Phase I study of adjuvant immunotherapy with autologous tumor-infiltrating lymphocytes in locally advanced cervical cancer
He Huang, … , Ji-Hong Liu, Jiang Li
He Huang, … , Ji-Hong Liu, Jiang Li
Published June 21, 2022
Citation Information: J Clin Invest. 2022;132(15):e157726. https://doi.org/10.1172/JCI157726.
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Clinical Research and Public Health Oncology

Phase I study of adjuvant immunotherapy with autologous tumor-infiltrating lymphocytes in locally advanced cervical cancer

Abstract

BACKGROUND Adoptive 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.METHODS Twenty-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.RESULTS TILs 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.CONCLUSION TIL-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 REGISTRATION ClinicalTrials.gov NCT04443296.FUNDING National 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.

Authors

He Huang, Cai-ping Nie, Xiu-feng Liu, Bin Song, Jian-hui Yue, Jing-xiao Xu, Jia He, Kui Li, Yan-ling Feng, Ting Wan, Min Zheng, Yan-Na Zhang, Wei-Jun Ye, Jun-Dong Li, Yan-Fang Li, Jun-yun Li, Xin-Ping Cao, Zhi-min Liu, Xiao-shi Zhang, Qing Liu, Xi Zhang, Ji-Hong Liu, Jiang Li

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Figure 3

Correlations of characteristics of infused TIL products and clinical response.

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Correlations of characteristics of infused TIL products and clinical res...
(A) Schematic illustration of biomarkers and functional identification of TIL products in this study. (B) Frequency of T cell reactivity against HPV E6 (left) and E7 (right) antigens in peripheral blood and TILs (n = 13). (C) Frequency of HPV E6 antigen–specific T cells in peripheral blood and in TILs from patients with HLA-A2+ CC (n = 5), by Wilcoxon test. (D) UMAP plot showing cells from 8 patients with CC. Bar graph shows the number of cells for each indicated patient (n = 8). (E) Expression and distribution of canonical T cell marker genes (CD3D, CD8A, and CD4) and genes related to cytotoxicity and proliferation among these cell subsets. (F) Volcano plots showing DEGs in CD8+ T cells (left) and CD4+ T cells (right) in responders versus nonresponders. Representative genes are labeled. adj, adjusted; avg, average; FC, fold change. (G) GSEA shows the pathway activities in CD8+ T cells (left) and CD4+ T cells (right) between responders and nonresponders. NES, normalized enrichment core. (H) Violin plots show the key signature scores of CD8+ T cells (top) and CD4+ T cells (bottom) (responders vs. nonresponders). ***P < 0.001 and ****P < 0.0001, by Mann-Whitney U test. R, responders; NR, nonresponders.