of patients with PM/PTX had HFNC alone, while 83.9% (47/56) had HFNC + CPAP/BiPAP. In comparison, 41.7% (521/1250) of patients without PM and PTX had HFNC alone (odds ratio [OR] 0.27; 95% confidence interval [95% CI] 0.13-0.55; < .001), while 58.3% (729/1250) had HFNC + CPAP/BiPAP (OR 3.73; 95% CI 1.81-7.68; < .001). The probability of needing IMV among patients with PM/PTX was 67.9% (36/53) (OR 7.46; 95% CI 4.12-13.50; < .001), while it was 22.1% (262/1185) among patients without PM and PTX. Mortality among patients with PM/PTX was 33.9% (19/56) (OR 4.39; 95% CI 2.45-7.85; < .001), while it was 10.5% (131/1250) among patients without PM and PTX.
CONCLUSIONS
In patients admitted to the IRCU for severe SARS-CoV-2 pneumonia requiring NIRS, incidences of PM/PTX, PM, PTX, and PM + PTX were observed to be 4.3%, 3.8%, 1.6%, and 1.1%, respectively. Most patients with PM/PTX had HFNC + CPAP/BiPAP as the NIRS device, much more frequently than patients without PM and PTX. The probabilities of IMV and death among patients with PM/PTX were 64.3% and 33.9%, respectively, higher than those observed in patients without PM and PTX, which were 21.0% and 10.5%, respectively.
Topics: Humans; SARS-CoV-2; COVID-19; Respiratory Care Units; Mediastinal Emphysema; Pneumothorax; Pneumonia; Oxygen Inhalation Therapy; Respiratory Insufficiency; Noninvasive Ventilation
PubMed: 37306158
DOI: 10.1177/08850666231180165 -
EClinicalMedicine Jun 2022The main objective of the present study was to analyze both clinical characteristics and evolution during hospitalization of a cohort of patients admitted for COVID-19...
BACKGROUND
The main objective of the present study was to analyze both clinical characteristics and evolution during hospitalization of a cohort of patients admitted for COVID-19 pneumonia who were not vaccinated, or with a complete or incomplete vaccination schedule.
METHODS
This COVID-19 specialized single-center cohort study of 1888 COVID-19 patients hospitalized at the "Enfermera Isabel Zendal" Emergencies Hospital (HEEIZ), Madrid (Spain) was performed between July 1 and September 30, 2021. It compared the results of 1327 hospitalized unvaccinated patients to 209 hospitalized fully vaccinated and 352 hospitalized partially vaccinated patients. The four different COVID-19 vaccines authorized in Spain during the time-period studied were: BNT162b2 (Pfizer); ChAdOx1 nCoV-19 (AstraZeneca), mRNA-1273 (Moderna); Ad26.COV2.S (Janssen).
FINDINGS
Hospitalized patients' median age was 41 years (IQR 33-50) for the unvaccinated and 61 years (IQR 53-67) for the fully vaccinated ones. The main comorbidities were obesity, hypertension and diabetes mellitus. 20% of unvaccinated patients (266) required noninvasive respiratory care, as did 14% (51) of partially and 14% (30) of fully vaccinated; 6% (78) of the unvaccinated patients also needed invasive respiratory care, as did 5% (16) of partially and 11 (5%) fully vaccinated.
INTERPRETATION
Fully vaccinated patients were 84% (95% CI: 82-86%) less likely to be admitted to hospital, and protection rose for those aged <50 years. Once hospitalized, vaccinated patients displayed more protection against requiring respiratory care than unvaccinated ones, despite being older and having more comorbidities. No differences appeared for the four studied COVID-19 vaccines and complying with vaccination recommendations proved relevant.
FUNDING
The research was funded by the "Plan Propio de Investigación" Program of the Castilla-La Mancha University /European Regional Development Fund (2021-GRIN-31,039).
PubMed: 35611064
DOI: 10.1016/j.eclinm.2022.101453 -
International Journal of Molecular... Mar 2023Eukaryotic elongation factor 1A (eEF1A) canonically delivers amino acyl tRNA to the ribosomal A site during the elongation stage of protein biosynthesis. Yet... (Review)
Review
Eukaryotic elongation factor 1A (eEF1A) canonically delivers amino acyl tRNA to the ribosomal A site during the elongation stage of protein biosynthesis. Yet paradoxically, the oncogenic nature of this instrumental protein has long been recognized. Consistently, eEF1A has proven to be targeted by a wide assortment of small molecules with excellent anticancer activity, among which plitidepsin has been granted approval for the treatment of multiple myeloma. Meanwhile, metarrestin is currently under clinical development for metastatic cancers. Bearing these exciting advances in mind, it would be desirable to present a systematic up-to-date account of the title topic, which, to the best of our knowledge, has thus far been unavailable in the literature. The present review summarizes recent advances in eEF1A-targeting anticancer agents, both naturally occurring and synthetically crafted, with regard to their discovery or design, target identification, structure-activity relationship, and mode of action. Their structural diversity and differential eEF1A-targeting mechanisms warrant continuing research in pursuit of curing eEF1A-driven malignancy.
Topics: Peptide Elongation Factor 1; Protein Biosynthesis; Saccharomyces cerevisiae; Ribosomes; Antineoplastic Agents
PubMed: 36982256
DOI: 10.3390/ijms24065184 -
Marine Drugs Mar 2024The inadequate vascularization seen in fast-growing solid tumors gives rise to hypoxic areas, fostering specific changes in gene expression that bolster tumor cell... (Review)
Review
The inadequate vascularization seen in fast-growing solid tumors gives rise to hypoxic areas, fostering specific changes in gene expression that bolster tumor cell survival and metastasis, ultimately leading to unfavorable clinical prognoses across different cancer types. Hypoxia-inducible factors (HIF-1 and HIF-2) emerge as druggable pivotal players orchestrating tumor metastasis and angiogenesis, thus positioning them as prime targets for cancer treatment. A range of HIF inhibitors, notably natural compounds originating from marine organisms, exhibit encouraging anticancer properties, underscoring their significance as promising therapeutic options. Bioprospection of the marine environment is now a well-settled approach to the discovery and development of anticancer agents that might have their medicinal chemistry developed into clinical candidates. However, despite the massive increase in the number of marine natural products classified as 'anticancer leads,' most of which correspond to general cytotoxic agents, and only a few have been characterized regarding their molecular targets and mechanisms of action. The current review presents a critical analysis of inhibitors of HIF-1 and HIF-2 and hypoxia-selective compounds that have been sourced from marine organisms and that might act as new chemotherapeutic candidates or serve as templates for the development of structurally similar derivatives with improved anticancer efficacy.
Topics: Animals; Humans; Antineoplastic Agents; Aquatic Organisms; Basic Helix-Loop-Helix Transcription Factors; Biological Products; Hypoxia-Inducible Factor 1; Neoplasms; Signal Transduction
PubMed: 38667760
DOI: 10.3390/md22040143 -
Annals of Hematology Sep 2019The randomized phase III ADMYRE trial evaluated plitidepsin plus dexamethasone (DXM) versus DXM alone in patients with relapsed/refractory multiple myeloma after at... (Randomized Controlled Trial)
Randomized Controlled Trial
The randomized phase III ADMYRE trial evaluated plitidepsin plus dexamethasone (DXM) versus DXM alone in patients with relapsed/refractory multiple myeloma after at least three but not more than six prior regimens, including at least bortezomib and lenalidomide or thalidomide. Patients were randomly assigned (2:1) to receive plitidepsin 5 mg/m on D1 and D15 plus DXM 40 mg on D1, D8, D15, and D22 (arm A, n = 171) or DXM 40 mg on D1, D8, D15, and D22 (arm B, n = 84) q4wk. The primary endpoint was progression-free survival (PFS). Median PFS without disease progression (PD) confirmation (IRC assessment) was 2.6 months (arm A) and 1.7 months (arm B) (HR = 0.650; p = 0.0054). Median PFS with PD confirmation (investigator's assessment) was 3.8 months (arm A) and 1.9 months (arm B) (HR = 0.611; p = 0.0040). Median overall survival (OS, intention-to-treat analysis) was 11.6 months (arm A) and 8.9 months (arm B) (HR = 0.797; p = 0.1261). OS improvement favoring arm A was found when discounting a crossover effect (37 patients crossed over from arm B to arm A) (two-stage method; HR = 0.622; p = 0.0015). The most common grade 3/4 treatment-related adverse events (% of patients arm A/arm B) were fatigue (10.8%/1.2%), myalgia (5.4%/0%), and nausea (3.6%/1.2%), being usually transient and reversible. The safety profile does not overlap with the toxicity observed with other agents used in multiple myeloma. In conclusion, efficacy data, the reassuring safety profile, and the novel mechanism of action of plitidepsin suggest that this combination can be an alternative option in patients with relapsed/refractory multiple myeloma after at least three prior therapy lines.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Depsipeptides; Dexamethasone; Disease-Free Survival; Female; Humans; Lenalidomide; Male; Middle Aged; Multiple Myeloma; Peptides, Cyclic; Survival Rate; Thalidomide
PubMed: 31240472
DOI: 10.1007/s00277-019-03739-2