Tumor-infiltrating lymphocytes-derived CD8+ clonotypes infiltrate the tumor tissue and mediate tumor regression in glioblastoma.

IF 6.5 2区 医学 Q1 IMMUNOLOGY
Oncoimmunology Pub Date : 2025-12-01 Epub Date: 2025-10-07 DOI:10.1080/2162402X.2025.2559784
Lucas C M Arruda, Julia Karbach, Dragan Kiselicki, Hans-Michael Altmannsberger, Evgueni Sinelnikov, Dirk Gustavus, Hans Hoffmeister, Akin Atmaca, Elke Jäger
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引用次数: 0

Abstract

Adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) has demonstrated consistent clinical efficacy in treating advanced melanoma and other "hot" tumors. However, it has shown limited success in "cold" tumors like glioblastoma. We present the successful treatment of a rapidly progressing glioblastoma patient with TILs expanded using a defined cytokine combination of IL-2, IL-15, and IL-21. The patient received lymphodepletion with cyclophosphamide one day pre-TIL infusion, followed by a single dose of IL-2 post-transfer. Complete tumor regression was observed after two TIL infusions administered two weeks apart. The TIL products were enriched for CD8+ T-cells and demonstrated specific lysis of the autologous tumor cell line. Transcriptomic analysis of tumor biopsies post-TIL infusion revealed increased expression of genes associated with immunological synapse formation and T-cell effector function, correlating with the patient's clinical outcome. T-cell receptor (TCR) next-generation sequencing of the infused TILs and post-treatment tumor biopsies confirmed the infiltration and expansion of TIL-derived clonotypes within the tumor microenvironment. CD8+ T-cell clonotypes exhibited robust tumor migration and expansion, while CD4+ T-cells showed limited tumor infiltration. In conclusion, TILs expanded with IL-2/IL-15/IL-21 represent a promising therapeutic approach for glioblastoma, overcoming traditional challenges posed by the tumor microenvironment and achieving significant clinical outcomes.

肿瘤浸润性淋巴细胞衍生的CD8+克隆型浸润肿瘤组织并介导胶质母细胞瘤的肿瘤消退。
肿瘤浸润淋巴细胞(til)过继细胞疗法在治疗晚期黑色素瘤和其他“热”肿瘤方面已显示出一致的临床疗效。然而,它对胶质母细胞瘤等“冷”肿瘤的治疗效果有限。我们介绍了使用IL-2, IL-15和IL-21的细胞因子组合成功治疗快速进展的til扩大的胶质母细胞瘤患者。患者在til输注前一天接受环磷酰胺淋巴细胞清除,然后在转移后接受单剂量IL-2。间隔两周注射两次TIL后,观察到肿瘤完全消退。TIL产物对CD8+ t细胞富集,对自体肿瘤细胞系具有特异性裂解作用。til输注后肿瘤活检的转录组学分析显示,与免疫突触形成和t细胞效应功能相关的基因表达增加,与患者的临床结果相关。t细胞受体(TCR)的下一代测序和治疗后的肿瘤活检证实了til衍生的克隆型在肿瘤微环境中的浸润和扩增。CD8+ t细胞克隆型表现出强劲的肿瘤迁移和扩张,而CD4+ t细胞表现出有限的肿瘤浸润。总之,IL-2/IL-15/IL-21扩展的til是一种很有前景的治疗胶质母细胞瘤的方法,克服了肿瘤微环境带来的传统挑战,并取得了显著的临床效果。
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来源期刊
Oncoimmunology
Oncoimmunology ONCOLOGYIMMUNOLOGY-IMMUNOLOGY
CiteScore
12.50
自引率
2.80%
发文量
276
审稿时长
24 weeks
期刊介绍: OncoImmunology is a dynamic, high-profile, open access journal that comprehensively covers tumor immunology and immunotherapy. As cancer immunotherapy advances, OncoImmunology is committed to publishing top-tier research encompassing all facets of basic and applied tumor immunology. The journal covers a wide range of topics, including: -Basic and translational studies in immunology of both solid and hematological malignancies -Inflammation, innate and acquired immune responses against cancer -Mechanisms of cancer immunoediting and immune evasion -Modern immunotherapies, including immunomodulators, immune checkpoint inhibitors, T-cell, NK-cell, and macrophage engagers, and CAR T cells -Immunological effects of conventional anticancer therapies.
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