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1.
Eur J Cancer ; 191: 112965, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37540921

RESUMO

PURPOSE: The safety and objective clinical responses were observed in the phase I study using adjuvant autologous tumour-infiltrating lymphocytes (TILs) following concurrent chemoradiotherapy (CCRT) in nasopharyngeal carcinoma (NPC) patients. METHODS AND MATERIALS: One hundred fifty-six patients with stage III-IVb and pretreatment Epstein-Barr virus DNA levels of ≥4000 copies/ml were randomly assigned to receive CCRT combined with TIL infusion (n = 78) or CCRT alone (n = 78). All patients received CCRT and patients assigned to the TIL group received TIL infusion within 1 week after CCRT. The primary endpoint was investigator-assessed progression-free survival (PFS) at 3 years. RESULTS: After a median follow-up of 62.3 months, no significant difference was observed in the 3-year PFS rate between the CCRT plus TIL infusion group and CCRT alone group (75.6% versus 74.4%, hazard ratios, 1.08; 95% confidence intervals, 0.62-1.89). TIL infusion was safe without grade 3 or 4 adverse events and all the high-grade adverse effects were associated with myelosuppression caused by CCRT. Exploratory analysis showed that a potential survival benefit was observed with TILs in patients with lower levels of circulating CD8+TIM3+ cells, serum IL-8 or PD-L1. The infused TIL products in patients with favourable outcomes were associated with increased transcription of interferon-γ and a series of inflammatory related genes and a lower exhausted score. CONCLUSION: The primary objective of prolonging PFS with CCRT plus TILs in high-risk NPC patients was not met. These findings may provide evidence for the design of future trials investigating the combination of TILs plus immune checkpoint inhibitors based on CCRT in high-risk NPC patients. TRIAL REGISTRATION NUMBER: NCT02421640.


Assuntos
Infecções por Vírus Epstein-Barr , Neoplasias Nasofaríngeas , Humanos , Adjuvantes Imunológicos , Quimiorradioterapia/métodos , Intervalo Livre de Doença , DNA , Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4 , Linfócitos do Interstício Tumoral , Carcinoma Nasofaríngeo/terapia , Neoplasias Nasofaríngeas/patologia
2.
J Immunother Cancer ; 10(9)2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36126994

RESUMO

BACKGROUND: Stimulator of interferon genes (STING) is an innate immune sensor of cytoplasmic double-stranded DNA originating from microorganisms and host cells. The activation of cytosolic DNA-STING pathway in tumor microenvironments is usually linked to more robust adaptive immune responses to tumors, however the intracellular function of STING in regulatory T cells is largely unknown. In the present study, we aimed to explore the contribution of intracellular STING activation to regulatory T cell induction (iTreg) in cervical cancer (CC) microenvironments. METHODS: Blood samples and tumor specimens were obtained from patients with CC. The intratumoral STING, CCL22, CD8 and forkhead box P3 (FOXP3) expression levels were measured by immunohistochemistry. T cell-specific STING conditional knockout mice (CD4-Cre/STINGflox/flox, TKO) were generated, and syngeneic TC-1 tumor model were investigated. The differentiation and molecular regulatory pathway of human and murine iTreg under different treatments were investigated by ex vivo assays, immunoblotting and quantitative PCR. Tumor-associated exosomes (T-EXO) were isolated from CC cell lines and exosomal contents were identified by ELISA and Western blot analysis. The impact of T-EXO on T cell differentiation was tested in in vitro cell culture. RESULTS: Increased STING, CCL22 level, FOXP3+ cells but decreased CD8+ cells in tumor tissues predicted poor survival. Tumor-bearing CD4-Cre-STINGflox/flox (TKO) mice displayed slower tumor growth tendencies as well as fewer FOXP3+ cells but higher CD8+ cell proportion in tumor tissues than wild-type (WT) mice. Activating of STING signaling cooperated with T cell receptor, interleukin-2 receptor and transforming growth factor-beta (TGF-ß) signals to promote CD4+CD25highFOXP3+ iTreg differentiation from both human and murine CD4+-naïve T cells from WT and IFNAR-/- mice but not TKO or IRF3-/- mice in vitro. Ectopic STING, TBK1 or IRF3 expression promoted iTreg differentiation from human CD4+-naïve T cells. T cell-intrinsic STING activation induced FOXP3 transcription through TBK1-IRF3-mediated SMAD3 and STAT5 phosphorylation independent of interferon-ß. In CC, tumor-derived exosomes activated STING signaling in tumor-infiltrated T cells by exosomal TGF-ß, cyclic GMP-AMP synthase and 2'-3'-cGAMP, leading to iTreg expansion. CONCLUSIONS: These findings highlight a novel mechanism for iTreg expansion mediated by tumor-derived exosome-activated T cell-intrinsic STING signal, and provide a rationale for developing immunotherapeutic strategies targeting STING signal in CC.


Assuntos
Linfócitos T Reguladores , Neoplasias do Colo do Útero , Animais , DNA/metabolismo , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Terapia de Imunossupressão , Interferon beta , Interferons/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Receptores de Interleucina-2/metabolismo , Fator de Transcrição STAT5/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fatores de Crescimento Transformadores/metabolismo , Microambiente Tumoral , Neoplasias do Colo do Útero/genética
3.
J Clin Invest ; 132(15)2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35727633

RESUMO

BACKGROUNDAdoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs) has achieved remarkable clinical efficacy in metastatic cancers such as melanoma and cervical cancer (CC). Here, we explored the safety, feasibility, and preliminary tumor response and performed translational investigations of adjuvant immunotherapy using infusion of autogenous TILs (auto-TILs) following concurrent chemoradiotherapy (CCRT) in patients with CC who had locally advanced disease.METHODSTwenty-seven patients with CC with stage III-IV disease were recruited in this single-center, phase I study. TILs were isolated from lesions in the uterine cervix and generated under good manufacturing practice (GMP) conditions and then infused after CCRT plus i.m. IL-2 injections.RESULTSTILs from 20 of the 27 patients were successfully expanded, with a feasibility of 74.1%. Twelve patients received TILs following CCRT. Adverse events (AEs) were primarily attributable to CCRT. Only 1 (8.3%) patient experienced severe toxicity with a grade 3 hypersensitivity reaction after TIL infusion. No autoimmune AEs, such as pneumonitis, hepatitis, or myocarditis, occurred, and there were no treatment-related mortalities. Nine of 12 patients (75.0%) attained a complete response, with a disease control duration of 9-22 months. Translational investigation showed that the transcriptomic characteristics of the infused TIL products and some immune biomarkers in the tumor microenvironment and serum of patients with CC at baseline were correlated with the clinical response.CONCLUSIONTIL-based ACT following CCRT was safe in an academic center setting, with potentially effective responses in patients with locally advanced CC. "Hot" inflammatory immune environments were beneficial to the clinical efficacy of TIL-based ACT as adjuvant therapy.TRIAL REGISTRATIONClinicalTrials.gov NCT04443296.FUNDINGNational Key R&D Program; Sci-Tech Key Program of the Guangzhou City Science Foundation; the Guangdong Province Sci-Tech International Key Program; the National Natural Science Foundation of China.


Assuntos
Imunoterapia , Neoplasias do Colo do Útero , Quimiorradioterapia , Feminino , Humanos , Imunoterapia/efeitos adversos , Linfócitos do Interstício Tumoral , Melanoma , Microambiente Tumoral , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/terapia
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