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1.
Cancer Immunol Immunother ; 73(7): 125, 2024 May 11.
Article in English | MEDLINE | ID: mdl-38733402

ABSTRACT

BACKGROUND: Despite the success of PD-1 blockade in recurrent/metastatic nasopharyngeal carcinoma (NPC), its effect for locoregionally advanced NPC (LANPC) remains unclear. This study aimed to evaluate the benefit of adding PD-1 blockade to the current standard treatment (gemcitabine and cisplatin IC  plus cisplatin CCRT ) for LANPC patients. METHODS: From January 2020 to November 2022, 347 patients with non-metastatic high-risk LANPC (stage III-IVA, excluding T3-4N0) were included. Of the 347 patients, 268 patients were treated with standard treatment (IC-CCRT), and 79 received PD-1 blockade plus IC-CCRT (PD-1 group). For the PD-1 group, PD-1 blockade was given intravenously once every 3 weeks for up to 9 cycles (3 induction and 6 adjuvant). The primary endpoint was disease-free survival (DFS) (i.e. freedom from local/regional/distant failure or death). The propensity score matching (PSM) with the ratio of 1:2 was performed to control confounding factors. RESULTS: After PSM analysis, 150 patients receiving standard treatment and 75 patients receiving additional PD-1 blockade remained in the current analysis. After three cycles of IC, the PD-1 group had significantly higher rates of complete response (defined as disappearance of all target lesions; 24% vs. 9%; P = 0.006) and complete biological response (defined as undetectable cell-free Epstein-Barr virus DNA, cfEBV DNA; 79% vs. 65%; P = 0.046) than that in the standard group. And the incidence of grade 3-4 toxicity during IC was 47% in the PD-1 group and 41% in the standard group, with no significant difference (P = 0.396). During follow-up period, additional PD-1 blockade to standard treatment improved 3-year DFS from 84 to 95%, with marginal statistical significance (HR, 0.28; 95%CI, 0.06-1.19; P = 0.064). CONCLUSION: Additiaonl PD-1 blockade to gemcitabine and cisplatin IC and adjuvant treatment results in significant improvement in tumor regression, cfEBV DNA clearance, superior DFS, and comparable toxicity profiles in high-risk LANPC patients.


Subject(s)
Chemoradiotherapy , Induction Chemotherapy , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms , Propensity Score , Humans , Male , Female , Nasopharyngeal Carcinoma/therapy , Nasopharyngeal Carcinoma/mortality , Nasopharyngeal Carcinoma/drug therapy , Middle Aged , Chemoradiotherapy/methods , Adult , Nasopharyngeal Neoplasms/therapy , Nasopharyngeal Neoplasms/mortality , Nasopharyngeal Neoplasms/drug therapy , Induction Chemotherapy/methods , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Immune Checkpoint Inhibitors/therapeutic use , Aged , Cisplatin/therapeutic use , Cisplatin/administration & dosage , Cisplatin/adverse effects , Deoxycytidine/analogs & derivatives , Deoxycytidine/therapeutic use , Deoxycytidine/administration & dosage , Retrospective Studies , Gemcitabine
2.
BMC Cancer ; 24(1): 578, 2024 May 11.
Article in English | MEDLINE | ID: mdl-38734620

ABSTRACT

OBJECTIVE: This study aims to develop a nomogram integrating inflammation (NLR), Prognostic Nutritional Index (PNI), and EBV DNA (tumor burden) to achieve personalized treatment and prediction for stage IVA NPC. Furthermore, it endeavors to pinpoint specific subgroups that may derive significant benefits from S-1 adjuvant chemotherapy. METHODS: A total of 834 patients diagnosed with stage IVA NPC were enrolled in this study and randomly allocated into training and validation cohorts. Multivariate Cox analyses were conducted to identify independent prognostic factors for constructing the nomogram. The predictive and clinical utility of the nomogram was assessed through measures including the AUC, calibration curve, DCA, and C-indexes. IPTW was employed to balance baseline characteristics across the population. Kaplan-Meier analysis and log-rank tests were utilized to evaluate the prognostic value. RESULTS: In our study, we examined the clinical features of 557 individuals from the training cohort and 277 from the validation cohort. The median follow-up period was 50.1 and 49.7 months, respectively. For the overall cohort, the median follow-up duration was 53.8 months. The training and validation sets showed 3-year OS rates of 87.7% and 82.5%, respectively. Meanwhile, the 3-year DMFS rates were 95.9% and 84.3%, respectively. We created a nomogram that combined PNI, NRI, and EBV DNA, resulting in high prediction accuracy. Risk stratification demonstrated substantial variations in DMFS and OS between the high and low risk groups. Patients in the high-risk group benefited significantly from the IC + CCRT + S-1 treatment. In contrast, IC + CCRT demonstrated non-inferior 3-year DMFS and OS compared to IC + CCRT + S-1 in the low-risk population, indicating the possibility of reducing treatment intensity. CONCLUSIONS: In conclusion, our nomogram integrating NLR, PNI, and EBV DNA offers precise prognostication for stage IVA NPC. S-1 adjuvant chemotherapy provides notable benefits for high-risk patients, while treatment intensity reduction may be feasible for low-risk individuals.


Subject(s)
Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms , Neoplasm Staging , Nomograms , Humans , Male , Female , Middle Aged , Nasopharyngeal Carcinoma/drug therapy , Nasopharyngeal Carcinoma/mortality , Nasopharyngeal Carcinoma/pathology , Chemotherapy, Adjuvant/methods , Prognosis , Nasopharyngeal Neoplasms/drug therapy , Nasopharyngeal Neoplasms/mortality , Nasopharyngeal Neoplasms/pathology , Inflammation , Adult , Nutrition Assessment , Herpesvirus 4, Human/isolation & purification , Tegafur/therapeutic use , Tegafur/administration & dosage , DNA, Viral , Drug Combinations , Oxonic Acid/therapeutic use , Oxonic Acid/administration & dosage , Aged , Kaplan-Meier Estimate
4.
Cancer Med ; 13(10): e7243, 2024 May.
Article in English | MEDLINE | ID: mdl-38752448

ABSTRACT

BACKGROUND: Toripalimab, combined with gemcitabine and cisplatin, has been approved as the first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (RM-NPC), representing a significant milestone as the first FDA-approved innovative therapy for this condition. Despite this achievement, there's a lack of data on the cost-effectiveness of toripalimab for RM-NPC patients in the American context. METHODS: To assess the cost-effectiveness of toripalimab plus chemotherapy versus chemotherapy alone, a 3-state partitioned survival model was constructed. The study involved participants with characteristics matching those in the JUPITER-02 trial. Cost and utility inputs were collected from literature. Main outcomes measured were quality-adjusted life year (QALY), and incremental cost-effectiveness ratio (ICER). Univariate and probabilistic sensitivity analyses, subgroup analyses, and scenario analyses were conducted to verify the robustness of results. RESULTS: The study found that the toripalimab regimen resulted in 4.390 QALYs at a cost of $361,813, while the chemotherapy-only regimen yielded 1.685 QALYs at a cost of $161,632. This translates to an ICER of $74,004/QALY, below the willingness-to-pay threshold of $150,000/QALY. Sensitivity analyses indicated that utility values, discount rate, and the price of toripalimab significantly impact INMB. With an 87.10% probability of being cost-effective at a $150,000/QALY threshold, the probabilistic sensitivity analysis supports toripalimab plus chemotherapy as a viable option. Scenario analysis showed that toripalimab remains cost-effective unless its price increases by 125%. Additionally, a simulated 15-year study period increases the ICER to $88,026/QALY. Subgroup analysis revealed ICERs of $76,538/QALY for PD-L1 positive and $70,158/QALY for PD-L1 negative groups. CONCLUSIONS: Toripalimab in combination with chemotherapy is likely to be a cost-effective alternative to standard chemotherapy for American patients with RM-NPC. This evidence can guide clinical and reimbursement decision-making in treating RM-NPC patients.


Subject(s)
Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols , Cost-Benefit Analysis , Nasopharyngeal Carcinoma , Neoplasm Recurrence, Local , Quality-Adjusted Life Years , Humans , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/economics , Nasopharyngeal Carcinoma/drug therapy , Neoplasm Recurrence, Local/drug therapy , Antibodies, Monoclonal, Humanized/economics , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , United States , Gemcitabine , Male , Female , Nasopharyngeal Neoplasms/drug therapy , Nasopharyngeal Neoplasms/pathology , Nasopharyngeal Neoplasms/economics , Nasopharyngeal Neoplasms/mortality , Deoxycytidine/analogs & derivatives , Deoxycytidine/therapeutic use , Deoxycytidine/administration & dosage , Deoxycytidine/economics , Cisplatin/administration & dosage , Cisplatin/economics , Cisplatin/therapeutic use , Middle Aged , Adult , Cost-Effectiveness Analysis
5.
Pak J Pharm Sci ; 37(2): 377-383, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38767105

ABSTRACT

Induction followed by concurrent chemoradiation (CCRT) is the standard of care for locally advanced nasopharyngeal carcinoma (LANPC). This study evaluated and compared the efficacy of two regimens of neoadjuvant chemotherapy along with CCRT in LANPC. Patients with LANPC were randomly divided in Group I (receiving neoadjuvant gemcitabine and cisplatin) and Group II (receiving neoadjuvant docetaxil, cisplatin and fluorouracil). Both groups also received concurrent single agent (i.e., cisplatin) chemotherapy and radiotherapy (70Gy). Treatment response was assessed at 8 weeks after the completion of CCRT using RECIST criteria. A total of 68 LANPC patients were enrolled. Group I comprised of 32 patients, with male to female ratio of 2.2, a mean (range, median) age of 38.6±11.3 (19-58, 36) years. Group II comprised of 36 patients, with male to female ratio of 3.5, mean (range, median) age of 40.9 ±11.6 (17-63, 40) years. The complete response was higher whereas the partial response was lower in Group I as compared to Group II (23/32 versus 16/36 and 06/32 versus 18/36, respectively). LANPC patients receiving gemcitabine plus cisplatin based neoadjuvant chemotherapy showed higher response, as compared with docetaxil, cisplatin and fluorouracil based neoadjuvant chemotherapy.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Cisplatin , Deoxycytidine , Fluorouracil , Gemcitabine , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms , Neoadjuvant Therapy , Humans , Male , Female , Cisplatin/administration & dosage , Cisplatin/therapeutic use , Adult , Middle Aged , Fluorouracil/administration & dosage , Fluorouracil/therapeutic use , Deoxycytidine/analogs & derivatives , Deoxycytidine/administration & dosage , Deoxycytidine/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Nasopharyngeal Carcinoma/drug therapy , Nasopharyngeal Carcinoma/pathology , Nasopharyngeal Neoplasms/drug therapy , Nasopharyngeal Neoplasms/pathology , Young Adult , Treatment Outcome , Adolescent
6.
Medicine (Baltimore) ; 103(19): e38017, 2024 May 10.
Article in English | MEDLINE | ID: mdl-38728499

ABSTRACT

Numerous inflammatory indicators have been demonstrated to be strongly correlated with tumor prognosis. However, the association between inflammatory indicators and the prognosis of patients with nasopharyngeal carcinoma (NPC) receiving treatment with programmed death receptor-1 (PD-1) immunosuppressant monoclonal antibodies remains uncertain. Inflammatory indicators in peripheral blood were collected from 161 NPC patients at 3 weeks after initial PD-1 treatment. Through univariate and multivariate analyses, as well as nomogram and survival analyses, we aimed to identify independent prognostic factors related to 1-year progression-free survival (PFS). Subsequently, a prognostic nomogram was devised, and its predictive and discriminating abilities were assessed utilizing calibration curves and the concordance index. Our univariate and multivariate analyses indicated that age (P = .012), M stage (P < .001), and systemic immune-inflammation index (SII) during the third week following initial PD-1 treatment (SII3, P = .005) were independently correlated with the 1-year PFS of NPC patients after PD-1 treatment. Notably, we constructed a novel nomogram based on the SII3, age, and M stage. Importantly, utilizing the derived cutoff point from the nomogram, the high-risk group exhibited significantly shorter PFS than did the low-risk group (P < .001). Furthermore, the nomogram demonstrated a greater concordance index for PFS than did the tumor node metastasis stage within the entire cohort. We successfully developed a nomogram that integrates the SII3 and clinical markers to accurately predict the 1-year PFS of NPC patients receiving PD-1 inhibitor treatment.


Subject(s)
Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms , Nomograms , Humans , Male , Female , Nasopharyngeal Carcinoma/drug therapy , Nasopharyngeal Carcinoma/mortality , Nasopharyngeal Carcinoma/blood , Middle Aged , Nasopharyngeal Neoplasms/drug therapy , Nasopharyngeal Neoplasms/mortality , Nasopharyngeal Neoplasms/blood , Adult , Aged , Immune Checkpoint Inhibitors/therapeutic use , Prognosis , Neoplasm Staging , Progression-Free Survival , Young Adult
7.
Int J Med Sci ; 21(7): 1204-1212, 2024.
Article in English | MEDLINE | ID: mdl-38818479

ABSTRACT

The mitochondrial unfolded protein response (UPRmt) is a pivotal cellular mechanism that ensures mitochondrial homeostasis and cellular survival under stress conditions. This study investigates the role of UPRmt in modulating the response of nasopharyngeal carcinoma cells to cisplatin-induced stress. We report that the inhibition of UPRmt via AEB5F exacerbates cisplatin cytotoxicity, as evidenced by increased lactate dehydrogenase (LDH) release and apoptosis, characterized by a surge in TUNEL-positive cells. Conversely, the activation of UPRmt with oligomycin attenuates these effects, preserving cell viability and reducing apoptotic markers. Immunofluorescence assays reveal that UPRmt activation maintains mitochondrial membrane potential and ATP production in the presence of cisplatin, countering the rise in reactive oxygen species (ROS) and inhibiting caspase-9 activation. These findings suggest that UPRmt serves as a cytoprotective mechanism in cancer cells, mitigating cisplatin-induced mitochondrial dysfunction and apoptosis. The data underscore the therapeutic potential of modulating UPRmt to improve the efficacy and reduce the side effects of cisplatin chemotherapy. This study provides a foundation for future research on the exploitation of UPRmt in cancer treatment, with the aim of enhancing patient outcomes by leveraging the cellular stress response pathways.


Subject(s)
Apoptosis , Cisplatin , Mitochondria , Reactive Oxygen Species , Unfolded Protein Response , Humans , Unfolded Protein Response/drug effects , Mitochondria/metabolism , Mitochondria/drug effects , Cisplatin/pharmacology , Cisplatin/therapeutic use , Apoptosis/drug effects , Cell Line, Tumor , Reactive Oxygen Species/metabolism , Membrane Potential, Mitochondrial/drug effects , Nasopharyngeal Neoplasms/pathology , Nasopharyngeal Neoplasms/drug therapy , Nasopharyngeal Neoplasms/metabolism , Nasopharyngeal Carcinoma/pathology , Nasopharyngeal Carcinoma/drug therapy , Nasopharyngeal Carcinoma/metabolism , Nasopharyngeal Carcinoma/genetics , Antineoplastic Agents/pharmacology , Cell Survival/drug effects
8.
Nat Commun ; 15(1): 4590, 2024 May 30.
Article in English | MEDLINE | ID: mdl-38816360

ABSTRACT

Nasopharyngeal carcinoma (NPC)-mediated immunosuppression within the tumor microenvironment (TME) frequently culminates in the failure of otherwise promising immunotherapies. In this study, we identify tumor-intrinsic FLI1 as a critical mediator in impairing T cell anti-tumor immunity. A mechanistic inquiry reveals that FLI1 orchestrates the expression of CBP and STAT1, facilitating chromatin accessibility and transcriptional activation of IDO1 in response to T cell-released IFN-γ. This regulatory cascade ultimately leads to augmented IDO1 expression, resulting in heightened synthesis of kynurenine (Kyn) in tumor cells. This, in turn, fosters CD8+ T cell exhaustion and regulatory T cell (Treg) differentiation. Intriguingly, we find that pharmacological inhibition of FLI1 effectively obstructs the CBP/STAT1-IDO1-Kyn axis, thereby invigorating both spontaneous and checkpoint therapy-induced immune responses, culminating in enhanced tumor eradication. In conclusion, our findings delineate FLI1-mediated Kyn metabolism as an immune evasion mechanism in NPC, furnishing valuable insights into potential therapeutic interventions.


Subject(s)
Indoleamine-Pyrrole 2,3,-Dioxygenase , Interferon-gamma , Kynurenine , Proto-Oncogene Protein c-fli-1 , STAT1 Transcription Factor , T-Lymphocytes, Regulatory , Tumor Microenvironment , Kynurenine/metabolism , Interferon-gamma/metabolism , Interferon-gamma/immunology , Animals , Proto-Oncogene Protein c-fli-1/metabolism , Proto-Oncogene Protein c-fli-1/genetics , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics , Tumor Microenvironment/immunology , Tumor Microenvironment/drug effects , Humans , Mice , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/metabolism , STAT1 Transcription Factor/metabolism , Cell Line, Tumor , Nasopharyngeal Carcinoma/immunology , Nasopharyngeal Carcinoma/metabolism , Nasopharyngeal Carcinoma/genetics , Nasopharyngeal Carcinoma/pathology , Nasopharyngeal Carcinoma/drug therapy , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/drug effects , Mice, Inbred C57BL , Nasopharyngeal Neoplasms/immunology , Nasopharyngeal Neoplasms/metabolism , Nasopharyngeal Neoplasms/pathology , Nasopharyngeal Neoplasms/drug therapy , Nasopharyngeal Neoplasms/genetics , Female , Gene Expression Regulation, Neoplastic/drug effects , Tumor Escape/drug effects , Mice, Knockout
9.
J Proteome Res ; 23(6): 2028-2040, 2024 Jun 07.
Article in English | MEDLINE | ID: mdl-38700954

ABSTRACT

Nasopharyngeal carcinoma (NPC) is a prevalent malignancy that usually occurs among the nose and throat. Due to mild initial symptoms, most patients are diagnosed in the late stage, and the recurrence rate of tumors is high, resulting in many deaths every year. Traditional radiotherapy and chemotherapy are prone to causing drug resistance and significant side effects. Therefore, searching for new bioactive drugs including anticancer peptides is necessary and urgent. LVTX-8 is a peptide toxin synthesized from the cDNA library of the spider Lycosa vittata, which is consisting of 25 amino acids. In this study, a series of in vitro cell experiments such as cell toxicity, colony formation, and cell migration assays were performed to exam the anticancer activity of LVTX-8 in NPC cells (5-8F and CNE-2). The results suggested that LVTX-8 significantly inhibited cell proliferation and migration of NPC cells. To find the potential molecular targets for the anticancer capability of LVTX-8, high-throughput proteomic and bioinformatics analysis were conducted on NPC cells. The results identified EXOSC1 as a potential target protein with significantly differential expression levels under LVTX-8+/LVTX-8- conditions. The results in this research indicate that spider peptide toxin LVTX-8 exhibits significant anticancer activity in NPC, and EXOSC1 may serve as a target protein for its anticancer activity. These findings provide a reference for the development of new therapeutic drugs for NPC and offer new ideas for the discovery of biomarkers related to NPC diagnosis. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium (https://proteomecentral.proteomexchange.org) via the iProX partner repository with the data set identifier PXD050542.


Subject(s)
Antineoplastic Agents , Cell Movement , Cell Proliferation , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms , Proteomics , Humans , Nasopharyngeal Carcinoma/drug therapy , Nasopharyngeal Carcinoma/metabolism , Nasopharyngeal Carcinoma/pathology , Proteomics/methods , Cell Line, Tumor , Cell Movement/drug effects , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Nasopharyngeal Neoplasms/drug therapy , Nasopharyngeal Neoplasms/metabolism , Nasopharyngeal Neoplasms/pathology , Spider Venoms/pharmacology , Spider Venoms/chemistry , Animals , Peptides/pharmacology , Peptides/chemistry , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/genetics
10.
Eur J Pharm Sci ; 198: 106789, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38710335

ABSTRACT

BACKGROUND: Cytoplasmic epidermal growth factor receptor (EGFR) is overexpressed in both nasopharyngeal carcinoma (NPC) and triple-negative breast cancer (TNBC), while clinical outcome and prognosis vary greatly among patients treated with gefitinib, and all patients eventually develop resistance to this agent. Therefore, we propose a new concept for synthesizing multitarget compounds and reveal new therapeutic strategies for NPC and TNBC expressing EGFR. METHODS: Compound H was synthesized in our previous study. Molecular docking, and cell thermal shift assays (CETSAs) and drug affinity responsive target stability(DARTS) were used to confirm the binding of compound H to EGFR and GLUT1. Methylthiazolyldiphenyl-tetrazolium bromide(MTT), annexin V-PE assays, mitochondrial membrane potential (MMP) assays, and animal models were used to evaluate the inhibitory effect of compound H on TNBC cell lines. Energy metabolism tests, Western blotting, and immunofluorescence staining were performed to evaluate the synergistic effects on EGFR- and glucose transporter type 1(GLUT1)-mediated energy metabolism. RESULTS: Compound H can simultaneously act on the EGFR tyrosine kinase ATP-binding site and inhibit GLUT1-mediated energy metabolism, resulting in reductions in ATP, MMP, intra-cellular lactic acid, and EGFR nuclear transfer. The anti-tumor activity of compound H is significantly superior to the combination of GLUT1 inhibitor BAY876 and EGFR inhibitor gefitinib. Compound H has remarkable anti-proliferative effects on TNBC MDA-MB231 cells, and importantly, no obvious toxicity effects of compound H were found in vivo. CONCLUSIONS: Synergistic effects of inhibition of EGFR- and GLUT1-mediated energy metabolism by compound H may present a new strategy for the treatment of TNBC and NPC.


Subject(s)
Antineoplastic Agents , ErbB Receptors , Glucose Transporter Type 1 , Nasopharyngeal Carcinoma , Triple Negative Breast Neoplasms , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/metabolism , Glucose Transporter Type 1/antagonists & inhibitors , Glucose Transporter Type 1/metabolism , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/metabolism , Humans , Animals , Cell Line, Tumor , Female , Nasopharyngeal Carcinoma/drug therapy , Nasopharyngeal Carcinoma/metabolism , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Molecular Docking Simulation , Nasopharyngeal Neoplasms/drug therapy , Nasopharyngeal Neoplasms/metabolism , Mice, Nude , Mice, Inbred BALB C , Gefitinib/pharmacology , Membrane Potential, Mitochondrial/drug effects , Mice
11.
BMC Immunol ; 25(1): 28, 2024 May 06.
Article in English | MEDLINE | ID: mdl-38710996

ABSTRACT

INTRODUCTION: Metronomic capecitabine used as an adjuvant therapy improves survival in patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC). This therapeutic approach may also contribute to improving immune function, consequently enhancing overall therapeutic efficacy. AIM: We aimed to evaluate the effect of metronomic capecitabine as adjuvant therapy on immune function and survival in cases of LA-NPC. SUBJECTS AND METHODS: 28 patients with LA-NPC were enrolled in the study and equally assigned to two groups of 14 each: experimental and control group. The experimental group received induction chemotherapy + concurrent chemotherapy + adjuvant chemotherapy as well as oral capecitabine at a dose of 650 mg/m² of body surface area twice daily for 1 year, with the option to discontinue in case of intolerance. The control group did not receive additional chemotherapy or targeted drugs after the induction chemotherapy + concurrent chemoradiotherapy; however, they were followed up regularly. Changes in immune function and survival were compared between the two groups. RESULTS: The median follow-up time was 43.5 months. One year after adjuvant chemotherapy, the experimental group showed higher levels of CD8 + cells, CD28 + CD8 + cells, and activated CD8 + cells compared to the control group (P < 0.05). The CD4/CD8 ratio and proportion of monocyte-derived dendritic cells were also higher in the experimental group than in the control group, but the difference was not statistically significant (P ≥ 0.05). Comparisons of 3-year overall survival, local-regional recurrence-free survival, progression-free survival, and distant metastasis-free survival between the two groups showed percentages of 92.9% vs. 78.6%, 92.9% vs. 92.9%, 78.6% vs. 71.4%, and 85.7% vs. 0.78 0.6% respectively, but these differences were not significant (P > 0 0.05 ). CONCLUSION: Metronomic capecitabine chemotherapy was observed to induce an immunomodulatory effect in LA-NPC. TRIAL REGISTRATION: NCT02958111, date of registration 04-11-2016.


Subject(s)
Administration, Metronomic , Capecitabine , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms , Humans , Capecitabine/administration & dosage , Capecitabine/therapeutic use , Male , Nasopharyngeal Carcinoma/drug therapy , Nasopharyngeal Carcinoma/immunology , Nasopharyngeal Carcinoma/mortality , Female , Middle Aged , Adult , Chemotherapy, Adjuvant/methods , Nasopharyngeal Neoplasms/drug therapy , Nasopharyngeal Neoplasms/immunology , CD8-Positive T-Lymphocytes/immunology , Aged , Neoplasm Staging , Treatment Outcome , Antimetabolites, Antineoplastic/administration & dosage , Antimetabolites, Antineoplastic/therapeutic use , Follow-Up Studies
12.
Nat Commun ; 15(1): 4343, 2024 May 21.
Article in English | MEDLINE | ID: mdl-38773197

ABSTRACT

Prodrugs have been explored as an alternative to conventional chemotherapy; however, their target specificity remains limited. The tumor microenvironment harbors a range of microorganisms that potentially serve as tumor-targeting vectors for delivering prodrugs. In this study, we harness bacteria-cancer interactions native to the tumor microbiome to achieve high target specificity for prodrug delivery. We identify an oral commensal strain of Lactobacillus plantarum with an intrinsic cancer-binding mechanism and engineer the strain to enable the surface loading of anticancer prodrugs, with nasopharyngeal carcinoma (NPC) as a model cancer. The engineered commensals show specific binding to NPC via OppA-mediated recognition of surface heparan sulfate, and the loaded prodrugs are activated by tumor-associated biosignals to release SN-38, a chemotherapy compound, near NPC. In vitro experiments demonstrate that the prodrug-loaded microbes significantly increase the potency of SN-38 against NPC cell lines, up to 10-fold. In a mouse xenograft model, intravenous injection of the engineered L. plantarum leads to bacterial colonization in NPC tumors and a 67% inhibition in tumor growth, enhancing the efficacy of SN-38 by 54%.


Subject(s)
Lactobacillus plantarum , Prodrugs , Xenograft Model Antitumor Assays , Prodrugs/pharmacology , Prodrugs/therapeutic use , Animals , Humans , Mice , Cell Line, Tumor , Nasopharyngeal Neoplasms/drug therapy , Nasopharyngeal Neoplasms/therapy , Nasopharyngeal Neoplasms/pathology , Nasopharyngeal Neoplasms/microbiology , Nasopharyngeal Carcinoma/drug therapy , Nasopharyngeal Carcinoma/therapy , Nasopharyngeal Carcinoma/pathology , Tumor Microenvironment/drug effects , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Mice, Nude , Female , Mice, Inbred BALB C
13.
Cell Death Dis ; 15(4): 279, 2024 Apr 18.
Article in English | MEDLINE | ID: mdl-38637504

ABSTRACT

Cisplatin (DDP)-based chemoradiotherapy is one of the standard treatments for nasopharyngeal carcinoma (NPC). However, the sensitivity and side effects of DDP to patients remain major obstacles for NPC treatment. This research aimed to study DDP sensitivity regulated by cancer-associated fibroblasts (CAFs) through modulating ferroptosis. We demonstrated that DDP triggered ferroptosis in NPC cells, and it inhibited tumor growth via inducing ferroptosis in xenograft model. CAFs secreted high level of FGF5, thus inhibiting DDP-induced ferroptosis in NPC cells. Mechanistically, FGF5 secreted by CAFs directly bound to FGFR2 in NPC cells, leading to the activation of Keap1/Nrf2/HO-1 signaling. Rescued experiments indicated that FGFR2 overexpression inhibited DDP-induced ferroptosis, and CAFs protected against DDP-induced ferroptosis via FGF5/FGFR2 axis in NPC cells. In vivo data further showed the protective effects of FGF5 on DDP-triggered ferroptosis in NPC xenograft model. In conclusion, CAFs inhibited ferroptosis to decrease DDP sensitivity in NPC through secreting FGF5 and activating downstream FGFR2/Nrf2 signaling. The therapeutic strategy targeting FGF5/FGFR2 axis from CAFs might augment DDP sensitivity, thus decreasing the side effects of DDP in NPC treatment.


Subject(s)
Cancer-Associated Fibroblasts , Ferroptosis , Nasopharyngeal Neoplasms , Humans , Cisplatin/pharmacology , Cisplatin/therapeutic use , Nasopharyngeal Carcinoma/drug therapy , Nasopharyngeal Carcinoma/metabolism , Kelch-Like ECH-Associated Protein 1/metabolism , Cancer-Associated Fibroblasts/metabolism , NF-E2-Related Factor 2/metabolism , Cell Line, Tumor , Nasopharyngeal Neoplasms/pathology , Drug Resistance, Neoplasm , Receptor, Fibroblast Growth Factor, Type 2/genetics , Receptor, Fibroblast Growth Factor, Type 2/metabolism , Fibroblast Growth Factor 5
14.
Colloids Surf B Biointerfaces ; 238: 113909, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38599076

ABSTRACT

Nasopharyngeal carcinoma (NPC) is a common head and neck malignancy, which is characterized by high incidence and aggression with poor diagnosis and limited therapeutic opportunity. The innovative strategy for achieving precise NPC active-targeting drug delivery has emerged as a prominent focus in clinical research. Here, a minimalist cancer cell membrane (CCM) shielded biomimetic nanoparticle (NP) was designed for NPC active-targeting therapy. Chemotherapeutant model drug doxorubicin (DOX) was loaded in polyamidoamine (PAMAM) dendrimer. The PAMAM/DOX (PD) NP was further shielded by human CNE-2 NPC CCM. Characterization results verified that the biomimetic PAMAM/DOX@CCM (abbreviated as PDC) NPs had satisfactory physical properties with high DOX-loading and excellent stability. Cell experiments demonstrated that the CNE-2 membrane-cloaked PDC NPs presented powerful cellular uptake in the sourcing cells by homologous targeting and adhesive interaction. Further in vivo results confirmed that this biomimetic nanoplatform had extended circulation and remarkable tumor-targeting capability, and the PDC NPs effectively suppressed the progression of CNE-2 tumors by systemic administration. This CCM-shielded biomimetic NP displayed a minimalist paradigm nanoplatform for precise NPC therapy, and the strategy of CCM-shielded biomimetic drug delivery system (DDS) has great potential for extensive cancer active-targeting therapy.


Subject(s)
Biomimetic Materials , Cell Membrane , Doxorubicin , Nanoparticles , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms , Humans , Doxorubicin/pharmacology , Doxorubicin/chemistry , Nanoparticles/chemistry , Nasopharyngeal Carcinoma/drug therapy , Nasopharyngeal Carcinoma/pathology , Biomimetic Materials/chemistry , Biomimetic Materials/pharmacology , Cell Membrane/chemistry , Cell Membrane/metabolism , Cell Membrane/drug effects , Animals , Nasopharyngeal Neoplasms/drug therapy , Nasopharyngeal Neoplasms/pathology , Dendrimers/chemistry , Mice , Cell Line, Tumor , Drug Delivery Systems , Antibiotics, Antineoplastic/pharmacology , Antibiotics, Antineoplastic/chemistry , Antibiotics, Antineoplastic/administration & dosage , Cell Proliferation/drug effects , Mice, Nude , Mice, Inbred BALB C , Biomimetics , Particle Size
15.
Front Biosci (Landmark Ed) ; 29(4): 160, 2024 Apr 23.
Article in English | MEDLINE | ID: mdl-38682208

ABSTRACT

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a malignant tumor associated with Epstein-Barr virus (EBV) infection. Chemoradiotherapy is the mainstream treatment for locally advanced NPC, and chemotherapeutic drugs are an indispensable part of NPC treatment. However, the toxic side-effects of chemotherapy drugs limit their therapeutic value, and new chemotherapy drugs are urgently needed for NPC. Silvestrol, an emerging natural plant anticancer molecule, has shown promising antitumor activity in breast cancer, melanoma, liver cancer, and other tumor types by promoting apoptosis in cancer cells to a greater extent than in normal cells. However, the effects of silvestrol on NPC and its possible molecular mechanisms have yet to be fully explored. METHODS: Cell counting kit-8 (CCK-8), cell scratch, flow cytometry, 5-ethynyl-2'-deoxyuridine (EdU), and Western blot (WB) assays were used to evaluate the effects of silvestrol on the cell viability, cell cycle, apoptosis, and migration of NPC cells. RNA sequencing (RNA-Seq) was used to study the effect of extracellular signal-regulated kinase (ERK) inhibitors on the cell transcriptome, and immunohistochemistry (IHC) to assess protein expression levels in patient specimens. RESULTS: Silvestrol inhibited cell migration and DNA replication of NPC cells, while promoting the expression of cleaved caspase-3, apoptosis, and cell cycle arrest. Furthermore, silvestrol altered the level of ERK phosphorylation. The ERK-targeted inhibitor LY3214996 attenuated silvestrol-mediated inhibition of NPC cell proliferation but not migration. Analysis of RNA-Seq data and WB were used to identify and validate the downstream regulatory targets of silvestrol. Expression of GADD45A, RAP1A, and hexokinase-II (HK2) proteins was inhibited by silvestrol and LY3214996. Finally, IHC revealed that GADD45A, RAP1A, and HK2 protein expression was more abundant in cancer tissues than in non-tumor tissues. CONCLUSIONS: Silvestrol inhibits the proliferation of NPC cells by targeting ERK phosphorylation. However, the inhibition of NPC cell migration by silvestrol was independent of the Raf-MEK-ERK pathway. RAP1A, HK2, and GADD45A may be potential targets for the action of silvestrol.


Subject(s)
Benzofurans , GADD45 Proteins , Hexokinase , MAP Kinase Signaling System , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms , rap1 GTP-Binding Proteins , Humans , Apoptosis/drug effects , Cell Cycle Proteins/metabolism , Cell Cycle Proteins/genetics , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , MAP Kinase Signaling System/drug effects , Nasopharyngeal Carcinoma/drug therapy , Nasopharyngeal Carcinoma/genetics , Nasopharyngeal Carcinoma/pathology , Nasopharyngeal Neoplasms/drug therapy , Nasopharyngeal Neoplasms/genetics , Nasopharyngeal Neoplasms/pathology , Hexokinase/genetics , Hexokinase/metabolism , rap1 GTP-Binding Proteins/genetics , rap1 GTP-Binding Proteins/metabolism , GADD45 Proteins/genetics , GADD45 Proteins/metabolism
16.
Eur J Radiol ; 175: 111438, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38613869

ABSTRACT

OBJECTIVE: To establish nomograms integrating multiparametric MRI radiomics with clinical-radiological features to identify the responders and non-responders to induction chemotherapy (ICT) in nasopharyngeal carcinoma (NPC). METHODS: We retrospectively analyzed the clinical and MRI data of 168 NPC patients between December 2015 and April 2022. We used 3D-Slicer to segment the regions of interest (ROIs) and the "Pyradiomic" package to extract radiomics features. We applied the least absolute shrinkage and selection operator regression to select radiomics features. We developed clinical-only, radiomics-only, and the combined clinical-radiomics nomograms using logistic regression analysis. The receiver operating characteristic curves, DeLong test, calibration, and decision curves were used to assess the discriminative performance of the models. The model was internally validated using 10-fold cross-validation. RESULTS: A total of 14 optimal features were finally selected to develop a radiomic signature, with an AUC of 0.891 (95 % CI, 0.825-0.946) in the training cohort and 0.837 (95 % CI, 0.723-0.932) in the testing cohort. The nomogram based on the Rad-Score and clinical-radiological factors for evaluating tumor response to ICT yielded an AUC of 0.926 (95 % CI, 0.875-0.965) and 0.901 (95 % CI, 0.815-0.979) in the two cohorts, respectively. Decision curves demonstrated that the combined clinical-radiomics nomograms were clinically useful. CONCLUSION: Nomograms integrating multiparametric MRI-based radiomics and clinical-radiological features could non-invasively discriminate ICT responders from non-responders in NPC patients.


Subject(s)
Induction Chemotherapy , Multiparametric Magnetic Resonance Imaging , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms , Nomograms , Humans , Male , Female , Nasopharyngeal Carcinoma/diagnostic imaging , Nasopharyngeal Carcinoma/drug therapy , Multiparametric Magnetic Resonance Imaging/methods , Middle Aged , Nasopharyngeal Neoplasms/diagnostic imaging , Nasopharyngeal Neoplasms/drug therapy , Retrospective Studies , Adult , Treatment Outcome , Aged , Young Adult , Radiomics
17.
Cell Death Dis ; 15(3): 237, 2024 Mar 30.
Article in English | MEDLINE | ID: mdl-38555280

ABSTRACT

End-stage nasopharyngeal carcinoma (NPC) has unsatisfactory survival. The limited benefit of chemotherapy and the scarcity of targeted drugs are major challenges in NPC. New approaches to treat late-stage NPC are urgently required. In this study, we explored whether the dual PI3K/mTOR inhibitor, PQR309, exerted a favorable antineoplastic effect and sensitized the response to gemcitabine in NPC. We observed that PI3K expression was positive and elevated in 14 NPC cell lines compared with that in normal nasopharygeal cell lines. Patients with NPC with higher PI3K levels displayed poorer prognosis. We subsequently showed that PQR309 alone effectively decreased the viability, invasiveness, and migratory capability of NPC cells and neoplasm development in mice xenograft models, and dose-dependently induced apoptosis. More importantly, PQR309 remarkably strengthened the anti-NPC function of gemcitabine both in vivo and in vitro. Mechanistically, PQR309 sensitized NPC to gemcitabine by increasing caspase pathway-dependent apoptosis, blocking GSK-3ß and STAT3/HSP60 signaling, and ablating epithelial-mesenchyme transition. Thus, targeting PI3K/mTOR using PQR309 might represent a treatment option to promote the response to gemcitabine in NPC, and provides a theoretical foundation for the study of targeted drugs combined with chemotherapy for NPC.


Subject(s)
Nasopharyngeal Neoplasms , Phosphatidylinositol 3-Kinases , STAT3 Transcription Factor , Humans , Animals , Mice , Nasopharyngeal Carcinoma/drug therapy , Nasopharyngeal Carcinoma/metabolism , Glycogen Synthase Kinase 3 beta/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Gemcitabine , Signal Transduction , TOR Serine-Threonine Kinases/metabolism , Protein Kinase Inhibitors/pharmacology , Phosphoinositide-3 Kinase Inhibitors/pharmacology , MTOR Inhibitors , Angiogenesis Inhibitors/pharmacology , Nasopharyngeal Neoplasms/pathology , Cell Line, Tumor , Cell Proliferation , Apoptosis , Proto-Oncogene Proteins c-akt/metabolism
18.
Sci Rep ; 14(1): 6681, 2024 03 20.
Article in English | MEDLINE | ID: mdl-38509141

ABSTRACT

Improving drug sensitivity is an important strategy in chemotherapy of cancer and accumulating evidence indicates that miRNAs are involved in the regulation of drug sensitivity, but the specific mechanism is still unclear. Our previous study has found that miR-296-5p was significantly downregulated in nasopharyngeal carcinoma (NPC). Here, we aim to explore whether miR-296-5p is involved in regulating cisplatin sensitivity in NPC by regulating STAT3/KLF4 signaling axis. The cell proliferation and clonogenic capacity of NPC cells were evaluated by CCK8 Assay and plate colony assay, respectively. The Annexin V-FITC staining kit was used to determine and quantify the apoptotic cells using flow cytometry. The drug efflux ability of NPC cells were determined by Rhodamine 123 efflux experiment. The expression of miR-296-5p, apoptosis-related genes and protein in NPC cell lines were detected by qPCR and Western blot, respectively. Animal study was used to evaluate the sensitivity of NPC cells to DDP treatment in vivo. Our results showed that elevated miR-296-5p expression obviously promoted the sensitivity of NPC cells to DDP by inhibiting cell proliferation and clonogenic capacity, and inducing apoptosis. In addition, we found that miR-296-5p inhibited the expression of STAT3 and KLF4 in NPC cells, while overexpression of exogenous STAT3 reversed miR-296-5p-mediated enhancement in cell death of DDP-treated NPC cells. In vivo studies further confirmed that miR-296-5p promotes the sensitivity of NPC cells to DDP treatment. miRNA-296-5p enhances the drug sensitivity of nasopharyngeal carcinoma cells to cisplatin via STAT3/KLF4 signaling pathway.


Subject(s)
MicroRNAs , Nasopharyngeal Neoplasms , Animals , Nasopharyngeal Carcinoma/drug therapy , Nasopharyngeal Carcinoma/genetics , Nasopharyngeal Carcinoma/metabolism , Cisplatin/pharmacology , Cisplatin/therapeutic use , Cisplatin/metabolism , Nasopharyngeal Neoplasms/drug therapy , Nasopharyngeal Neoplasms/genetics , Nasopharyngeal Neoplasms/metabolism , Cell Line, Tumor , MicroRNAs/genetics , MicroRNAs/metabolism , Signal Transduction , Cell Proliferation , Gene Expression Regulation, Neoplastic , Drug Resistance, Neoplasm/genetics
19.
Anticancer Drugs ; 35(6): 501-511, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38478015

ABSTRACT

Taxol is widely used in the treatment of nasopharyngeal carcinoma (NPC); nevertheless, the acquired resistance of NPC to Taxol remains one of the major obstacles in clinical treatment. In this study, we aimed to investigate the role and mechanism of insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) in Taxol resistance of NPC. Taxol-resistant NPC cell lines were established by exposing to gradually increased concentration of Taxol. Relative mRNA and protein levels were tested using qRT-PCR and western blot, respectively. NPC cell viability and apoptosis were assessed by cell counting kit-8 and flow cytometry analysis, respectively. Cell migration and invasion capacities were measured using transwell assay. Interaction between IGF2BP1 and AKT2 was examined by RNA immunoprecipitation assay. The N6-methyladenosine level of AKT2 was tested using methylated RNA immunoprecipitation-qPCR. IGF2BP1 expression was enhanced in Taxol-resistant NPC cell lines. Knockdown of IGF2BP1 strikingly enhanced the sensitivity of NPC cells to Taxol and repressed the migration and invasion of NPC cells. Mechanistically, IGF2BP1 elevated the expression of AKT2 by increasing its mRNA stability. Furthermore, overexpression of AKT2 reversed the inhibitory roles of IGF2BP1 silence on Taxol resistance and metastasis. Our results indicated that IGF2BP1 knockdown enhanced the sensitivity of NPC cells to Taxol by decreasing the expression of AKT2, implying that IGF2BP1 might be promising candidate target for NPC treatment.


Subject(s)
Apoptosis , Cell Movement , Drug Resistance, Neoplasm , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms , Paclitaxel , Proto-Oncogene Proteins c-akt , RNA-Binding Proteins , Humans , Paclitaxel/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolism , Nasopharyngeal Carcinoma/pathology , Nasopharyngeal Carcinoma/drug therapy , Nasopharyngeal Carcinoma/metabolism , Nasopharyngeal Carcinoma/genetics , Drug Resistance, Neoplasm/drug effects , Nasopharyngeal Neoplasms/drug therapy , Nasopharyngeal Neoplasms/pathology , Nasopharyngeal Neoplasms/metabolism , Nasopharyngeal Neoplasms/genetics , Cell Movement/drug effects , Apoptosis/drug effects , Cell Line, Tumor , Antineoplastic Agents, Phytogenic/pharmacology , Up-Regulation , Cell Proliferation/drug effects , Adenosine/analogs & derivatives , Adenosine/pharmacology , Gene Expression Regulation, Neoplastic/drug effects
20.
J Med Econ ; 27(sup3): 1-8, 2024.
Article in English | MEDLINE | ID: mdl-38488887

ABSTRACT

AIMS: To estimate, in the setting of recurrent or metastatic nasopharyngeal carcinoma (R/M NPC) for an assumed 1,207 incident US cases in 2024, (1) the cost-efficiency of a toripalimab-gemcitabine-cisplatin regimen compared to a similar pembrolizumab regimen; and (2) the budget-neutral expanded access to additional toripalimab cycles and regimens afforded by the accrued savings. METHODS: Simulation modeling utilized two cost inputs (wholesale acquisition cost (WAC) at market entry and an ex ante toripalimab price point of 80% of pembrolizumab average sales price (ASP)) and drug administration costs over 1 and 2 years of treatment with treatment rates ranging from 45% to 90%. In the absence of trial data for pembrolizumab-gemcitabine-cisplatin in R/M NPC, it is assumed that such a regimen would be comparable to toripalimab-gemcitabine-cisplatin in efficacy and safety. RESULTS: In the models utilizing the WAC, toripalimab saves $2,223 per patient per cycle and $40,014 over 1 year of treatment ($77,805 over 2 years). Extrapolated to the 1,207-patient panel, estimated 1-year savings range from $21,733,702 (45% treatment rate) to $43,467,404 (90% rate). Reallocating these savings permits budget-neutral expanded access to an additional 2,359 (45% rate) to 4,717 (90% rate) toripalimab maintenance cycles or to an additional 126 (45% rate) to 252 (90%) full 1-year toripalimab regimens with all agents. Two-year savings range from $42,259,976 (45% rate) to $84,519,952 (90% rate). Reallocating these efficiencies provides expanded access, ranging from an additional 4,586 (45% rate) to 9,172 (90% rate) toripalimab cycles or to an additional 128-257 full 2-year toripalimab regimens. The ex ante ASP model showed similar results. CONCLUSION: This simulation demonstrates that treatment with toripalimab generates savings that enable budget-neutral funding for up to an additional 252 regimens with toripalimab-gemcitabine-cisplatin for one full year, the equivalent of approximately 21% of the 2024 incident cases of R/M NPC in the US.


An estimated 1,207 patients will be diagnosed with late-stage nasopharyngeal cancer in the US in 2024. Toripalimab is a novel PD-1 inhibitor drug approved by the US Food and Drug Administration on October 27, 2023 as first-line treatment for patients with recurrent or metastatic nasopharyngeal cancer when used in combination with gemcitabine and cisplatin. We conducted economic evaluations of the costs of this toripalimab regimen versus the costs of a similar regimen with the PD-1 inhibitor pembrolizumab. Our simulation models used two pricing scenarios: the wholesale acquisition cost (WAC) or "list price" at market entry and, as no average sales price (ASP) will be available for toripalimab for several quarters, an estimated toripalimab price point of 80% of the pembrolizumab ASP. We compared the savings in each scenario when between 45% and 90% of the 1,207 patients are treated with the toripalimab regimen. We then evaluated how these savings could be re-allocated, on a budget-neutral basis and without requiring extra cash outlays, to provide more patients with access to toripalimab treatment; specifically, how many toripalimab doses and how many full toripalimab regimens could be purchased to provide more patients with treatment. We found that, if 90% of new cases of recurrent or metastatic nasopharyngeal cancer were treated with toripalimab over 1 year, these savings are enough to purchase up to 4,717 additional doses on a budget-neutral basis, which could provide up to an additional 252 newly diagnosed patients with 1 year of treatment with toripalimab. In combination with gemcitabine and cisplatin, toripalimab can markedly improve access to care for patients with recurrent or metastatic nasopharyngeal cancer in a cost-responsible way.


Subject(s)
Antibodies, Monoclonal, Humanized , Gemcitabine , Nasopharyngeal Neoplasms , Humans , Cisplatin/therapeutic use , Nasopharyngeal Carcinoma/drug therapy , Immune Checkpoint Inhibitors/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasm Recurrence, Local/drug therapy , Deoxycytidine/therapeutic use , Nasopharyngeal Neoplasms/drug therapy , Nasopharyngeal Neoplasms/pathology
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