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Clinical outcomes of chimeric antigen receptor T-cell therapy following autologous hematopoietic stem cell transplantation in 38 patients with refractory/relapsed primary or secondary central nervous system lymphoma. 自体造血干细胞移植后嵌合抗原受体T细胞疗法对38名原发性或继发性中枢神经系统淋巴瘤难治/复发患者的临床疗效。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-11-11 DOI: 10.1007/s00262-024-03855-7
Jiaying Wu, Wanying Liu, Yang Cao, Yang Yang, Zhen Shang, Mi Zhou, Yicheng Zhang, Fankai Meng, Xiaojian Zhu, Yi Xiao

Background: Several reports have indicated that chimeric antigen receptor (CAR) T-cell therapy following autologous hematopoietic stem cell transplantation (ASCT) is a promising strategy for refractory/relapsed (r/r) central nervous system lymphoma (CNSL), but the number of reported cases is limited.

Methods: The cohort in this retrospective study consisted of 38 patients with r/r CNSL who received CAR T-cell therapy following ASCT at our center between January 2019 and April 2024. Group comparisons of continuous variables were tested using the unpaired Student's t-test or the Mann-Whitney U-test, while categorical variables were analyzed using Fisher's exact test. The Kaplan-Meier method was employed to estimate survival curves, and group comparisons were performed using the log-rank test.

Results: The cohort comprised 38 patients with r/r CNSL, all of whom had active CNS involvement. After therapy, the best overall response rate (ORR) of all patients was 78.9%. Subgroup analysis found that a lower ORR was observed in patients with lactate dehydrogenase levels above the upper limit of normal (60.0% vs. 91.3%, P = 0.039). With a median follow-up of 37.5 months, the estimated 1-year overall survival (OS) and progression-free survival (PFS) rates were 72.8% and 57.4%, respectively. The risk factors associated with PFS was no response to current therapy (adjusted hazard ratio: 22.87, P < 0.001). The incidence rates of severe cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome were both 13.2%. Among the 25 patients with secondary CNSL (SCNSL), the best ORRs were 91.7% for those with CNS lesions only and 61.5% for those with CNS and systemic lesions (P = 0.160), while the estimated 1-year PFS rates were 83.3% and 38.5%, respectively (P = 0.030).

Conclusions: CAR T-cell therapy following ASCT shows promising efficacy for r/r CNSL patients. Besides, SCNSL patients with CNS and systemic lesions have inferior treatment efficacy compared to those with CNS lesions only.

背景:一些报道指出,自体造血干细胞移植(ASCT)后的嵌合抗原受体(CAR)T细胞疗法是治疗难治性/复发性(r/r)中枢神经系统淋巴瘤(CNSL)的一种有前途的策略,但报道的病例数量有限:这项回顾性研究的队列包括2019年1月至2024年4月期间在本中心接受ASCT后接受CAR T细胞治疗的38例r/r CNSL患者。连续变量的组间比较采用非配对学生 t 检验或 Mann-Whitney U 检验,而分类变量则采用费雪精确检验进行分析。采用 Kaplan-Meier 法估算生存曲线,使用对数秩检验进行组间比较:结果:研究组由38名r/r CNSL患者组成,所有患者均有活动性中枢神经系统受累。治疗后,所有患者的最佳总反应率(ORR)为78.9%。亚组分析发现,乳酸脱氢酶水平高于正常上限的患者总反应率较低(60.0% vs. 91.3%,P = 0.039)。中位随访时间为37.5个月,估计1年总生存率(OS)和无进展生存率(PFS)分别为72.8%和57.4%。与PFS相关的风险因素是对当前治疗无反应(调整后危险比:22.87,P 结论:CAR T细胞疗法与ASCT治疗的相关性较低:ASCT后的CAR T细胞疗法对r/r CNSL患者有很好的疗效。此外,与仅有中枢神经系统病变的患者相比,中枢神经系统和全身病变的SCNSL患者疗效较差。
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引用次数: 0
Spontaneous high clonal expansion of Wilms' tumor gene 1-specific cytotoxic T-lymphocytes in patients with Wilms' tumor gene 1-expressing solid tumor. 表达 Wilms 肿瘤基因 1 的实体瘤患者体内 Wilms 肿瘤基因 1 特异性细胞毒性 T 淋巴细胞的自发性高度克隆扩增。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-11-07 DOI: 10.1007/s00262-024-03862-8
Soyoko Morimoto, Yukie Tanaka, Jun Nakata, Fumihiro Fujiki, Kana Hasegawa, Hiroko Nakajima, Sumiyuki Nishida, Akihiro Tsuboi, Naoki Hosen, Naoki Kagawa, Motohiko Maruno, Akira Myoui, Takayuki Enomoto, Shuichi Izumoto, Mitsugu Sekimoto, Naoya Hashimoto, Toshiki Yoshimine, Atsushi Kumanogoh, Yusuke Oji, Yoshihiro Oka, Haruo Sugiyama

Wilms' tumor protein 1 (WT1)-targeted immunotherapy has been used in patients with leukemia and solid tumors. However, the spontaneous WT1-specific immune response before WT1 peptide vaccination in patients with WT1-expressing tumors (PTs) remains unclear. Therefore, we investigated whether WT1-specific cytotoxic CD8+ T-lymphocytes (CTLs) are clonally expanded in the peripheral blood outside of tumor sites. Clonal expansion of WT1126 peptide (a.a.126-134)-specific CTLs (WT1126-CTLs) was compared between seven PTs and five healthy volunteers (HVs), and their T-cell receptors (TCRs) were analyzed at the single-cell level. Overall, 433 and 351 TCR β-chains of WT1126-CTLs were detected from PTs and HVs, respectively, and complementarity-determining region 3 was sequenced for clonality analysis. The frequencies of WT1126-CTLs were higher in human leukocyte antigen (HLA)-A*02:01+ PTs than in HLA-A*02:01+ HVs, although the difference was not statistically significant. WT1126-CTLs of differentiated types, including memory and effector, were higher in PTs than in HVs; whereas, those of the naïve type were higher in HVs than in PTs. WT1126-CTL clonality was significantly higher in PTs than in HVs. Furthermore, the frequency of effector WT1126-CTLs positively correlated with WT1126-CTL clonality in PTs; whereas, the frequency of naïve phenotype WT1126-CTLs tended to be negatively correlated with clonality. In conclusion, these results suggest that the WT1 protein in tumor cells is highly immunogenic, thereby stimulating endogenous naïve-type WT1126-CTLs and enabling them to clonally expand and differentiate into effector-type WT1126-CTLs.

Wilms 肿瘤蛋白 1(WT1)靶向免疫疗法已用于白血病和实体瘤患者。然而,WT1表达肿瘤(PTs)患者在接种WT1肽疫苗前的自发WT1特异性免疫反应仍不清楚。因此,我们研究了WT1特异性细胞毒性CD8+ T淋巴细胞(CTL)是否在肿瘤部位以外的外周血中克隆扩增。我们比较了 7 名 PT 和 5 名健康志愿者(HV)的 WT1126 肽(a.a.126-134)特异性 CTL(WT1126-CTLs)的克隆扩增情况,并在单细胞水平上分析了它们的 T 细胞受体(TCRs)。从 PT 和 HV 中分别检测到 433 和 351 个 WT1126-CTL 的 TCR β 链,并对互补决定区 3 进行测序,以进行克隆性分析。在人类白细胞抗原(HLA)-A*02:01+ PTs 中,WT1126-CTLs 的频率高于 HLA-A*02:01+ HVs,但差异无统计学意义。WT1126-CTL的分化型(包括记忆型和效应型)在PTs中高于HVs;而幼稚型在HVs中高于PTs。在 PTs 中,WT1126-CTL 的克隆性明显高于 HVs。此外,在 PTs 中,效应WT1126-CTLs 的频率与 WT1126-CTL 克隆率呈正相关;而天真表型 WT1126-CTLs 的频率与克隆率呈负相关。总之,这些结果表明,肿瘤细胞中的WT1蛋白具有高度免疫原性,从而刺激内源性幼稚型WT1126-CTL,使其克隆扩增并分化为效应型WT1126-CTL。
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引用次数: 0
Differences in immune-related toxicity between PD-1 and PD-L1 inhibitors: a retrospective cohort study in patients with advanced cancer. PD-1和PD-L1抑制剂的免疫相关毒性差异:一项针对晚期癌症患者的回顾性队列研究。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-11-07 DOI: 10.1007/s00262-024-03869-1
Cecilia Olsson Ladjevardi, Marcus Skribek, Anthoula Koliadi, Viktoria Rydén, Ali Inan El-Naggar, Evangelos Digkas, Antonios Valachis, Gustav J Ullenhag

Immunotherapy with PD-1 or PD-L1 inhibitors has become an essential treatment strategy for a growing number of malignancies. These treatments have a risk for immune-related adverse events (IRAEs). Pooled analyses based on clinical trials show a favorable toxicity profile for treatment with PD-L1 compared to PD-1 inhibitors. This study aimed to investigate differences in IRAEs between patients with advanced solid malignances treated with PD-L1 and PD-1 inhibitors in a real-world setting. We conducted a retrospective cohort study at four Swedish Regions. Patients (n = 605) treated for advanced cancer with a PD-L1 or PD-1 inhibitor in monotherapy between June 2016 and August 2022 were included. Non-small cell lung cancer (NSCLC) was the most common malignant disease (n = 251; 41.5%), followed by malignant melanoma (n = 173; 28.6%), renal cell carcinoma (n = 71; 11.7%) and urothelial carcinoma (n = 35; 5.8%). Among patients receiving PD-L1 inhibitors, NSCLC (94.4%) was the predominant malignancy, whereas for those treated with PD-1 inhibitor, malignant melanoma constituted the most prevalent malignancy (34.5%). Discontinuation of treatment due to IRAEs overall and IRAEs grade ≥ 2 were significantly less common in patients treated with PD-L1 compared to PD-1 inhibitors [Odds Ratio (OR): 0.38 (95% Confidence Interval (CI) 0.16-0.88) and OR: 0.63 (95% CI 0.35-0.98) respectively]. Any grade IRAE, IRAE grade ≥ 3 and multiple IRAEs were numerically more frequent in patients treated with PD-1 inhibitors.In conclusion, our study of patients with advanced solid malignancies in a real-world setting supports the results from clinical trials demonstrating a favorable toxicity profile for PD-L1 inhibitors versus PD-1 inhibitors.

使用 PD-1 或 PD-L1 抑制剂进行免疫治疗已成为越来越多恶性肿瘤的基本治疗策略。这些治疗方法存在免疫相关不良事件(IRAEs)的风险。基于临床试验的汇总分析表明,与PD-1抑制剂相比,PD-L1抑制剂的治疗具有良好的毒性。本研究旨在调查在真实世界环境中接受 PD-L1 和 PD-1 抑制剂治疗的晚期实体恶性肿瘤患者的 IRAEs 差异。我们在瑞典的四个地区开展了一项回顾性队列研究。研究纳入了2016年6月至2022年8月期间接受PD-L1或PD-1抑制剂单药治疗的晚期癌症患者(n = 605)。非小细胞肺癌(NSCLC)是最常见的恶性疾病(n = 251;41.5%),其次是恶性黑色素瘤(n = 173;28.6%)、肾细胞癌(n = 71;11.7%)和尿路上皮癌(n = 35;5.8%)。在接受PD-L1抑制剂治疗的患者中,NSCLC(94.4%)是最常见的恶性肿瘤,而在接受PD-1抑制剂治疗的患者中,恶性黑色素瘤是最常见的恶性肿瘤(34.5%)。与PD-1抑制剂相比,接受PD-L1治疗的患者因总体IRAE和IRAE≥2级而中断治疗的情况明显较少[比值比(OR):0.38(95% 置信区间(CI)0.16-0.88)和OR:0.63(95% CI 0.35-0.98)]。总之,我们在真实世界环境中对晚期实体恶性肿瘤患者进行的研究支持了临床试验的结果,即 PD-L1 抑制剂与 PD-1 抑制剂相比具有良好的毒性特征。
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引用次数: 0
Efficacy, safety, and biomarker analysis of TACE combined with lenvatinib plus sintilimab in unresectable hepatocellular carcinoma: a real-world study. TACE联合来伐替尼加辛替利单抗治疗不可切除肝细胞癌的疗效、安全性和生物标志物分析:一项真实世界研究。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-11-05 DOI: 10.1007/s00262-024-03857-5
Lingzhan Meng, Hu Li, Yingjie Ji, Peng Yu, Zizheng Wang, Li Cao, Bin Shi, Yanling Shao, Jin Yan, Yinjie Gao, Zhenyu Zhu

Background: The integration of transarterial chemoembolization (TACE) with systemic therapy has demonstrated improved survival outcomes in patients with unresectable hepatocellular carcinoma (HCC). However, there is limited evidence evaluating the combination of TACE with the systemic regimen of anti-PD-1/L1 inhibitor plus lenvatinib. This study aims to assess the efficacy and safety of TACE combined with lenvatinib and sintilimab in unresectable HCC patients.

Methods: Unresectable HCC patients who received TACE in combination with sintilimab plus Lenvatinib as first-line treatment from 1 January 2020 to 31 March 2023 were included for the analysis. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) were evaluated by modified Response Evaluation Criteria in Solid Tumors criteria. Exploratory biomarker analysis was conducted.

Results: The study included 70 patients with unresectable HCC, predominantly male and infected with Hepatitis B. The median follow-up duration for the whole cohort was 13.8 months (95% CI 11.08-16.7). The ORR was 61.4% (95% CI, 49.0%-72.8%) and the DCR was 68.6% (95%CI, 56.4%-79.2%). The median PFS was 13.2 months (95% CI 11.0-NA), with a corresponding 1-year PFS rate of 50.3% (95% CI 39.7%-65.5%). The median OS was not reached, and the 1-year OS rate was 89.3% (95% CI 81.4%-97.9%). The most common treatment-related adverse events (TRAEs) were fatigue 38.6% (27/70), hypertension 32.9% (23/70), and hand-foot syndrome 31.4% (22/70). Most TRAEs were mild-to-moderate and manageable. In addition, significant predictive value was found in alpha-fetoprotein levels (AFP), with patients showing a level of decrease post-treatment having better PFS.

Conclusion: The combination regimen demonstrated promising efficacy in treating unresectable HCC, accompanied by manageable safety profiles. Furthermore, the results of this investigation suggest that AFP holds promise as predictive biomarkers for this treatment strategy.

背景:经动脉化疗栓塞术(TACE)与全身治疗的结合改善了不可切除肝细胞癌(HCC)患者的生存预后。然而,目前评估TACE与抗PD-1/L1抑制剂加来伐替尼的全身治疗方案联合应用的证据有限。本研究旨在评估TACE联合来伐替尼和辛替利单抗治疗不可切除的HCC患者的有效性和安全性:纳入2020年1月1日至2023年3月31日期间接受TACE联合来伐替尼和辛替利单抗一线治疗的不可切除HCC患者进行分析。总生存期(OS)、无进展生存期(PFS)、客观反应率(ORR)和疾病控制率(DCR)按照修改后的实体瘤反应评估标准进行评估。研究还进行了探索性生物标志物分析:研究纳入了70例无法切除的HCC患者,其中男性居多,且感染了乙肝。ORR为61.4%(95%CI,49.0%-72.8%),DCR为68.6%(95%CI,56.4%-79.2%)。中位 PFS 为 13.2 个月(95% CI 11.0-NA),相应的 1 年 PFS 率为 50.3%(95% CI 39.7%-65.5%)。未达到中位OS,1年OS率为89.3%(95% CI 81.4%-97.9%)。最常见的治疗相关不良事件(TRAEs)为疲劳 38.6%(27/70)、高血压 32.9%(23/70)和手足综合征 31.4%(22/70)。大多数 TRAE 为轻度至中度,可控。此外,甲胎蛋白水平(AFP)具有重要的预测价值,治疗后水平下降的患者PFS更佳:结论:联合疗法在治疗不可切除的 HCC 方面具有良好的疗效,同时安全性可控。此外,这项研究结果表明,甲胎蛋白有望成为这种治疗策略的预测性生物标志物。
{"title":"Efficacy, safety, and biomarker analysis of TACE combined with lenvatinib plus sintilimab in unresectable hepatocellular carcinoma: a real-world study.","authors":"Lingzhan Meng, Hu Li, Yingjie Ji, Peng Yu, Zizheng Wang, Li Cao, Bin Shi, Yanling Shao, Jin Yan, Yinjie Gao, Zhenyu Zhu","doi":"10.1007/s00262-024-03857-5","DOIUrl":"10.1007/s00262-024-03857-5","url":null,"abstract":"<p><strong>Background: </strong>The integration of transarterial chemoembolization (TACE) with systemic therapy has demonstrated improved survival outcomes in patients with unresectable hepatocellular carcinoma (HCC). However, there is limited evidence evaluating the combination of TACE with the systemic regimen of anti-PD-1/L1 inhibitor plus lenvatinib. This study aims to assess the efficacy and safety of TACE combined with lenvatinib and sintilimab in unresectable HCC patients.</p><p><strong>Methods: </strong>Unresectable HCC patients who received TACE in combination with sintilimab plus Lenvatinib as first-line treatment from 1 January 2020 to 31 March 2023 were included for the analysis. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) were evaluated by modified Response Evaluation Criteria in Solid Tumors criteria. Exploratory biomarker analysis was conducted.</p><p><strong>Results: </strong>The study included 70 patients with unresectable HCC, predominantly male and infected with Hepatitis B. The median follow-up duration for the whole cohort was 13.8 months (95% CI 11.08-16.7). The ORR was 61.4% (95% CI, 49.0%-72.8%) and the DCR was 68.6% (95%CI, 56.4%-79.2%). The median PFS was 13.2 months (95% CI 11.0-NA), with a corresponding 1-year PFS rate of 50.3% (95% CI 39.7%-65.5%). The median OS was not reached, and the 1-year OS rate was 89.3% (95% CI 81.4%-97.9%). The most common treatment-related adverse events (TRAEs) were fatigue 38.6% (27/70), hypertension 32.9% (23/70), and hand-foot syndrome 31.4% (22/70). Most TRAEs were mild-to-moderate and manageable. In addition, significant predictive value was found in alpha-fetoprotein levels (AFP), with patients showing a level of decrease post-treatment having better PFS.</p><p><strong>Conclusion: </strong>The combination regimen demonstrated promising efficacy in treating unresectable HCC, accompanied by manageable safety profiles. Furthermore, the results of this investigation suggest that AFP holds promise as predictive biomarkers for this treatment strategy.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"74 1","pages":"13"},"PeriodicalIF":4.6,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11538227/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Dendritic cell maturation is induced by p53-armed oncolytic adenovirus via tumor-derived exosomes enhancing systemic antitumor immunity. 树突状细胞成熟是由带有 p53 的溶瘤腺病毒通过肿瘤衍生的外泌体诱导的,可增强全身抗肿瘤免疫力。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-11-05 DOI: 10.1007/s00262-024-03849-5
Tomoko Ohtani, Shinji Kuroda, Nobuhiko Kanaya, Yoshihiko Kakiuchi, Kento Kumon, Masashi Hashimoto, Chiaki Yagi, Ryoma Sugimoto, Satoru Kikuchi, Shunsuke Kagawa, Hiroshi Tazawa, Yasuo Urata, Toshiyoshi Fujiwara

Dendritic cells (DCs) are crucial in cancer immunity, because they activate cytotoxic T cells by presenting tumor antigens. Recently, oncolytic virus therapy has been recognized as a systemic immune stimulator. We previously developed a telomerase-specific oncolytic adenovirus (OBP-301) and a p53-armed OBP-301 (OBP-702), demonstrating that these viruses strongly activate systemic antitumor immunity. However, their effects on DCs remained unclear. In the present study, the aim was to elucidate the mechanisms of DC activation by OBP-702, focusing particularly on tumor-derived exosomes. Exosomes (Exo53, Exo301, or Exo702) were isolated from conditioned media of human or murine pancreatic cancer cell lines (Panc-1, MiaPaCa-2, and PAN02) after treatment with Ad-p53, OBP-301, or OBP-702. Exo702 derived from Panc-1 and MiaPaCa-2 cells significantly upregulated CD86, CD80, CD83 (markers of DC maturation), and IFN-γ in DCs in vitro. Similarly, Exo702 derived from PAN02 cells upregulated CD86 and IFN-γ in bone marrow-derived DCs in a bilateral PAN02 subcutaneous tumor model. This DC maturation was inhibited by GW4869, an inhibitor of exosome release, and anti-CD63, an antibody targeting the exosome marker. Intratumoral injection of OBP-702 into PAN02 subcutaneous tumors significantly increased the presence of mature DCs and CD8-positive T cells in draining lymph nodes, leading to long-lasting antitumor effects through the durable activation of systemic antitumor immunity. In conclusion, tumor-derived exosomes play a significant role in DC maturation following OBP-702 treatment and are critical for the systemic activation of antitumor immunity, leading to the abscopal effect.

树突状细胞(DC)在癌症免疫中至关重要,因为它们通过呈现肿瘤抗原激活细胞毒性 T 细胞。最近,溶瘤病毒疗法被认为是一种全身性免疫刺激剂。我们之前开发了一种端粒酶特异性溶瘤腺病毒(OBP-301)和一种带有 p53 的 OBP-301 (OBP-702),证明这些病毒能强烈激活全身抗肿瘤免疫。然而,它们对直流细胞的影响仍不清楚。本研究旨在阐明 OBP-702 激活直流细胞的机制,尤其关注肿瘤衍生的外泌体。用 Ad-p53、OBP-301 或 OBP-702 处理人或鼠胰腺癌细胞系(Panc-1、MiaPaCa-2 和 PAN02)后,从其条件培养基中分离出外泌体(Exo53、Exo301 或 Exo702)。来自 Panc-1 和 MiaPaCa-2 细胞的 Exo702 能显著上调体外直流细胞中的 CD86、CD80、CD83(直流细胞成熟的标志物)和 IFN-γ。同样,在双侧 PAN02 皮下肿瘤模型中,源自 PAN02 细胞的 Exo702 上调了骨髓源性直流细胞中的 CD86 和 IFN-γ。外泌体释放抑制剂 GW4869 和靶向外泌体标记物的抗体抗 CD63 可抑制这种 DC 成熟。向 PAN02 皮下肿瘤瘤体内注射 OBP-702 能显著增加引流淋巴结中成熟 DC 和 CD8 阳性 T 细胞的存在,从而通过持久激活全身抗肿瘤免疫产生持久的抗肿瘤效果。总之,肿瘤衍生的外泌体在OBP-702治疗后的DC成熟过程中发挥了重要作用,并且对全身抗肿瘤免疫的激活至关重要,从而导致了脱灶效应。
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引用次数: 0
Combination of ataxia telangiectasia and Rad3-related inhibition with ablative radiotherapy remodels the tumor microenvironment and enhances immunotherapy response in lung cancer. 将共济失调毛细血管扩张症和 Rad3 相关抑制与消融放疗相结合,可重塑肿瘤微环境并增强肺癌的免疫治疗反应。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-11-02 DOI: 10.1007/s00262-024-03864-6
Jenny Ling-Yu Chen, Chun-Kai Pan, Li-Cheng Lin, Yu-Sen Huang, Tsung-Hsuan Huang, Shu-Jyuan Yang, Sung-Hsin Kuo, Yu-Li Lin

We investigated the combined effects of ataxia telangiectasia and Rad3-related (ATR) inhibition, ablative radiotherapy, and immune checkpoint inhibitor (ICI) therapy against lung cancer. ATR inhibitor was administered combined with ablative radiotherapy to assess its radiosensitizing effect on lung cancer cells. Treatment response and survival were evaluated in vivo using A549 xenograft flank tumor and synchronous LLC lung and flank tumor mouse models. Mice received ablative radiotherapy (12 Gy/d for 2 d), ATR inhibitor, and ICI. The tumor microenvironment was assessed in irradiated flank and non-irradiated lung tumors. Programmed death-ligand 1 expression was upregulated after irradiation. ATR inhibition attenuated this upregulation. ATR inhibitor pretreatment decreased cell survival after irradiation by inhibiting DNA double-strand break repair, inducing mitotic cell death, and altering cell cycle progression. ATR inhibition enhanced radiation-induced damage-associated molecular patterns determined by high mobility group box 1 quantification and activated the cyclic GMP-AMP synthase-stimulator of interferon genes pathway. Combined ATR inhibition and ablative radiotherapy inhibited tumor growth and improved survival in mice. Adding ICI therapy further enhanced local antitumor effects, reducing the metastatic lung tumor burden and remodeling the tumor microenvironment through immunogenic cell death induction and enhanced immune cell infiltration. Triple therapy increased immune cell infiltration in distant non-irradiated lung tumors and stimulated the generation of protective T-cell immunity in splenocytes. Safety analysis showed minimal toxicity. ATR inhibition enhanced the efficacy of ablative radiotherapy and immunotherapy in lung cancer. These findings underscore the importance of combination therapies for enhancing systemic antitumor immune responses and outcomes.

我们研究了共济失调毛细血管扩张症和Rad3相关(ATR)抑制剂、消融放疗和免疫检查点抑制剂(ICI)疗法对肺癌的联合作用。ATR 抑制剂与烧蚀放疗联合使用,以评估其对肺癌细胞的放射增敏作用。使用A549异种侧腹肿瘤和同步LLC肺部和侧腹肿瘤小鼠模型对治疗反应和存活率进行了体内评估。小鼠接受了消融放疗(12 Gy/d,2 d)、ATR抑制剂和ICI。对照射过的侧腹肿瘤和未照射过的肺部肿瘤的肿瘤微环境进行了评估。照射后,程序性死亡配体1的表达上调。ATR抑制剂减轻了这种上调。ATR抑制剂通过抑制DNA双链断裂修复、诱导有丝分裂期细胞死亡和改变细胞周期进程,降低了辐照后细胞的存活率。ATR抑制增强了高迁移率组盒1定量测定的辐射诱导损伤相关分子模式,并激活了环GMP-AMP合成酶-干扰素基因刺激器通路。联合抑制 ATR 和消融放疗可抑制肿瘤生长并提高小鼠存活率。加入 ICI 治疗可进一步增强局部抗肿瘤效果,减少转移性肺肿瘤负荷,并通过诱导免疫原性细胞死亡和增强免疫细胞浸润重塑肿瘤微环境。三联疗法增加了远处非辐照肺肿瘤的免疫细胞浸润,并刺激脾细胞产生保护性T细胞免疫。安全性分析表明毒性极小。ATR抑制增强了肺癌消融放疗和免疫疗法的疗效。这些发现强调了联合疗法对增强全身抗肿瘤免疫反应和疗效的重要性。
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引用次数: 0
Differential T cell accumulation within intracranial and subcutaneous melanomas is associated with differences in intratumoral myeloid cells. 颅内和皮下黑色素瘤内不同的 T 细胞聚集与瘤内髓样细胞的差异有关。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-11-02 DOI: 10.1007/s00262-024-03832-0
Katarzyna Stasiak, Aaron D Stevens, Ashley C Bolte, Colleen T Curley, Mirna Perusina Lanfranca, Robin S Lindsay, Ukpong B Eyo, John R Lukens, Richard J Price, Timothy N J Bullock, Victor H Engelhard

Patients with metastatic brain melanomas (MBM) experience shorter-lasting survival than patients with extracranial metastases, and this is associated with a higher fraction of dysfunctional CD8 T cells. The goal of this study was to understand the underlying cause of T cell dysfunction in MBM. To accomplish this, we compared murine B16 melanomas implanted intracranially (IC) or subcutaneously (SC). CD8 T cell activation was not altered, but representation in IC tumors was lower. Transferred activated or naïve CD8 T cells accumulated in similar numbers in both tumors, suggesting that the vasculature does not differentially impair T cell presence. Surprisingly, we found no evidence for T cell activation in draining lymph nodes of SC or IC tumor-bearing mice, consistent with the fact that dendritic cells (DC) that had acquired tumor antigen showed an immature phenotype. Instead, T cell activation occurred within both tumors, where the majority of tumor antigen+ myeloid cells were found. While, the numbers of intratumoral DC were comparable, those in IC tumors acquired less tumor antigen, and were alternatively matured based on upregulation of MHCII without upregulation of CD86. Additionally, in IC tumors, the largest population of tumor antigen+ myeloid cells were microglia. However, their presence did not influence either antigen acquisition or the phenotype of other myeloid cell populations. Overall, our data suggest that diminished representation of CD8 T cells in IC tumors is a consequence of alternatively matured DC and/or microglia that induce distinctly activated T cells, which ultimately fail to continue to accumulate inside the tumor.

与颅外转移患者相比,转移性脑黑色素瘤(MBM)患者的存活期更短,而这与功能失调的 CD8 T 细胞比例较高有关。本研究的目的是了解T细胞功能障碍在MBM中的根本原因。为此,我们比较了植入颅内(IC)或皮下(SC)的小鼠 B16 黑色素瘤。CD8 T 细胞活化没有改变,但在 IC 肿瘤中的代表性较低。转移的活化或天真 CD8 T 细胞在两种肿瘤中积累的数量相似,这表明血管不会对 T 细胞的存在造成不同程度的影响。令人惊讶的是,我们没有在SC或IC肿瘤小鼠的引流淋巴结中发现T细胞活化的证据,这与获得肿瘤抗原的树突状细胞(DC)表现出不成熟表型的事实一致。相反,T细胞活化发生在两种肿瘤内,在肿瘤内发现了大多数肿瘤抗原+髓系细胞。虽然瘤内DC的数量相当,但IC肿瘤中的DC获得的肿瘤抗原较少,而且是根据MHCII的上调而非CD86的上调成熟的。此外,在 IC 肿瘤中,肿瘤抗原+髓系细胞的最大群体是小胶质细胞。但是,它们的存在既不影响抗原的获得,也不影响其他髓系细胞群的表型。总之,我们的数据表明,CD8 T 细胞在 IC 肿瘤中的代表性降低是另类成熟的 DC 和/或小胶质细胞诱导出明显活化的 T 细胞的结果,这些 T 细胞最终无法继续在肿瘤内聚集。
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引用次数: 0
Uncovering the role of tumor cGAS expression in predicting response to PD-1/L1 inhibitors in non-small cell lung cancer. 揭示肿瘤 cGAS 表达在预测非小细胞肺癌患者对 PD-1/L1 抑制剂反应中的作用。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-11-02 DOI: 10.1007/s00262-024-03861-9
Yuichi Ozawa, Yasuhiro Koh, Ryota Shibaki, Yuhei Harutani, Hiroaki Akamatsu, Atsushi Hayata, Takeya Sugimoto, Yuka Kitamura, Junya Fukuoka, Masanori Nakanishi, Nobuyuki Yamamoto

Objectives: The impact of cGAS/STING tumor expression on PD-1/L1 inhibitor efficacy and the tumor microenvironment remain to be elucidated.

Methods: In a post-hoc analysis of a prospective biomarker study with 106 advanced NSCLC patients treated with PD-1/L1 inhibitors from December 2015 to September 2018, tumor tissue before treatment from 68 patients was analyzed. cGAS and STING expression were measured using immunohistochemical staining and H-scores. Additionally, 40 serum proteins were quantified before and 4-6 weeks after treatment initiation.

Results: Median cGAS and STING H-scores were 220 (range, 5-300) and 190 (range, 0-300), respectively. There were no differences in cGAS or STING H-scores between the high (tumor proportion score [TPS] ≥ 50) and low (TPS < 50) PD-L1groups (p = 0.990 and 0.283, respectively). Unexpectedly, patients with high cGAS (H-score ≥ 220) demonstrated significantly shorter progression-free survival (PFS) of PD-1/L1 inhibitors when the PD-L1 TPS was high (median PFS: 143 days vs. not reached; p = 0.028); PFS at 18 months was 7% and 53% in the high and low cGAS groups, respectively while STING expression did not impact PFS. In serum protein analyses, high cGAS H-score was associated with significantly higher TGF-β1 and TGF-β2 before PD-1/L1 inhibition (47.5 vs. 22.3 ng/l, p = 0.023; 2118 vs. 882 pg/ml, p = 0.037); additionally, the cGAS H-score significantly correlated with TGF-β1 (r = 0.451, p = 0.009) and TGF-β2 (r = 0.375, p = 0.031) basal levels.

Conclusion: cGAS expression, but not STING, predicts poor PD-1/L1 inhibitor efficacy in NSCLC with high PD-L1, potentially due to a TGF-β-mediated immunosuppressive environment (UMIN000024414).

目的:cGAS/STING肿瘤表达对PD-1/L1抑制剂疗效和肿瘤微环境的影响仍有待阐明:cGAS/STING肿瘤表达对PD-1/L1抑制剂疗效和肿瘤微环境的影响仍有待阐明:在2015年12月至2018年9月对106例接受PD-1/L1抑制剂治疗的晚期NSCLC患者进行的一项前瞻性生物标志物研究的事后分析中,分析了68例患者治疗前的肿瘤组织,使用免疫组化染色和H-评分测量了cGAS和STING的表达。此外,还对治疗开始前和治疗开始后4-6周的40种血清蛋白进行了量化:结果:cGAS和STING H评分的中位数分别为220(范围为5-300)和190(范围为0-300)。结论:在PD-L1较高的NSCLC中,cGAS表达(而非STING)可预测PD-1/L1抑制剂疗效不佳,这可能是由于TGF-β介导的免疫抑制环境所致 (UMIN000024414)。
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引用次数: 0
Immune checkpoint inhibitors-related thyroid dysfunction: influencing factor analysis, prediction model development, and management strategy proposal. 免疫检查点抑制剂相关甲状腺功能障碍:影响因素分析、预测模型开发和管理策略建议。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-11-02 DOI: 10.1007/s00262-024-03816-0
Xinya Li, Zaiwei Song, Yixuan Chen, Jingjing Wu, Dan Jiang, Zhen Zhang, Zeyuan Wang, Rongsheng Zhao

Background: With the extensive utilization of immune checkpoint inhibitors (ICIs) across various cancers, ICIs-related thyroid dysfunction (ICI-TD) has become a growing concern in clinical practice. This study aimed to devise an individualized management strategy for ICI-TD to enhance the early identification and proactive management in cancer patients.

Methods: We designed and conducted a three-phase study. Initially, we analyzed the influencing factors through a systematic review and meta-analysis, which adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Moreover, the study protocol was registered with PROSPERO (CRD42019131133). Subsequently, prediction models for ICI-TD were developed utilizing 11 algorithms based on the real-world cohort data from July 20, 2018 (the approval date of the first ICIs, Pembrolizumab in China), to October 31, 2022. Considering discrimination, calibration, and clinical utility, we selected the model with the best performance for web calculator development. Finally, individualized management strategies for ICI-TD were proposed by combining evidence-based analysis with practical considerations.

Results: The systematic review encompassed 21 observational studies involving 4,145 patients, revealing associations between ICI-TD and factors such as female gender, age, receipt of Pembrolizumab (versus other ICIs), and baseline levels of thyroid-stimulating hormone, free thyroxine, and antithyroid antibodies. In the prediction model development phase, 621 participants were enrolled, with 36 patients developing ICI-TD. The model based on the LightGBM algorithm demonstrated superior performance, leading to the development of a web calculator. Based on these findings and existing guidelines, individualized monitoring and treatment pathways for pharmacists were devised.

Conclusion: This study offers comprehensive insights into managing ICI-TD, potentially enhancing tailored cancer immunotherapy management.

背景:随着免疫检查点抑制剂(ICIs)在各种癌症中的广泛应用,ICIs相关甲状腺功能障碍(ICI-TD)已成为临床实践中日益关注的问题。本研究旨在为ICI-TD制定个体化管理策略,以加强对癌症患者的早期识别和积极管理:我们设计并开展了一项三阶段研究。首先,我们根据系统综述和荟萃分析(PRISMA)指南,通过系统综述和荟萃分析分析了影响因素。此外,研究方案已在 PROSPERO 注册(CRD42019131133)。随后,根据从2018年7月20日(中国首个ICIs--彭博利珠单抗的批准日期)到2022年10月31日的真实世界队列数据,利用11种算法开发了ICI-TD的预测模型。考虑到辨别力、校准和临床实用性,我们选择了性能最佳的模型用于网络计算器的开发。最后,结合循证分析和实际情况,提出了ICI-TD的个体化管理策略:系统综述包括21项观察性研究,涉及4145名患者,揭示了ICI-TD与女性性别、年龄、接受Pembrolizumab治疗(与其他ICI相比)以及促甲状腺激素、游离甲状腺素和抗甲状腺抗体基线水平等因素之间的关联。在预测模型开发阶段,共招募了 621 名参与者,其中 36 名患者出现了 ICI-TD。基于 LightGBM 算法的模型表现出卓越的性能,因此开发了网络计算器。根据这些研究结果和现有指南,为药剂师设计了个性化的监测和治疗路径:本研究为 ICI-TD 的管理提供了全面的见解,有可能加强量身定制的癌症免疫疗法管理。
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引用次数: 0
Breaking the shield of solid tumors: a combined approach for enhanced efficacy of CAR-T cells. 打破实体肿瘤的防护罩:增强 CAR-T 细胞疗效的综合方法。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-11-02 DOI: 10.1007/s00262-024-03817-z
Marat Khaliulin, Aygul Valiullina, Alexey Petukhov, Youyong Yuan, Sheila Spada, Emil Bulatov

The use of chimeric antigen receptor (CAR)-T cells has enhanced the range of available therapeutic modalities in the context of cancer treatment. CAR-T cells have demonstrated considerable efficacy in the targeted eradication of blood cancer cells, thereby stimulating substantial interest in the advancement of such therapeutic approaches. However, the efficacy of CAR-T cells against solid tumor cells has been limited due to the presence of various obstacles. Solid tumors exhibit antigenic diversity and an immunosuppressive microenvironment, which presents a challenge for immune cells attempting to penetrate the tumor. CAR-T cells also demonstrate decreased proliferative activity and cytotoxicity. Furthermore, concerns exist regarding tumor antigen loss and therapy-associated toxicity. Currently, scientists are working to enhance the structure of the CAR and improve the survival and efficiency of CAR-T cells in recognizing tumor antigens in solid tumors. Chemotherapy drugs are frequently employed in the treatment of malignant neoplasms and can also be used prior to cell therapy to enhance CAR-T cell engraftment. Recent studies have demonstrated that chemotherapy drugs can mitigate the suppressive impact of TME, eliminate the physical barrier by destroying the tumor stroma, and facilitate greater penetration of immune cells and CAR-T cells into the tumor. This, in turn, increases their survival, persistence, and cytotoxicity, as well as affects the metabolism of immune cells inside the tumor. However, the effectiveness of the combined approach against solid tumors depends on several factors, including the type of tumor, dosage, population of CAR-T cells, and individual characteristics of the body. This review examines the principal obstacles to the utilization of CAR-T cells against solid tumors, proposes solutions to these issues, and assesses the potential advantages of a combined approach to radiation exposure, which has the potential to enhance the sensitivity of the tumor to other agents.

嵌合抗原受体(CAR)-T 细胞的使用扩大了癌症治疗的可用治疗方法范围。CAR-T 细胞在有针对性地根除血癌细胞方面已显示出相当大的疗效,从而激发了人们对推进此类治疗方法的浓厚兴趣。然而,由于存在各种障碍,CAR-T 细胞对实体瘤细胞的疗效受到了限制。实体瘤表现出抗原多样性和免疫抑制微环境,这给试图穿透肿瘤的免疫细胞带来了挑战。CAR-T 细胞的增殖活性和细胞毒性也有所下降。此外,肿瘤抗原丢失和治疗相关毒性也令人担忧。目前,科学家们正在努力增强 CAR 的结构,提高 CAR-T 细胞的存活率和识别实体瘤中肿瘤抗原的效率。化疗药物是治疗恶性肿瘤的常用药物,也可在细胞治疗前使用,以提高 CAR-T 细胞的接种率。最近的研究表明,化疗药物可减轻TME的抑制作用,通过破坏肿瘤基质消除物理屏障,促进免疫细胞和CAR-T细胞更好地穿透肿瘤。这反过来又会提高它们的存活率、持久性和细胞毒性,并影响肿瘤内免疫细胞的新陈代谢。然而,联合疗法对实体瘤的疗效取决于多种因素,包括肿瘤类型、剂量、CAR-T 细胞的数量以及机体的个体特征。这篇综述探讨了利用 CAR-T 细胞治疗实体瘤的主要障碍,提出了解决这些问题的方法,并评估了辐射照射联合方法的潜在优势,因为这种方法有可能提高肿瘤对其他药物的敏感性。
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引用次数: 0
期刊
Cancer Immunology, Immunotherapy
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