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Angewandte Chemie (International Ed. in... Feb 2020Immunotherapy has emerged as a promising new approach for cancer treatment. However, clinically available drugs have been limited until recently, and the antitumor...
Immunotherapy has emerged as a promising new approach for cancer treatment. However, clinically available drugs have been limited until recently, and the antitumor efficacy of most cancer immunotherapies still needs to be improved. Herein, we develop diselenide-pemetrexed assemblies that combine natural killer (NK) cell-based cancer immunotherapy with radiotherapy and chemotherapy in a single system. The assemblies are prepared by co-assembly between pemetrexed and cytosine-containing diselenide through hydrogen bonds. Under γ-radiation, the hydrogen bonds are cleaved, resulting in the release of pemetrexed. At the same time, diselenide can be oxidized to seleninic acid, which suppresses the expression of human leukocyte antigen E (HLA-E) in cancer cells, thus activating the immune response of NK cells. In this way, cancer immunotherapy is combined with radiotherapy and chemotherapy, providing a new strategy for cancer treatment.
Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Histocompatibility Antigens Class I; Humans; Immunotherapy; Killer Cells, Natural; Molecular Structure; Organoselenium Compounds; Pemetrexed
PubMed: 31805209
DOI: 10.1002/anie.201914453 -
Cancer Science Jul 2023Chemotherapy, in combination with immune checkpoint blockade (ICB) targeting to programmed death-1 (PD-1) or its ligand PD-L1, is one of the first-line treatments for...
Chemotherapy, in combination with immune checkpoint blockade (ICB) targeting to programmed death-1 (PD-1) or its ligand PD-L1, is one of the first-line treatments for patients with advanced non-small-cell lung cancer (NSCLC). However, a large proportion of patients, especially those with PD-L1 negative tumors, do not benefit from this treatment. This may be due to the existence of multiple immunosuppressive mechanisms other than the PD-1/PD-L1 axis. Human leukocyte antigen-G (HLA-G) has been identified as an immune checkpoint protein (ICP) and a neoexpressed tumor-associated antigen (TAA) in a large proportion of solid tumors. In this study, we evaluated the induction of HLA-G as well as PD-L1 using sublethal doses of chemotherapeutics including pemetrexed in different NSCLC cell lines. Except for gefitinib, most of the chemotherapeutic agents enhanced HLA-G and PD-L1 expression in a dose-dependent manner, whereas pemetrexed and carboplatin treatments showed the most consistent upregulation of PD-L1 and HLA-G in each cell line. In addition to protein levels, a novel finding of this study is that pemetrexed enhanced the glycosylation of HLA-G and PD-L1. Pemetrexed potentiated the cytotoxicity of cytotoxic T lymphocytes (CTLs) to treat NSCLC. Both in vitro and in vivo experiments revealed that CTL-mediated cytotoxicity was most pronounced when both anti-PD-L1 and anti-HLA-G ICBs were combined with pemetrexed treatment. In conclusion, anti-HLA-G could be an intervention strategy in addition to the anti-PD-1/PD-L1 pathway for NSCLC. Moreover, dual targeting of PD-L1 and HLA-G combined with pemetrexed might have a better extent of CTL-based immunotherapy.
Topics: Humans; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; T-Lymphocytes, Cytotoxic; Pemetrexed; Immune Checkpoint Inhibitors; B7-H1 Antigen
PubMed: 37017116
DOI: 10.1111/cas.15806 -
Lancet (London, England) Dec 2023
Topics: Humans; Mesothelioma, Malignant; Mesothelioma; Antibodies, Monoclonal, Humanized; Pleural Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Pemetrexed; Lung Neoplasms
PubMed: 37931626
DOI: 10.1016/S0140-6736(23)01883-4 -
Journal of Comparative Effectiveness... Feb 2023In the absence of head-to-head trials comparing immunotherapies for advanced nonsquamous non-small-cell lung cancer (NsqNSCLC), a network meta-analysis (NMA) was... (Meta-Analysis)
Meta-Analysis Review
In the absence of head-to-head trials comparing immunotherapies for advanced nonsquamous non-small-cell lung cancer (NsqNSCLC), a network meta-analysis (NMA) was conducted to compare the relative efficacy of these treatments. A systematic literature review of randomized controlled trials evaluating first-line-to-progression and second-line treatments for advanced NsqNSCLC informed Bayesian NMAs for overall survival (OS) and progression-free survival (PFS) end points. Among first-line-to-progression treatments, pembrolizumab + pemetrexed + platinum showed the greatest OS benefit versus other regimens and a PFS benefit versus all but three regimens. Among second-line treatments, an OS benefit was seen for atezolizumab, nivolumab and pembrolizumab versus docetaxel. Pembrolizumab + pemetrexed + platinum showed the maximum OS benefit in the first-line setting. In the second-line setting, anti-PD-1/anti-PD-L1 monotherapies were better than docetaxel.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Docetaxel; Pemetrexed; Network Meta-Analysis; Platinum; Bayes Theorem; Immunotherapy; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36621905
DOI: 10.2217/cer-2022-0016 -
Surgical Oncology Dec 2016Pemetrexed is a systemic chemotherapeutic agent used in the treatment of malignant mesothelioma. This drug represents a potentially promising intraperitoneal (IP) agent...
BACKGROUND
Pemetrexed is a systemic chemotherapeutic agent used in the treatment of malignant mesothelioma. This drug represents a potentially promising intraperitoneal (IP) agent to use for hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of peritoneal mesothelioma. However, this has yet to be supported by preclinical studies. Therefore, we aimed to study the effect of pemetrexed dose and perfusion temperature on the resultant pemetrexed concentration in 3 different compartments (systemic circulation, portal circulation and peritoneal tissues) using a murine model.
METHODS
Under general anesthesia, 29 Sprague-Dawley rats were submitted to 3 different doses of IP pemetrexed (500, 1000 and 1500 mg/m) combined with 3 different perfusion temperatures (37, 40 and 43 °C) for a total duration of 25 min. At the end of perfusion, samples in different compartments (systemic circulation, portal circulation and peritoneum) were harvested and concentrations of pemetrexed were measured using high performance liquid chromatography.
RESULTS
With increasing dose of IP pemetrexed, higher concentrations were measured in the 3 compartments tested. In peritoneal cells, the difference between IP doses of 500 and 1000 mg/m (2.03 vs. 19.17 μg/g, p < 0.001) was greater than the difference between 1000 and 1500 mg/m (19.17 vs. 22.80 μg/g, p = 0.027). When the perfusion temperature increased, we observed a proportional rise of pemetrexed concentration in both the portal and systemic compartments; while in the peritoneal cells, the pemetrexed concentration increased up to 40 °C, after which it plateaued.
CONCLUSION
Both heat and increasing doses of IP pemetrexed enhance peritoneal cell concentration of pemetrexed. However, for temperatures above 40 °C, pemetrexed concentration reached a plateau in peritoneal cells. Systemic and portal concentrations increased proportionally with both increasing temperatures and IP doses. We believe these results should be taken into consideration for the design of an eventual clinical study in humans.
Topics: Animals; Antineoplastic Agents; Hot Temperature; Injections, Intraperitoneal; Male; Models, Animal; Pemetrexed; Peritoneum; Rats; Rats, Sprague-Dawley; Tissue Distribution
PubMed: 27251757
DOI: 10.1016/j.suronc.2016.05.014 -
JAMA Network Open Mar 2022Some recently proposed frontline therapies for malignant pleural mesothelioma (MPM) are very costly, yet their impact on quality of life and overall survival of these...
IMPORTANCE
Some recently proposed frontline therapies for malignant pleural mesothelioma (MPM) are very costly, yet their impact on quality of life and overall survival of these patients remains arguable. Given the high social toll of this aggressive occupational cancer, it is paramount to establish the real clinical benefit of these treatments.
OBJECTIVE
To directly compare and analyze the statistical robustness of the 3 randomized clinical trials (RCTs) of frontline therapies recommended for MPM since 2003.
DESIGN, SETTING, AND PARTICIPANTS
This comparative effectiveness study assessed the following phase 3 RCTs: the Mesothelioma Cisplatin Pemetrexed Study (MPS) of cisplatin plus pemetrexed vs cisplatin; the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS) of cisplatin plus pemetrexed plus bevacizumab vs cisplatin plus pemetrexed; and the CheckMate743 (CM743) study of nivolumab plus ipilimumab vs cisplatin plus pemetrexed. Data collection dates for the RCTs ranged from April 1999 to April 2018. Data for this study were analyzed from February to October 2021.
MAIN OUTCOMES AND MEASURES
Patient selection criteria, superiority of the intervention groups, survival-inferred fragility index, and censoring patterns in each RCT.
RESULTS
A total of 1501 patients were included in the analysis (1170 men [77.9%]; range of median age for treatment groups, 60 [IQR, 19-84] to 69 [IQR, 65-75] years). A virtual comparison of overall survival in MAPS vs the CM743 study showed no statistically significant difference (hazard ratio [HR], 0.97 [95% CI, 0.79-1.20]; P = .79), and the survival-inferred fragility index in the intention-to-treat (ITT) populations was as low as 0.22% of the total sample size in MPS, -0.45% of the total sample size in MAPS, and 0.99% of the total sample size in the CM743 trial. Moreover, reverse restricted mean survival time (RMST) analysis of overall survival using RMST-difference (RMST-D) demonstrated differential censoring in the ITT population of the CM743 trial favoring the control group (0.56 [95% CI, 0.18-0.94]; P = .004) and in the nonepithelioid group (reverse RMST-D, 0.90 [95% CI, 0.001-1.79]; P = .048).
CONCLUSIONS AND RELEVANCE
This comparative effectiveness study found no survival benefit in the CM743 trial over MAPS, despite the inclusion of patients with worse prognosis in the latter trial. Moreover, the statistical conclusions of all the examined trials were shown to be extremely fragile, and the findings of differential censoring in the CM743 trial and in the ITT nonepithelial subset raised additional areas of concern. These findings suggest that selection criteria, fragility, and censoring patterns may affect the original conclusions drawn for the respective trials, casting a shadow on the real benefit. This model of analysis lays a rigorous groundwork extendable to trials of all cancer treatments before their registration.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Female; Humans; Male; Mesothelioma; Mesothelioma, Malignant; Middle Aged; Pemetrexed; Randomized Controlled Trials as Topic; Young Adult
PubMed: 35262715
DOI: 10.1001/jamanetworkopen.2022.1490 -
American Journal of Kidney Diseases :... Oct 2016Pemetrexed is an approved antimetabolite agent, now widely used for treating locally advanced or metastatic nonsquamous non-small cell lung cancer. Although no...
Pemetrexed is an approved antimetabolite agent, now widely used for treating locally advanced or metastatic nonsquamous non-small cell lung cancer. Although no electrolyte abnormalities are described in the prescribing information for this drug, several case reports have noted nephrogenic diabetes insipidus with associated acute kidney injury. We present a case of nephrogenic diabetes insipidus without severely reduced kidney function and propose a mechanism for the isolated finding. Severe hypernatremia can lead to encephalopathy and osmotic demyelination, and our report highlights the importance of careful monitoring of electrolytes and kidney function in patients with lung cancer receiving pemetrexed.
Topics: Adult; Antineoplastic Agents; Diabetes Insipidus, Nephrogenic; Humans; Male; Pemetrexed
PubMed: 27241854
DOI: 10.1053/j.ajkd.2016.04.016 -
Clinical Lung Cancer Jun 2022Better therapies are needed to improve survival in metastatic non-small cell lung cancer (NSCLC). Given the synergy of combination nab-paclitaxel and gemcitabine in...
BACKGROUND
Better therapies are needed to improve survival in metastatic non-small cell lung cancer (NSCLC). Given the synergy of combination nab-paclitaxel and gemcitabine in metastatic pancreatic cancer and their individual activity in advanced NSCLC, we sought to determine whether the same combination would confer a therapeutic benefit in the second-line therapy of recurrent or metastatic non-squamous (NSQ) NSCLC.
MATERIALS AND METHODS
This single-arm phase II trial of nab-paclitaxel and gemcitabine was performed from June 2015 to April 2020 at an academic referral cancer center. Patients with advanced NSQ-NSCLC whose disease progressed on first-line pemetrexed plus platinum +/- immunotherapy were enrolled. Patients received intravenous nab-paclitaxel 100 mg/m and gemcitabine 1000 mg/m on days 1 and 8 of each 21-day cycle. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Safety and tolerability were evaluated by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
RESULTS
Thirty-seven patients (15 men [41%] and 22 women [59%]; median age, 66 years [range, 41-81 years]) were accrued. ORR was 13.5% (95% CI, 2.5-24.5%). DCR was 59.5% (95% CI, 43.5-75.5%). Median PFS was 2.6 months (95% CI, 1.4-3.8 months). Median OS was 6.2 months (95% CI, 4.2-8.2 months). 1-year OS was 24% (95% CI, 10-38%). Safety and tolerability were similar to other second-line chemotherapies, although there was an 11% incidence of grade 2-3 pneumonitis.
CONCLUSION
Combination nab-paclitaxel and gemcitabine after platinum and pemetrexed for NSQ-NSCLC was not associated with greater efficacy than would be expected for single-agent chemotherapy in this setting. The higher-than-expected risk of pneumonitis was also concerning.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02303977 MICRO-ABSTRACT: In this phase II trial, 37 patients with metastatic non-squamous non-small cell lung cancer were treated with nab-paclitaxel/gemcitabine in second-line. ORR = 13.5% (95% CI, 2.5%-24.5%). Median PFS = 2.6 months (95% CI, 1.4-3.8 months). Median OS = 6.2 months (95% CI, 4.2-8.2 months). Nab-paclitaxel and gemcitabine was not associated with greater efficacy than would be expected for single-agent chemotherapy in this setting.
Topics: Aged; Albumins; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Deoxycytidine; Female; Humans; Lung Neoplasms; Male; Paclitaxel; Pemetrexed; Platinum; Gemcitabine
PubMed: 35393247
DOI: 10.1016/j.cllc.2022.02.004 -
European Journal of Medicinal Chemistry Dec 2017Malignant Pleural Mesothelioma (MPM) is an aggressive malignancy highly resistant to chemotherapy, with a response rate of 20% of patients and for this reason an... (Review)
Review
Malignant Pleural Mesothelioma (MPM) is an aggressive malignancy highly resistant to chemotherapy, with a response rate of 20% of patients and for this reason an efficient treatment is still a challenge. Platinum-based chemotherapy in association with a third-generation antifolate is the front-line standard of care whereas any second-line treatment was approved for MPM thus making it a pathology that evokes the need for new therapeutic agents. Different platinum-drugs were synthesised and tested as an option for patients who are not candidates to cisplatin-based therapy. Among these, monofunctional cationic antineoplastic platinum compounds received a special attention in the last decade. Alternative strategies to the commonly used combination-therapy resulted from the use of Mesenchymal Stromal Cells (MSC) widely used in the field of regenerative medicine and recently proposed as natural carriers for a selective delivery of chemotherapeutic agents and from the use of immune checkpoint and kinase inhibitors. The present short review shed light on the recent state of art and the future perspectives relative to MPM therapy.
Topics: Animals; Antineoplastic Agents; Cell- and Tissue-Based Therapy; Cisplatin; Drug Delivery Systems; Humans; Immunotherapy; Lung Neoplasms; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mesothelioma; Mesothelioma, Malignant; Organoplatinum Compounds; Pemetrexed; Pleural Neoplasms
PubMed: 28800871
DOI: 10.1016/j.ejmech.2017.07.063 -
International Journal of Molecular... Sep 2022Pleural mesothelioma (PM) is an aggressive cancer with poor prognosis and no effective therapies, mainly caused by exposure to asbestos. Antagonists of growth...
Pleural mesothelioma (PM) is an aggressive cancer with poor prognosis and no effective therapies, mainly caused by exposure to asbestos. Antagonists of growth hormone-releasing hormone (GHRH) display strong antitumor effects in many experimental cancers, including lung cancer and mesothelioma. Here, we aimed to determine whether GHRH antagonist MIA-690 potentiates the antitumor effect of cisplatin and pemetrexed in PM. In vitro, MIA-690, in combination with cisplatin and pemetrexed, synergistically reduced cell viability, restrained cell proliferation and enhanced apoptosis, compared with drugs alone. In vivo, the same combination resulted in a strong growth inhibition of MSTO-211H xenografts, decreased tumor cell proliferation and increased apoptosis. Mechanistically, MIA-690, particularly with chemotherapeutic drugs, inhibited proliferative and oncogenic pathways, such as MAPK ERK1/2 and cMyc, and downregulated cyclin D1 and B1 mRNAs. Inflammatory pathways such as NF-kB and STAT3 were also reduced, as well as oxidative, angiogenic and tumorigenic markers (iNOS, COX-2, MMP2, MMP9 and HMGB1) and growth factors (VEGF and IGF-1). Overall, these findings strongly suggest that GHRH antagonists of MIA class, such as MIA-690, could increase the efficacy of standard therapy in PM.
Topics: Cell Line, Tumor; Cisplatin; Cyclin D1; Cyclooxygenase 2; Growth Hormone-Releasing Hormone; HMGB1 Protein; Humans; Insulin-Like Growth Factor I; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mesothelioma; Mesothelioma, Malignant; NF-kappa B; Pemetrexed; Pleural Neoplasms; Vascular Endothelial Growth Factor A
PubMed: 36232554
DOI: 10.3390/ijms231911248