Complete response to PD-1 blockade following EBV-specific T-cell therapy in metastatic nasopharyngeal carcinoma.
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ABSTRACT:
SUBMITTER: Smith C
PROVIDER: S-EPMC7979738 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In this single arm non-randomized phase II trial, 40 patients with recurrent/metastatic EBV-positive nasopharyngeal carcinoma who failed prior chemotherapy received nivolumab 3 mg/kg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks. The best overall objective response rate was 38% with a median progression-free and overall survival of 5.3 and 19.5 months, respectively. This regimen was well-tolerated and treatment-related adverse events requiring discontinuation were low. There was no correlation of response with PD-L1 expression or tumor mutation burden, however patients with low plasma circulating EBV-DNA titre (<7,800 IU/ml) showed a trend to better response and progression-free survival. Deep immunophenotyping of pre- and on-treatment tumor biopsies demonstrated early activation of the adaptive immune response, with T-cell cytotoxicity seen in responders prior to any clinically evident response. Profiling immune-subpopulations also identified a specific PD-1 and CTLA-4 expressing CD8 subpopulation that predicted for response to combined immune checkpoint blockade in nasopharyngeal carcinoma.
2023-04-13 | GSE224450 | GEO
Project description:PD-L1 expression is a feature of Epstein-Barr virus (EBV) associated malignancies such as nasopharyngeal carcinoma (NPC). Here, we found that EBV-induced latent membrane protein 1 (LMP1) and IFN-? pathways cooperate to regulate programmed cell death protein 1 ligand (PD-L1). Expression of PD-L1 was higher in EBV positive NPC cell lines compared with EBV negative cell lines. PD-L1 expression could be increased by exogenous and endogenous induction of LMP1 induced PD-L1. In agreement, expression of PD-L1 was suppressed by knocking down LMP1 in EBV positive cell lines. We further demonstrated that LMP1 up-regulated PD-L1 through STAT3, AP-1, and NF-?B pathways. Besides, IFN-? was independent of but synergetic with LMP1 in up-regulating PD-L1 in NPC. Furthermore, we showed that PD-L1 was associated with worse disease-free survival in NPC patients. These results imply that blocking both the LMP1 oncogenic pathway and PD-1/PD-L1 checkpoints may be a promising therapeutic approach for EBV positive NPC patients.
| S-EPMC4322961 | biostudies-literature
Project description:Programmed death-1 (PD-1) is an immunosuppressive receptor functionally bound with programmed death-ligand 1 (PD-L1), which has been reported in various malignancies. However, only a few studies are available for the clinical significance of PD-1/PD-L1 in nasopharyngeal carcinoma (NPC). In this study, we aim to investigate alterations in PD-1/PD-L1 by using immunohistochemistry analysis in a cohort of consecutively enrolled NPC patients (n?=?99). To further analyse the correlation between PD-1/PD-L1 and factors involved in clinico-pathology, haematologic biomarkers, EBV-DNA load and outcomes, we collected clinical data for statistical analysis. We observed that lower haemoglobin (HB) and Body Mass Index (BMI) levels were associated with high levels of PD-L1 staining in NPC patients. Importantly, our results suggested that PD-L1 might be a negative indicator for NPC patients. In contrast, a correlation between the PD-1/PD-L1 level and EBV load was not identified. Moreover, PD-1 positivity was suggested to not be significantly correlated with clinical outcomes. Taken together, our results revealed that PD-L1 might be a potential prognostic biomarker for NPC patients. However, further studies are needed to clarify the underlying mechanism of EBV status in the immunosuppression process induced by the PD-1/PD-L1 axis.
| S-EPMC5335261 | biostudies-literature
Project description:Nasopharyngeal carcinoma (NPC) is highly incident in southern China. Distant metastasis is the leading cause of death in NPC patients. However, the phenotypical feature of this patient population is largely undefined. The current study aimed to categorize metastatic NPC patients into novel subgroups based on their EBV DNA trajectories. In this retrospective study, 446 eligible patients with metastatic NPC treated at Sun Yat-Sen University Cancer Center between 2012 and 2016 were analyzed. Using a mixture model analysis, we identified distinct trajectories based on longitudinal EBV DNA measurements. We evaluated their associations with metastatic NPC mortality using Cox regression analysis. The two-class trajectory model provided the best fit, in which 272 patients were classified as non-sustained EBV DNA class and 174 patients as sustained EBV DNA class. After a median follow-up of 60.8 months, the median OS was 61.7 months in the sustained EBV DNA clearance class versus 20.0 months in the non-sustained EBV DNA clearance class (P<0.001). Compared with patients in the non-sustained EBV DNA clearance class, patients in the sustained EBV DNA clearance class demonstrated superior PFS (HR, 3.238; 95% CI, 2.601-4.032; P<0.001). Forty-three patients experienced disease-free for longer than 36 months, defined as long-term survivors (LTS). Notably, 41 patients were presented in the sustained EBV DNA clearance class (95.3%), along with only 2 patients in the non-sustained EBV DNA clearance class. Collectively, we identified two EBV DNA trajectory sub-phenotypes of patients with metastatic NPC, providing more reliable survival information for physicians and patients during their informed decision-making process.
| S-EPMC8414373 | biostudies-literature
Project description:Nasopharyngeal carcinoma (NPC) is a rare cancer of the nasopharyngeal mucosa with a specific geographic predisposition. NPC is often associated with Epstein-Barr Virus (EBV) infection and as a result contains many characteristic biomarkers. Treatment of locally-contained NPC is generally achieved through use of radiotherapy (RT), as part of a multimodality treatment regimen. Induction chemotherapy followed by concurrent RT and platinum-based chemotherapy regimen has emerged as the definitive treatment of choice for locoregionally-advanced NPC. Recently, immunotherapy is finding a role in the treatment of recurrent or metastatic NPC. Immune checkpoint blockade therapies targeted against the programmed death-1 (PD-1) receptor have demonstrated efficacy in early phase clinical trials, with ongoing phase III trials in effect. Biomarkers for treatment efficacy remain an ongoing area of investigation, with important prognostic implications on the horizon.
| S-EPMC8657235 | biostudies-literature
Project description:Background/objectivesOral maintenance chemotherapy can effectively prolong overall survival (OS) in many types of metastatic cancer, but its role in metastatic nasopharyngeal carcinoma (mNPC) is unclear. In this study, the efficacy of oral maintenance chemotherapy in mNPC and the effectiveness of circulating tumor EBV-DNA for screening patients were evaluated.MethodsBetween June 2016 and December 2017, 141 patients with mNPC who received platinum-based systemic chemotherapy were included (median follow-up time, 21 months). Patients were classified into two groups according to the administration of oral maintenance chemotherapy. Plasma samples were collected before, during, and after treatment for the measurement of circulating EBV DNA.ResultsThe 2-year OS was higher for patients who received maintenance chemotherapy than for patients without maintenance chemotherapy (78.9% vs 62.7%, P = .016). Patients with undetectable posttreatment EBV-DNA after 4-6 cycles of systemic chemotherapy (n = 73) had a higher 2-year OS than that of patients with detectable EBV-DNA (n = 68) (82.16% vs 51.45%, P = .001). For patients with undetectable posttreatment EBV-DNA, OS was better for those with maintenance chemotherapy than for those without (86.7% vs 73%, P = .027). For patients with detectable posttreatment EBV-DNA, maintenance chemotherapy did not improve outcomes (49.5% vs 55.4%, P = .824). The most common acute events were hematological toxicity, and all were tolerable and curable.ConclusionsOral maintenance chemotherapy with S1 or capecitabine can improve OS in mNPC. Posttreatment EBV-DNA was not only an independent prognosis factor for mNPC but also can screen out beneficiaries of maintenance chemotherapy.
| S-EPMC7163084 | biostudies-literature
Project description:Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV) associated malignancy with high prevalence in Southern Chinese. In order to assess whether defects of EBV-specific immunity may contribute to the tumor, the phenotype and function of circulating T-cells and tumor infiltrating lymphocytes (TILs) were investigated in untreated NPC patients. Circulating naïve CD3+CD45RA+ and CD4+CD25- cells were decreased, while activated CD4+CD25+ T-cells and CD3-CD16+ NK-cells were increased in patients compared to healthy donors. The frequency of T-cells recognizing seven HLA-A2 restricted epitopes in LMP1 and LMP2 was lower in the patients and remained low after stimulation with autologous EBV-carrying cells. TILs expanded in low doses of IL-2 exhibited an increase of CD3+CD4+, CD3+CD45RO+ and CD4+CD25+ cells and 2 to 5 fold higher frequency of LMP1 and LMP2 tetramer positive cells compared to peripheral blood. EBV-specific cytotoxicity could be reactivated from the blood of most patients, whereas the TILs lacked cytotoxic activity and failed to produce IFNgamma upon specific stimulation. Thus, EBV-specific rejection responses appear to be functionally inactivated at the tumor site in NPC.
| S-EPMC2048575 | biostudies-literature
Project description:Immunotherapies that block inhibitory checkpoint receptors on T cells have transformed the clinical care of patients with cancer1. However, whether the T cell response to checkpoint blockade relies on reinvigoration of pre-existing tumor-infiltrating lymphocytes or on recruitment of novel T cells remains unclear2-4. Here we performed paired single-cell RNA and T cell receptor sequencing on 79,046 cells from site-matched tumors from patients with basal or squamous cell carcinoma before and after anti-PD-1 therapy. Tracking T cell receptor clones and transcriptional phenotypes revealed coupling of tumor recognition, clonal expansion and T cell dysfunction marked by clonal expansion of CD8+CD39+ T cells, which co-expressed markers of chronic T cell activation and exhaustion. However, the expansion of T cell clones did not derive from pre-existing tumor-infiltrating T lymphocytes; instead, the expanded clones consisted of novel clonotypes that had not previously been observed in the same tumor. Clonal replacement of T cells was preferentially observed in exhausted CD8+ T cells and evident in patients with basal or squamous cell carcinoma. These results demonstrate that pre-existing tumor-specific T cells may have limited reinvigoration capacity, and that the T cell response to checkpoint blockade derives from a distinct repertoire of T cell clones that may have just recently entered the tumor.
| S-EPMC6689255 | biostudies-literature
Project description:BackgroundTreatment options for patients with recurrent/metastatic nasopharyngeal carcinoma (RM-NPC) are not clear after progression on previous treatment with PD-(L)1 inhibitor; critical gaps in evidence remain for such cases. Immunotherapy combined with antiangiogenic therapy has been reported to have synergistic antitumor activity. Therefore, we evaluated the efficacy and safety of camrelizumab plus famitinib in patients with RM-NPC who failed treatment with PD-1 inhibitor-containing regimens.MethodsThis multicenter, adaptive Simon minimax two-stage, phase II study enrolled patients with RM-NPC refractory to at least one line of systemic platinum-containing chemotherapy and anti-PD-(L)1 immunotherapy. The patient received camrelizumab 200 mg every 3 weeks and famitinib 20 mg once per day. The primary endpoint was objective response rate (ORR), and the study could be stopped early as criterion for efficacy was met (>5 responses). Key secondary endpoints included time to response (TTR), disease control rate (DCR), progression-free survival (PFS), duration of response (DoR), overall survival (OS), and safety. This trial was registered with ClinicalTrials.gov, NCT04346381.FindingsBetween October 12, 2020, and December 6, 2021, a total of 18 patients were enrolled since six responses were observed. The ORR was 33.3% (90% CI, 15.6-55.4) and the DCR was 77.8% (90% CI, 56.1-92.0). The median TTR was 2.1 months, the median DoR was 4.2 months (90% CI, 3.0-not reach), and the median PFS was 7.2 months (90% CI, 4.4-13.3), with a median follow-up duration of 16.7 months. Treatment-related adverse events (TRAEs) of grade ≥3 were reported in eight (44.4%) patients, with the most common being decreased platelet count and/or neutropenia (n = 4, 22.2%). Treatment-related serious AEs occurred in six (33.3%) patients, and no deaths occurred due to TRAEs. Four patients developed grade ≥3 nasopharyngeal necrosis; two of them developed grade 3-4 major epistaxis, and they were cured by nasal packing and vascular embolization.InterpretationCamrelizumab plus famitinib exhibited encouraging efficacy and tolerable safety profiles in patients with RM-NPC who failed frontline immunotherapy. Further studies are needed to confirm and expand these findings.FundingJiangsu Hengrui Pharmaceutical Co., Ltd.
| S-EPMC10319986 | biostudies-literature
Project description:Introduction: The prognostic role of plasma Epstein-Barr virus (EBV) DNA clearance when intensity-modulated radiotherapy (IMRT) and the 8th edition of American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) TNM Staging Classification are fully implemented remains undeciphered. We investigated if its half-life clearance during radical treatment for non-metastatic nasopharyngeal carcinoma (NPC) was an early prognosticator. Patients and methods: Patients with previously untreated non-metastatic NPC were prospectively treated with radical IMRT and concurrent chemotherapy +/- induction/adjuvant chemotherapy from 2014 to 2018. Their plasma EBV DNA was measured immediately before treatment followed by weekly schedules until 0 copy/ml in two consecutive measurements. Cox regression models were employed to identify prognostic factors. Results: Forty-five patients were prospectively recruited and analyzed. After a median follow-up of 30.3 months, 2 (4.5%), 1 (2.3%), and 6 (13.6%) patients experienced local, regional, and distant relapses, respectively. The median half-life clearance of plasma EBV DNA was 7.92 days. Those with half-life clearance of >15 days had a worse 3-years progression-free survival (PFS) (79.5 vs. 25.0%, p = 0.005), distant metastasis-free survival (DMFS) (85.0 vs. 31.3%, p = 0.009), and overall survival (OS) (91.3 vs. 75.0%, p = 0.024) when compared to those with a shorter half-life. Multivariable analyses demonstrated that only half-life (>15 days) was prognostic of DMFS [HR (95% CI): 4.91 (1.31; 18.39), p = 0.01] and OS [HR (95% CI): 5.24 (1.06; 26.05)] while half-life (>15 days) [HR (95% CI): 5.14 (1.28; 22.73), p = 0.02] and sum of pretreatment gross tumor volumes of the primary nasopharyngeal tumor and the radiologically positive neck nodes (GTV_P+N) [HR (95% CI): 1.01 (1.00; 1.03), p = 0.02] were prognostic of PFS. Conclusion: The half-life clearance of plasma EBV DNA was prognostic in non-metastatic NPC staged and treated in the contemporary era. Earlier biomarker surveillance during treatment should be considered. Clinical Trial Registration: This study has been registered with ClinicalTrials.gov (Identifier: NCT03830996).
| S-EPMC7472777 | biostudies-literature