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Phase I trial of adoptively transferred tumor-infiltrating lymphocyte immunotherapy following concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma.

ABSTRACT: Adoptive cell therapy (ACT) for cancers using autologous tumor-infiltrating lymphocytes (TILs) can induce immune responses and antitumor activity in metastatic melanoma patients. Here, we aimed to assess the safety and antitumor activity of ACT using expanded TILs following concurrent chemoradiotherapy (CCRT) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC). Twenty-three newly diagnosed, locoregionally advanced NPC patients were enrolled, of whom 20 received a single-dose of TIL infusion following CCRT. All treated patients were assessed for toxicity, survival and clinical and immunologic responses. Correlations between immunological responses and treatment effectiveness were further studied. Only mild adverse events (AEs), including Grade 3 neutropenia (1/23, 5%) consistent with immune-related causes, were observed. Nineteen of 20 patients exhibited an objective antitumor response, and 18 patients displayed disease-free survival longer than 12 mo after ACT. A measurable plasma Epstein-Barr virus (EBV) load was detected in 14 patients at diagnosis, but a measurable EBV load was not found in patients after one week of ACT, and the plasma EBV load remained undetectable in 17 patients at 6 mo after ACT. Expansion and persistence of T cells specific for EBV antigens in peripheral blood following TIL therapy were observed in 13 patients. The apparent positive correlation between tumor regression and the expansion of T cells specific for EBV was further investigated in four patients. This study shows that NPC patients can tolerate ACT with TILs following CCRT and that this treatment results in sustained antitumor activity and anti-EBV immune responses. A larger phase II trial is in progress.

SUBMITTER: Li J

PROVIDER: S-EPMC4404907 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Phase I trial of adoptively transferred tumor-infiltrating lymphocyte immunotherapy following concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma.

Li Jiang J Chen Qiu-Yan QY He Jia J Li Ze-Lei ZL Tang Xiao-Feng XF Chen Shi-Ping SP Xie Chuan-Miao CM Li Yong-Qiang YQ Huang Li-Xi LX Ye Shu-Bio SB Ke Miao-La M Tang Lin-Quan LQ Liu Huai H Zhang Lu L Guo Shan-Shan SS Xia Jian-Chuan JC Zhang Xiao-Shi XS Zheng Li-Min LM Guo Xiang X Qian Chao-Nan CN Mai Hai-Qiang HQ Zeng Yi-Xin YX

Oncoimmunology 20150201 2

Adoptive cell therapy (ACT) for cancers using autologous tumor-infiltrating lymphocytes (TILs) can induce immune responses and antitumor activity in metastatic melanoma patients. Here, we aimed to assess the safety and antitumor activity of ACT using expanded TILs following concurrent chemoradiotherapy (CCRT) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC). Twenty-three newly diagnosed, locoregionally advanced NPC patients were enrolled, of whom 20 received a single-dose ...[more]

PMID: 25949875

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Project description:ImportanceInduction or adjuvant chemotherapy with concurrent chemoradiotherapy (CCRT) are first-line treatment options for treatment of locoregionally advanced nasopharyngeal carcinoma (LA-NPC). Adjuvant platinum regimens are, however, poorly tolerated, highlighting the unmet need for an efficacious, tolerable adjuvant regimen.ObjectiveTo investigate the efficacy and safety of adjuvant capecitabine with CCRT for the treatment of patients with LA-NPC.Design, setting, and participantsThis open-label randomized clinical trial recruited patients from March 31, 2014, to July 27, 2018, at 3 institutions in China, with at least 3 years of follow-up. The data collection cutoff date was February 9, 2022. Eligibility included stage III-IVb nasopharyngeal carcinoma and at least 1 of the following: T3-4N2 or T1-4N3; plasma Epstein-Barr virus DNA titer higher than 20 000 copies/mL; primary gross tumor volume larger than 30.0 cm3; fluorodeoxyglucose F 18 positron emission tomography/computed tomography maximum standard uptake value of the primary gross tumor volume larger than 10.0; or multiple nodal metastases and any larger than 4.0 cm.InterventionsPatients were randomly assigned 1:1 to receive either capecitabine (1000 mg/m2 twice daily for 14 days every 3 weeks for 8 cycles) or observation following CCRT (100 mg/m2 cisplatin every 3 weeks for 2 to 3 cycles, depending on duration of radiotherapy).Main outcomes and measuresFailure-free survival in the intention-to-treat cohort was assessed using Kaplan-Meier survival curves compared with the log-rank test. Unstratified Cox proportional hazards regression models were used to estimate hazard ratios, with corresponding 95% CIs based on the Wald test.ResultsThere were 180 patients enrolled (median [IQR] age, 47 [40-55] years; 143 [79.4%] men). Among 90 patients in the capecitabine group, 76 (84.4%) had at least 2 high-risk factors; among 90 patients in the control group, 80 (88.9%) had at least 2 high-risk factors. All patients completed CCRT, except 1 patient in the capecitabine group who received 1 cycle of cisplatin. Of the 90 patients in the capecitabine group, 85 (94.4%) received capecitabine, with 71 (78.9%) completing 8 cycles. With a median (IQR) follow-up of 58.0 (49.5-80.1) months, 18 events were recorded in the capecitabine group vs 31 events in the control group. Failure-free survival was improved with adjuvant capecitabine (3 years, 83.3% vs 72.2%; 5 years, 78.5% vs 65.9%; hazard ratio, 0.53 [95% CI, 0.30-0.94]; P = .03). The incidence of grade 3 treatment-related adverse events (TRAEs) was higher in the capecitabine group than in the control group (54 of 90 patients [60.0%] vs 46 of 90 patients [51.1%]). Treatment-related adverse events included xerostomia (17 [18.9%] vs 9 [10.0%] patients), mucositis (21 [23.3%] vs 15 [16.7%] patients), and anorexia (8 [8.9%] vs 4 [4.4%] patients). The incidence of grade 3 delayed treatment-related adverse events was comparable in both groups (9 of 83 [10.8%] vs 7 of 81 [8.6%] patients).Conclusions and relevanceIn this randomized clinical trial, adjuvant capecitabine at the full dose following CCRT was well tolerated and improved failure-free survival among patients with LA-NPC and high-risk factors. Further investigations assessing optimal dose and duration are warranted.Trial registrationClinicalTrials.gov Identifier: NCT02143388.

Project description:BackgroundStudies on several malignancies have suggested that the time to commencement of adjuvant chemotherapy (AC) is associated with survival outcomes. There have, however, been no relevant reports of nasopharyngeal carcinoma (NPC).Patients and methodsThis clinical study examined newly diagnosed patients between April 2017 and December 2020. The primary endpoint was progression-free survival (PFS). Inverse probability of treatment weighting was used to control for confounding factors. Cox models with restricted cubic splines, Kaplan-Meier method and log-rank tests were used to evaluate the relationship between AC timing and survival.ResultsA total of 551 patients were identified [median age, 45 years (interquartile range 36-52 years); 383 (69.5%) male]. Restricted cubic splines demonstrated that the timing of AC initiation had a U-shaped association with PFS. The risk of disease progression decreased within 37 days and subsequently increased. From 37 to 90 days, each additional 7-day delay conferred worse PFS of 1.32 months {hazard ratio (HR): 1.14 [95% confidence interval (CI) 1.01-1.28], P = 0.04}. The cut-off value of the receiver operating characteristic curve for initiation was 69.5 days. At a median follow-up of 48 months, the PFS was significantly better in patients initiated within 69.5 days [HR: 2.18 (95% CI 1.17-4.06), log-rank P = 0.009], with a higher 3-year rate [78.8% (95% CI 75.1% to 82.7%) versus 59.0% (95% CI 42.2% to 82.5%)] than beyond 69.5 days. Positive results were also observed in secondary endpoints. The initiation group was an independent prognostic factor [HR: 2.28 (95% CI 1.42-3.66), P < 0.001].ConclusionsThe optimal timing of AC initiation is ∼37 days after concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma. A delay beyond 69.5 days is associated with compromised survival. Efforts should be made to address the reasons for delays and ensure the timely initiation of AC.

Project description:PurposeThis large population-based analysis aims to investigate whether the additional induction chemotherapy to concurrent chemoradiotherapy improved overall survival (OS) and disease-free survival (DFS) for locoregionally advanced nasopharyngeal carcinoma (LRANPC).Patients and methodsThe study group comprised 3,980 patients who were treated either with IC+CCRT (1,888 patients) or CCRT alone (2,092 patients) between January 1998 and June 2013. Survival outcomes were compared using Cox proportional hazards regression models with adjustments for confounding provided by propensity score methods. Primary outcome variables included OS and DFS.ResultsKaplan-Meier analysis showed that CCRT and IC+CCRT were of similar benefit to OS (P=0.099), whereas there was a marginal benefit of CCRT to DFS (P=0.063) in the overall cohort, which showed no differences between the two treatment regimens using multivariate Cox analysis and propensity score. Interestingly, for patients with 2D radiationtherapy (2DRT), CCRT had OS and DFS benefits for stage III, with 5-year and 10-year OS for CCRT vs IC+CCRT being 88% and 75% vs 81% and 67%, respectively (P=0.002); 5-year and 10-year DFS for CCRT vs IC+CCRT being 84% and 74% vs 76% and 66%, respectively (P=0.002). In contrast, IC + CCRT had OS and DFS benefits for stage IVa-b, with 5-year and 10-year OS for CCRT vs IC+CCRT being 71% and 55% vs 76% and 60%, respectively (P=0.037, HR=0.786); 5-year and 10-year DFS for CCRT vs IC+CCRT were 64% and 50% vs 69% and 58%, respectively (P=0.038, HR=0.801). No difference was found in intensity-modulated radiotherapy (IMRT) subgroup.ConclusionOur study indicates that CCRT and IC+CCRT may have similar OS and DFS benefits for overall LRANPC. Stage-specific chemoradiotherapy may be administered based on the greatest benefit of IC+CCRT for stage IVa-b patients and CCRT alone for stage III patients received 2DRT. The optimal chemotherapy pattern in combination with IMRT needs further investigation.Trial registration ClinicalTrials.gov ID: NCT02604472.

Project description:PurposeThe aims of this study focusing on Locoregionally advanced nasopharyngeal carcinoma (LANPC) were mainly two-fold: on the one hand, to establish a cut-off value to differentiate early and late failure based on prognosis after recurrence or metastasis; and on the other hand, to investigate the duration of concurrent cisplatin benefit over follow-up time. The results of our study have the potential to guide clinical practice and follow-up.MethodsIn total, 3123 patients with stage III-IVa NPC receiving Induction chemotherapy followed by concurrent cisplatin or not were analysed. The cut-off value of treatment failure was calculated using the minimum P-value approach. Random survival forest (RSF) model was to simulate the cumulative probabilities of treatment failure (locoregional recurrence and /or distant metastasis) over-time, as well as the monthly time-specific, event-occurring probabilities, for patients at different treatment groups.ResultsBased on subsequent prognosis, early locoregional failure (ELRF) should be defined as recurrence within 14 months (P = 1.47 × 10 - 3), and early distant failure (EDF) should be defined as recurrence within 20 months (P = 1.95 × 10 - 4). A cumulative cisplatin dose (CCD) > 200 mg/m2 independently reduced the risk of EDF (hazard ratio, 0.351; 95% confidence interval (CI), 0.169-0.732; P = 0.005). Better failure-free survival (FFS) and overall survival (OS) were observed in concurrent chemotherapy settings ([0 mg/m2 vs. 1-200 mg/m2 vs. >200 mg/m2]: FFS: 70.4% vs. 74.4% vs. 82.6%, all P < 0.03; OS: 79.5% vs. 83.8% vs. 90.8%, all P < 0.01). In the monthly analysis, treatment failure mainly occurred during the first 4 years, and the risk of distant failure in patients treated with concurrent chemotherapy never exceeded that of patients without concurrent chemotherapy.ConclusionLocoregional failure that developed within 14 months and/or distant failure within 20 months had poorer subsequent survival. Concurrent chemotherapy provides a significant FFS benefit, primarily by reducing EDF, translating into a long-term OS benefit.

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Phase I trial of adoptively transferred tumor-infiltrating lymphocyte immunotherapy following concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma.

Publications

Phase I trial of adoptively transferred tumor-infiltrating lymphocyte immunotherapy following concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma.

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