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Tumor immunogenicity regulates host immune responses, and conventional dendritic cell type 2 uptakes the majority of tumor antigens in an orthotopic lung cancer model. 肿瘤的免疫原性调节宿主的免疫反应,传统的树突状细胞 2 型在正位肺癌模型中吸收了大部分肿瘤抗原。
IF 5.4 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-03 DOI: 10.1007/s00262-024-03828-w
Ki-Hyun Kim, Seung-Jae Kim, Jacob D Eccles, Christian Ascoli, Gye Young Park

Human lung cancer carries high genetic alterations, expressing high tumor-specific neoantigens. Although orthotopic murine lung cancer models recapitulate many characteristics of human lung cancers, genetically engineered mouse models have fewer somatic mutations than human lung cancer, resulting in scarce immune cell infiltration and deficient immune responses. The endogenous mouse lung cancer model driven by Kras mutation and Trp53 deletion (KP model) has minimal immune infiltration because of a scarcity of neoantigens. Fine-tuning tumor antigenicity to trigger the appropriate level of antitumor immunity would be key to investigating immune responses against human lung cancer. We engineered the KP model to express antigens of OVA peptides (minOVA) as neoantigens along with ZsGreen, a traceable fluorescent conjugate. The KP model expressing minOVA exhibited stronger immunogenicity with higher immune cell infiltration comprised of CD8+ T cells and CD11c+ dendritic cells (DCs). Consequently, the KP model expressing minOVA exhibits suppressed tumor growth compared to its origin. We further analyzed tumor-infiltrated DCs. The majority of ZsGreen conjugated with minOVA was observed in the conventional type 2 DCs (cDC2), whereas cDC1 has minimal. These data indicate that tumor immunogenicity regulates host immune responses, and tumor neoantigen is mostly recognized by cDC2 cells, which may play a critical role in initiating antitumor immune responses in an orthotopic murine lung cancer model.

人类肺癌具有高度基因改变,表达大量肿瘤特异性新抗原。虽然正位小鼠肺癌模型再现了人类肺癌的许多特征,但基因工程小鼠模型的体细胞突变少于人类肺癌,导致免疫细胞浸润稀少和免疫反应不足。由 Kras 突变和 Trp53 缺失驱动的内源性小鼠肺癌模型(KP 模型)由于缺乏新抗原,免疫浸润极少。微调肿瘤抗原性以触发适当水平的抗肿瘤免疫是研究人类肺癌免疫反应的关键。我们设计了 KP 模型,以表达作为新抗原的 OVA 肽抗原(minOVA)和 ZsGreen(一种可追踪的荧光共轭物)。表达 minOVA 的 KP 模型表现出更强的免疫原性和更高的免疫细胞浸润,其中包括 CD8+ T 细胞和 CD11c+ 树突状细胞(DC)。因此,表达 minOVA 的 KP 模型的肿瘤生长比其原发模型受到抑制。我们进一步分析了肿瘤浸润的 DCs。在传统的 2 型 DCs(cDC2)中观察到了大部分与 minOVA 结合的 ZsGreen,而 cDC1 中的 ZsGreen 极少。这些数据表明,肿瘤免疫原性调控宿主免疫反应,肿瘤新抗原主要由 cDC2 细胞识别,它们可能在正位小鼠肺癌模型中启动抗肿瘤免疫反应中发挥关键作用。
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引用次数: 0
Efficacy and safety of lenvatinib combined with anti-PD-1 antibodies plus GEMOX chemotherapy as non-first-line systemic therapy in advanced gallbladder cancer. 来伐替尼联合抗PD-1抗体加GEMOX化疗作为晚期胆囊癌非一线系统疗法的有效性和安全性。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-03 DOI: 10.1007/s00262-024-03831-1
Yang Tan, Kai Liu, Chengpei Zhu, Shanshan Wang, Yunchao Wang, Jingnan Xue, Cong Ning, Nan Zhang, Jiashuo Chao, Longhao Zhang, Junyu Long, Xiaobo Yang, Daobing Zeng, Lijin Zhao, Haitao Zhao

Background: Lenvatinib, programmed cell death 1 (PD-1) antibodies, and gemcitabine and oxaliplatin (GEMOX) chemotherapy have shown significant antitumor activity as first-line therapy against biliary tract cancer. This study evaluated their efficacy and safety as non-first-line therapy in advanced gallbladder cancer (GBC).

Methods: Patients with advanced GBC who received lenvatinib combined with anti-PD-1 antibodies and GEMOX chemotherapy as a non-first-line therapy were retrospectively analyzed. The primary endpoints were overall survival (OS) and progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR) and safety.

Results: A total of 36 patients with advanced GBC were included in this study. The median follow-up time was 11.53 (95% confidence interval (CI): 2.2-20.9) months, and the ORR was 36.1%. The median OS and PFS were 15.1 (95% CI: 3.2-26.9) and 6.1 (95% CI: 4.9-7.2) months, respectively. The disease control rate (DCR) and clinical benefit rate (CBR) were 75% and 61.1%, respectively. Subgroup analysis demonstrated that patients with programmed cell death-ligand 1 (PD-L1) expression had significantly longer PFS and OS than those without PD-L1 expression. Additionally, patients with a neutrophil-lymphocyte ratio (NLR) < 5.57 had a longer OS than those with an NLR ≥ 5.57. All patients experienced adverse events (AEs), with 61.1% experiencing grade 3 or 4 AEs, including myelosuppression (13.9%) and fatigue (13.3%), alanine transaminase or aspartate transaminase levels (8.3%), and diarrhea (8.3%). No grade 5 AEs were reported.

Conclusion: Anti-PD-1 antibodies combined with lenvatinib and GEMOX chemotherapy are effective and well-tolerated as a non-first-line therapy in advanced GBC. PD-L1 expression and baseline NLR may potentially predict treatment efficacy.

背景:伦伐替尼、程序性细胞死亡1(PD-1)抗体以及吉西他滨和奥沙利铂(GEMOX)化疗作为胆道癌的一线疗法已显示出显著的抗肿瘤活性。本研究评估了它们作为晚期胆囊癌(GBC)非一线疗法的有效性和安全性:回顾性分析了接受来伐替尼联合抗PD-1抗体和GEMOX化疗作为非一线疗法的晚期胆囊癌患者。主要终点是总生存期(OS)和无进展生存期(PFS),次要终点是客观反应率(ORR)和安全性:本研究共纳入了36名晚期GBC患者。中位随访时间为11.53个月(95%置信区间(CI):2.2-20.9),ORR为36.1%。中位OS和PFS分别为15.1个月(95% 置信区间:3.2-26.9)和6.1个月(95% 置信区间:4.9-7.2)。疾病控制率(DCR)和临床获益率(CBR)分别为75%和61.1%。亚组分析显示,有程序性细胞死亡配体1(PD-L1)表达的患者的PFS和OS明显长于无PD-L1表达的患者。此外,中性粒细胞-淋巴细胞比值(NLR)结论也表明,PD-L1表达的患者的PFS和OS明显长于无PD-L1表达的患者:抗PD-1抗体联合来伐替尼和GEMOX化疗作为晚期GBC的非一线疗法有效且耐受性良好。PD-L1 表达和基线 NLR 有可能预测疗效。
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引用次数: 0
NitraTh epitope-based neoantigen vaccines for effective tumor immunotherapy. 基于 NitraTh 表位的新抗原疫苗用于有效的肿瘤免疫疗法。
IF 5.4 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-03 DOI: 10.1007/s00262-024-03830-2
Wanli Zhang, Xupeiyao Shi, Shitong Huang, Qiumin Yu, Zijie Wu, Wenbin Xie, Binghua Li, Yanchao Xu, Zheng Gao, Guozhi Li, Qianqian Qian, Tiandi He, Jiaxue Zheng, Tingran Zhang, Yue Tong, Danni Deng, Xiangdong Gao, Hong Tian, Wenbing Yao

Neoantigen vaccines represent an emerging and promising strategy in the field of tumor immunotherapy. Despite their potential, designing an effective neoantigen vaccine remains a challenge due to the current limitations in predicting CD4+ T cell epitopes with high accuracy. Here, we introduce a novel approach to neoantigen vaccine design that does not rely on computational prediction of CD4+ T cell epitopes. Utilizing nitrated helper T cell epitope containing p-nitrophenylalanine, termed "NitraTh epitope," we have successfully engineered a series of tumor neoantigen vaccines capable of eliciting robust neoantigen-specific immune responses. With the help of NitraTh epitope, even mutations with low predicted affinity for MHC class I molecules were successfully induced to elicit neoantigen-specific responses. In H22 cell allograft and patient-derived xenograft (PDX) liver cancer mouse models, the NitraTh epitope-based neoantigen vaccines significantly suppressed tumor progression. More strikingly, through single-cell sequencing we found that the NitraTh epitope-based neoantigen vaccines regulate macrophage reprogramming and modulate macrophages to decrease the levels of the immunosuppressive molecule prostaglandin E2 (PGE2), which in turn reshapes the tumor immunosuppressive microenvironment. In summary, NitraTh epitope-based neoantigen vaccines possess the dual effects of potently activating neoantigen-specific immunity and alleviating immunosuppression, potentially providing a new paradigm for the design of tumor neoantigen vaccines.

在肿瘤免疫疗法领域,新抗原疫苗是一种新兴且前景广阔的策略。尽管新抗原疫苗潜力巨大,但由于目前在高精度预测 CD4+ T 细胞表位方面的局限性,设计有效的新抗原疫苗仍是一项挑战。在这里,我们介绍了一种不依赖于 CD4+ T 细胞表位计算预测的新抗原疫苗设计方法。利用含有对硝基苯丙氨酸的硝化辅助 T 细胞表位(称为 "NitraTh 表位"),我们成功地设计出了一系列肿瘤新抗原疫苗,这些疫苗能够引起强大的新抗原特异性免疫反应。在 NitraTh 表位的帮助下,即使是对 MHC I 类分子亲和力较低的突变也能成功诱导出新抗原特异性反应。在 H22 细胞异种移植和患者来源异种移植(PDX)肝癌小鼠模型中,基于 NitraTh 表位的新抗原疫苗显著抑制了肿瘤进展。更引人注目的是,通过单细胞测序,我们发现基于 NitraTh 表位的新抗原疫苗能调节巨噬细胞重编程,并调节巨噬细胞以降低免疫抑制分子前列腺素 E2 (PGE2) 的水平,进而重塑肿瘤免疫抑制微环境。总之,基于 NitraTh 表位的新抗原疫苗具有强效激活新抗原特异性免疫和缓解免疫抑制的双重作用,有可能为肿瘤新抗原疫苗的设计提供新的范例。
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引用次数: 0
The relevance of tumor target expression levels on IgA-mediated cytotoxicity in cancer immunotherapy. 肿瘤靶点表达水平与癌症免疫疗法中 IgA 介导的细胞毒性的相关性。
IF 5.4 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-03 DOI: 10.1007/s00262-024-03824-0
Chilam Chan, Núria Casalé Cabanes, J H Marco Jansen, Joël Guillaume, Maaike Nederend, Elsemieke M Passchier, Valentina E Gómez-Mellado, Matthias Peipp, Marianne Boes, Geert van Tetering, Jeanette H W Leusen

Recent advances in cancer immunotherapy, particularly the success of immune checkpoint inhibitors, have reignited interest in targeted monoclonal antibodies for immunotherapy. Antibody therapies aim to minimize on-target, off-tumor toxicity by targeting antigens overexpressed on tumor cells but not on healthy cells. Despite considerable efforts, some therapeutic antibodies have been linked to dose-limiting side effects. Our hypothesis suggests that the efficacy of IgG leads to a lower target expression threshold for tumor cell killing, contributing to these side effects. Earlier, therapeutic IgG antibodies were reformatted into the IgA isotype. Unlike IgG, which primarily engages Fc gamma receptors (FcγR) to induce antibody-dependent cellular cytotoxicity (ADCC) by NK cells and antibody-dependent cellular phagocytosis (ADCP) by monocytes/macrophages, IgA antibodies activate neutrophils through the Fc alpha receptor I (CD89, FcαRI). In previous studies, it appeared that IgA may require a higher target expression threshold for effective killing, and we aimed to investigate this in our current study. Moreover, we investigated how blocking the myeloid checkpoint CD47/SIRPα axis affect the target expression threshold. Using a tetracycline-inducible expression system, we regulated target expression in different cell lines. Our findings from ADCC assays indicate that IgA-mediated PMN ADCC requires a higher antigen expression level than IgG-mediated PBMC ADCC. Furthermore, blocking CD47 enhanced IgA-mediated ADCC, lowering the antigen threshold. Validated in two in vivo models, our results show that IgA significantly reduces tumor growth in high-antigen-expressing tumors without affecting low-antigen-expressing healthy tissues. This suggests IgA-based immunotherapy could potentially minimize on-target, off-tumor side effects, improving treatment efficacy and patient safety.

癌症免疫疗法的最新进展,尤其是免疫检查点抑制剂的成功,重新点燃了人们对免疫疗法靶向单克隆抗体的兴趣。抗体疗法的目的是通过靶向肿瘤细胞上过度表达而健康细胞上不表达的抗原,最大限度地减少靶上毒性和瘤外毒性。尽管做了大量努力,但一些治疗性抗体仍与剂量限制性副作用有关。我们的假设表明,IgG 的疗效降低了杀伤肿瘤细胞的靶点表达阈值,从而导致了这些副作用。早些时候,治疗性 IgG 抗体被重新格式化为 IgA 同工型。IgG主要通过Fcγ受体(FcγR)诱导NK细胞的抗体依赖性细胞毒性(ADCC)和单核细胞/巨噬细胞的抗体依赖性细胞吞噬(ADCP),而IgA抗体则通过Fcα受体I(CD89,FcαRI)激活中性粒细胞。在以前的研究中,IgA 似乎需要更高的目标表达阈值才能有效杀伤,我们在目前的研究中旨在调查这一点。此外,我们还研究了阻断髓系检查点 CD47/SIRPα 轴对靶表达阈值的影响。利用四环素诱导表达系统,我们调节了不同细胞系的靶点表达。我们的 ADCC 试验结果表明,与 IgG 介导的 PBMC ADCC 相比,IgA 介导的 PMN ADCC 需要更高的抗原表达水平。此外,阻断 CD47 可增强 IgA 介导的 ADCC,降低抗原阈值。通过两个体内模型的验证,我们的结果表明,IgA能显著降低高抗原表达肿瘤的生长,而不影响低抗原表达的健康组织。这表明,基于 IgA 的免疫疗法有可能最大限度地减少靶上和瘤外副作用,提高治疗效果和患者安全性。
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引用次数: 0
Development and validation of a new tool to estimate early mortality in patients with advanced cancer treated with immunotherapy. 开发并验证用于估算接受免疫疗法的晚期癌症患者早期死亡率的新工具。
IF 5.4 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-03 DOI: 10.1007/s00262-024-03836-w
Andrea De Giglio, Alessandro Leonetti, Francesca Comito, Daria Maria Filippini, Veronica Mollica, Karim Rihawi, Marianna Peroni, Giulia Mazzaschi, Ilaria Ricciotti, Francesca Carosi, Andrea Marchetti, Matteo Rosellini, Ambrogio Gagliano, Valentina Favorito, Elisabetta Nobili, Francesco Gelsomino, Barbara Melotti, Paola Valeria Marchese, Francesca Sperandi, Alessandro Di Federico, Sebastiano Buti, Fabiana Perrone, Francesco Massari, Maria Abbondanza Pantaleo, Marcello Tiseo, Andrea Ardizzoni

Background: Immune checkpoint inhibitors (ICIs) are standard treatments for advanced solid cancers. Resistance to ICIs, both primary and secondary, poses challenges, with early mortality (EM) within 30-90 days indicating a lack of benefit. Prognostic factors for EM, including the lung immune prognostic index (LIPI), remain underexplored.

Methods: We performed a retrospective, observational study including patients affected by advanced solid tumors, treated with ICI as single agent or combined with other agents. Logistic regression models identified factors associated with EM and 90-day progression risks. A nomogram for predicting 90-day mortality was built and validated within an external cohort.

Results: In total, 637 patients received ICIs (single agent or in combination with other drugs) for advanced solid tumors. Most patients were male (61.9%), with NSCLC as the prevalent tumor (61.8%). Within the cohort, 21.3% died within 90 days, 8.4% died within 30 days, and 34.5% experienced early progression. Factors independently associated with 90-day mortality included ECOG PS 2 and a high/intermediate LIPI score. For 30-day mortality, lung metastasis and a high/intermediate LIPI score were independent risk factors. Regarding early progression, high/intermediate LIPI score was independently associated. A predictive nomogram for 90-day mortality combining LIPI and ECOG PS achieved an AUC of 0.76 (95% CI 0.71-0.81). The discrimination ability of the nomogram was confirmed in the external validation cohort (n = 255) (AUC 0.72, 95% CI 0.64-0.80).

Conclusion: LIPI and ECOG PS independently were able to estimate 90-day mortality, with LIPI also demonstrating prognostic validity for 30-day mortality and early progression.

背景:免疫检查点抑制剂(ICIs免疫检查点抑制剂(ICIs)是晚期实体瘤的标准疗法。对 ICIs 的耐药性(包括原发性和继发性)带来了挑战,30-90 天内的早期死亡率(EM)表明缺乏获益。包括肺免疫预后指数(LIPI)在内的EM预后因素仍未得到充分探讨:我们进行了一项回顾性观察研究,研究对象包括晚期实体瘤患者,他们接受了 ICI 单药治疗或与其他药物联合治疗。逻辑回归模型确定了与EM和90天进展风险相关的因素。建立了预测90天死亡率的提名图,并在外部队列中进行了验证:共有 637 名晚期实体瘤患者接受了 ICIs(单药或与其他药物联用)治疗。大多数患者为男性(61.9%),主要肿瘤为 NSCLC(61.8%)。在队列中,21.3%的患者在90天内死亡,8.4%的患者在30天内死亡,34.5%的患者病情出现早期进展。与90天死亡率独立相关的因素包括ECOG PS 2和高/中LIPI评分。就30天死亡率而言,肺转移和高/中LIPI评分是独立的风险因素。在早期进展方面,高/中LIPI评分是独立的相关因素。结合 LIPI 和 ECOG PS 的 90 天死亡率预测提名图的 AUC 为 0.76(95% CI 0.71-0.81)。外部验证队列(n = 255)证实了该提名图的区分能力(AUC 0.72,95% CI 0.64-0.80):结论:LIPI和ECOG PS能够独立估算90天死亡率,LIPI还显示出对30天死亡率和早期进展的预后有效性。
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引用次数: 0
A random survival forest-based pathomics signature classifies immunotherapy prognosis and profiles TIME and genomics in ES-SCLC patients. 基于随机生存森林的病理组学特征可对ES-SCLC患者的免疫疗法预后进行分类,并对TIME和基因组学进行分析。
IF 5.4 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-03 DOI: 10.1007/s00262-024-03829-9
Yuxin Jiang, Yueying Chen, Qinpei Cheng, Wanjun Lu, Yu Li, Xueying Zuo, Qiuxia Wu, Xiaoxia Wang, Fang Zhang, Dong Wang, Qin Wang, Tangfeng Lv, Yong Song, Ping Zhan

Background: Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor with high mortality, and only a limited subset of extensive-stage SCLC (ES-SCLC) patients demonstrate prolonged survival under chemoimmunotherapy, which warrants the exploration of reliable biomarkers. Herein, we built a machine learning-based model using pathomics features extracted from hematoxylin and eosin (H&E)-stained images to classify prognosis and explore its potential association with genomics and TIME.

Methods: We retrospectively recruited ES-SCLC patients receiving first-line chemoimmunotherapy at Nanjing Jinling Hospital between April 2020 and August 2023. Digital H&E-stained whole-slide images were acquired, and targeted next-generation sequencing, programmed death ligand-1 staining, and multiplex immunohistochemical staining for immune cells were performed on a subset of patients. A random survival forest (RSF) model encompassing clinical and pathomics features was established to predict overall survival. The function of putative genes was assessed via single-cell RNA sequencing.

Results and conclusion: During the median follow-up period of 12.12 months, 118 ES-SCLC patients receiving first-line immunotherapy were recruited. The RSF model utilizing three pathomics features and liver metastases, bone metastases, smoking status, and lactate dehydrogenase, could predict the survival of first-line chemoimmunotherapy in patients with ES-SCLC with favorable discrimination and calibration. Underlyingly, the higher RSF-Score potentially indicated more infiltration of CD8+ T cells in the stroma as well as a greater probability of MCL-1 amplification and EP300 mutation. At the single-cell level, MCL-1 was associated with TNFA-NFKB signaling and apoptosis-related processes. Hopefully, this noninvasive model could act as a biomarker for immunotherapy, potentially facilitating precision medicine in the management of ES-SCLC.

背景:小细胞肺癌(SCLC)是一种侵袭性很强的神经内分泌肿瘤,死亡率很高,只有少数广泛期SCLC(ES-SCLC)患者在化疗免疫治疗下能延长生存期,因此需要探索可靠的生物标志物。在此,我们利用从苏木精和伊红(H&E)染色图像中提取的病理组学特征建立了一个基于机器学习的模型,对预后进行分类,并探索其与基因组学和TIME的潜在关联:我们回顾性地招募了2020年4月至2023年8月期间在南京金陵医院接受一线化疗免疫治疗的ES-SCLC患者。我们采集了数字化H&E染色的全切片图像,并对部分患者进行了靶向新一代测序、程序性死亡配体-1染色和免疫细胞多重免疫组化染色。建立了一个包含临床和病理组学特征的随机生存森林(RSF)模型来预测总生存率。通过单细胞RNA测序评估了推测基因的功能:在中位随访期12.12个月期间,共招募了118名接受一线免疫疗法的ES-SCLC患者。利用三个病理组学特征和肝转移、骨转移、吸烟状态及乳酸脱氢酶的RSF模型,可以预测ES-SCLC患者一线化疗免疫治疗的生存率,并具有良好的区分度和校准性。RSF-Score越高,表明基质中CD8+ T细胞浸润越多,MCL-1扩增和EP300突变的可能性越大。在单细胞水平上,MCL-1 与 TNFA-NFKB 信号转导和细胞凋亡相关过程有关。希望这种非侵入性模型能成为免疫疗法的生物标记物,从而促进ES-SCLC治疗的精准医疗。
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引用次数: 0
PD-1 blockade does not improve efficacy of EpCAM-directed CAR T-cell in lung cancer brain metastasis. PD-1阻断不能提高EpCAM引导的CAR T细胞对肺癌脑转移的疗效。
IF 5.4 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-03 DOI: 10.1007/s00262-024-03837-9
Jens Blobner, Laura Dengler, Constantin Eberle, Julika J Herold, Tao Xu, Alexander Beck, Anton Mühlbauer, Katharina J Müller, Nico Teske, Philipp Karschnia, Dominic van den Heuvel, Ferdinand Schallerer, Hellen Ishikawa-Ankerhold, Niklas Thon, Joerg-Christian Tonn, Marion Subklewe, Sebastian Kobold, Patrick N Harter, Veit R Buchholz, Louisa von Baumgarten

Background: Lung cancer brain metastasis has a devastating prognosis, necessitating innovative treatment strategies. While chimeric antigen receptor (CAR) T-cell show promise in hematologic malignancies, their efficacy in solid tumors, including brain metastasis, is limited by the immunosuppressive tumor environment. The PD-L1/PD-1 pathway inhibits CAR T-cell activity in the tumor microenvironment, presenting a potential target to enhance therapeutic efficacy. This study aims to evaluate the impact of anti-PD-1 antibodies on CAR T-cell in treating lung cancer brain metastasis.

Methods: We utilized a murine immunocompetent, syngeneic orthotopic cerebral metastasis model for repetitive intracerebral two-photon laser scanning microscopy, enabling in vivo characterization of red fluorescent tumor cells and CAR T-cell at a single-cell level over time. Red fluorescent EpCAM-transduced Lewis lung carcinoma cells (EpCAM/tdtLL/2 cells) were implanted intracranially. Following the formation of brain metastasis, EpCAM-directed CAR T-cell were injected into adjacent brain tissue, and animals received either anti-PD-1 or an isotype control.

Results: Compared to controls receiving T-cell lacking a CAR, mice receiving EpCAM-directed CAR T-cell showed higher intratumoral CAR T-cell densities in the beginning after intraparenchymal injection. This finding was accompanied with reduced tumor growth and translated into a survival benefit. Additional anti-PD-1 treatment, however, did not affect intratumoral CAR T-cell persistence nor tumor growth and thereby did not provide an additional therapeutic effect.

Conclusion: CAR T-cell therapy for brain malignancies appears promising. However, additional anti-PD-1 treatment did not enhance intratumoral CAR T-cell persistence or effector function, highlighting the need for novel strategies to improve CAR T-cell therapy in solid tumors.

背景:肺癌脑转移的预后极具破坏性,因此需要创新的治疗策略。虽然嵌合抗原受体(CAR)T细胞在血液恶性肿瘤中显示出良好的前景,但它们在实体瘤(包括脑转移瘤)中的疗效却受到免疫抑制性肿瘤环境的限制。PD-L1/PD-1 通路抑制 CAR T 细胞在肿瘤微环境中的活性,为提高疗效提供了潜在靶点。本研究旨在评估抗PD-1抗体对CAR T细胞治疗肺癌脑转移的影响:方法:我们利用小鼠免疫功能健全的同种异体正位脑转移模型进行重复脑内双光子激光扫描显微镜检查,从而在单细胞水平上对红色荧光肿瘤细胞和CAR T细胞随时间变化的情况进行体内表征。红色荧光 EpCAM 转化的 Lewis 肺癌细胞(EpCAM/tdtLL/2 细胞)被植入颅内。在脑转移形成后,将 EpCAM 引导的 CAR T 细胞注射到邻近的脑组织,动物接受抗 PD-1 或同型对照:结果:与接受缺乏CAR的T细胞的对照组相比,接受EpCAM定向CAR T细胞的小鼠在实质内注射后的初期表现出更高的瘤内CAR T细胞密度。这一发现伴随着肿瘤生长的减少,并转化为生存获益。然而,额外的抗PD-1治疗并没有影响瘤内CAR T细胞的持续性或肿瘤生长,因此也没有提供额外的治疗效果:结论:CAR T细胞疗法治疗脑部恶性肿瘤似乎很有前景。然而,额外的抗PD-1治疗并不能增强瘤内CAR T细胞的持久性或效应功能,这凸显出需要新的策略来改善CAR T细胞治疗实体瘤的效果。
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引用次数: 0
Toripalimab combined with definitive chemoradiotherapy for locally advanced cervical squamous cell carcinoma patients (TRACE): A single-arm, phase I/II trial. 局部晚期宫颈鳞状细胞癌患者托利帕利单抗联合放化疗(TRACE):单臂 I/II 期试验。
IF 5.4 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-03 DOI: 10.1007/s00262-024-03823-1
Dan Ou, Rong Cai, Wei-Xiang Qi, Can Cui, Lu Cao, Shu-Bei Wang, Huan Li, Tao Ma, Ying Miao, Cheng Xu, Gang Cai, Wei-Guo Cao, Yun-Sheng Gao, Jia-Yi Chen, Hao-Ping Xu

Purpose: This phase I/II trial (ChiCTR2000032879) assessed the safety and efficacy of toripalimab combined with chemoradiotherapy for locally advanced cervical squamous cell carcinoma.

Methods and materials: Twenty-two patients, regardless of their programmed death ligand-1 (PD-L1) status, received toripalimab combined with concurrent chemoradiotherapy (CCRT). CCRT included cisplatin (40 mg/m2, once weekly for 5 weeks), radiotherapy (45-50.4 Gy/25-28 Fx, 5 fractions weekly), followed by brachytherapy (24-30 Gy/3-5 Fx) and toripalimab (240 mg, intravenous) on days 1, 22 and 43 during CCRT. The primary endpoints were safety and 2-year progression-free survival (PFS). The secondary endpoints included 2-year local control (LC), local regional control and overall survival (OS).

Results: All patients successfully completed CCRT and toripalimab treatment. Grade III and higher adverse events (AEs) were observed in 11 patients (11/22, 50%), and no patient experienced grade V AEs. The objective response rate (ORR) was 100%. At the data cutoff (June 30, 2023), the median follow-up was 31.8 months (9.5 to 37.8 months). The 2-year PFS rate was 81.8%. The 2-year LC and local regional control rates were both 95.5%, and the 2-year OS rate was 90.9%.

Conclusions: Toripalimab combined with CCRT achieved good tolerance and showed promising anti-tumor effects in patients with locally advanced cervical cancer.

目的:这项I/II期试验(ChiCTR2000032879)评估了托利帕利单抗联合化放疗治疗局部晚期宫颈鳞癌的安全性和有效性:22名患者,无论其程序性死亡配体-1(PD-L1)状态如何,均接受了托利帕利单抗联合同期化放疗(CCRT)。CCRT包括顺铂(40 mg/m2,每周一次,持续5周)、放疗(45-50.4 Gy/25-28 Fx,每周5次),然后是近距离放射治疗(24-30 Gy/3-5 Fx),以及在CCRT期间的第1、22和43天使用托利帕利单抗(240 mg,静脉注射)。主要终点是安全性和两年无进展生存期(PFS)。次要终点包括2年局部控制(LC)、局部区域控制和总生存期(OS):所有患者都顺利完成了CCRT和托瑞帕利单抗治疗。11名患者(11/22,50%)出现了III级及以上不良反应(AEs),没有患者出现V级不良反应。客观反应率(ORR)为100%。截至数据截止日(2023 年 6 月 30 日),中位随访时间为 31.8 个月(9.5 至 37.8 个月)。2年PFS率为81.8%。2年LC和局部区域控制率均为95.5%,2年OS率为90.9%:结论:托利帕利单抗联合CCRT对局部晚期宫颈癌患者具有良好的耐受性和抗肿瘤效果。
{"title":"Toripalimab combined with definitive chemoradiotherapy for locally advanced cervical squamous cell carcinoma patients (TRACE): A single-arm, phase I/II trial.","authors":"Dan Ou, Rong Cai, Wei-Xiang Qi, Can Cui, Lu Cao, Shu-Bei Wang, Huan Li, Tao Ma, Ying Miao, Cheng Xu, Gang Cai, Wei-Guo Cao, Yun-Sheng Gao, Jia-Yi Chen, Hao-Ping Xu","doi":"10.1007/s00262-024-03823-1","DOIUrl":"10.1007/s00262-024-03823-1","url":null,"abstract":"<p><strong>Purpose: </strong>This phase I/II trial (ChiCTR2000032879) assessed the safety and efficacy of toripalimab combined with chemoradiotherapy for locally advanced cervical squamous cell carcinoma.</p><p><strong>Methods and materials: </strong>Twenty-two patients, regardless of their programmed death ligand-1 (PD-L1) status, received toripalimab combined with concurrent chemoradiotherapy (CCRT). CCRT included cisplatin (40 mg/m<sup>2</sup>, once weekly for 5 weeks), radiotherapy (45-50.4 Gy/25-28 Fx, 5 fractions weekly), followed by brachytherapy (24-30 Gy/3-5 Fx) and toripalimab (240 mg, intravenous) on days 1, 22 and 43 during CCRT. The primary endpoints were safety and 2-year progression-free survival (PFS). The secondary endpoints included 2-year local control (LC), local regional control and overall survival (OS).</p><p><strong>Results: </strong>All patients successfully completed CCRT and toripalimab treatment. Grade III and higher adverse events (AEs) were observed in 11 patients (11/22, 50%), and no patient experienced grade V AEs. The objective response rate (ORR) was 100%. At the data cutoff (June 30, 2023), the median follow-up was 31.8 months (9.5 to 37.8 months). The 2-year PFS rate was 81.8%. The 2-year LC and local regional control rates were both 95.5%, and the 2-year OS rate was 90.9%.</p><p><strong>Conclusions: </strong>Toripalimab combined with CCRT achieved good tolerance and showed promising anti-tumor effects in patients with locally advanced cervical cancer.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"73 12","pages":"244"},"PeriodicalIF":5.4,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11447187/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364527","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
Effectiveness, safety, and biomarker analysis of lenvatinib plus toripalimab as chemo-free therapy in advanced intrahepatic cholangiocarcinoma: a real-world study. 来伐替尼联合托瑞帕利单抗作为晚期肝内胆管癌免化疗疗法的有效性、安全性和生物标志物分析:一项真实世界研究。
IF 5.4 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-03 DOI: 10.1007/s00262-024-03841-z
Shanshan Wang, Jiashuo Chao, Hao Wang, Shuofeng Li, Yunchao Wang, Chengpei Zhu, Nan Zhang, Mingjian Piao, Xu Yang, Kai Liu, Ziyu Xun, Xinting Sang, Xiaobo Yang, Weidong Duan, Haitao Zhao

Background: Treatment options for advanced intrahepatic cholangiocarcinoma (ICC) are currently limited. Chemo-containing regimens are the mainstay treatments but associated with notable toxicity, poor tolerance, and reduced compliance, necessitating exploration of alternative therapies. Lenvatinib plus PD-1 inhibitors has shown substantial clinical activity in preliminary studies. This study aimed to assess the effectiveness and safety of lenvatinib plus toripalimab (a novel PD-1 antibody) as chemo-free therapy in advanced ICC.

Methods: This retrospective study included consecutive advanced ICC patients receiving lenvatinib plus toripalimab between February 2019 and December 2023. The main outcomes were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety. Prognostic factors and exploratory analyses for genetic alternations were also conducted.

Results: A total of 78 patients were included, with a median follow-up of 25.9 months. Median OS and PFS were 11.3 (95% CI: 9.5-13.1) and 5.4 (95% CI: 3.8-7.0) months, respectively. ORR was 19.2% and DCR was 75.6%. The incidence of grade 3 or 4 adverse events (AEs) was 50.0%, with no grade 5 AEs reported. Patients with normal baseline CA19-9 levels exhibited a higher ORR (p = 0.011), longer PFS (11.5 versus 4.6 months; HR 0.47; p=0.005), and OS (21.0 versus 9.7 months; HR 0.43; p=0.003). The presence of IDH1 mutations correlated with increased ORR (60.0% versus 8.9%, p=0.016).

Conclusion: Lenvatinib plus toripalimab represents an effective and well-tolerated chemo-free therapeutic option for advanced ICC. Baseline CA19-9 levels and IDH1 mutations may serve as predictive treatment-related biomarkers.

背景:晚期肝内胆管癌(ICC)的治疗方案目前很有限。含化疗方案是主流治疗方法,但毒性显著、耐受性差、依从性低,因此有必要探索替代疗法。伦伐替尼联合PD-1抑制剂已在初步研究中显示出巨大的临床活性。本研究旨在评估来伐替尼联合托瑞帕单抗(一种新型PD-1抗体)作为晚期ICC免化疗疗法的有效性和安全性:这项回顾性研究纳入了2019年2月至2023年12月期间接受来伐替尼联合托瑞帕利单抗治疗的连续晚期ICC患者。主要结果为总生存期(OS)、无进展生存期(PFS)、客观反应率(ORR)、疾病控制率(DCR)和安全性。此外,还对预后因素和基因变异进行了探索性分析:共纳入 78 名患者,中位随访时间为 25.9 个月。中位OS和PFS分别为11.3个月(95% CI:9.5-13.1)和5.4个月(95% CI:3.8-7.0)。ORR为19.2%,DCR为75.6%。3级或4级不良事件(AE)发生率为50.0%,无5级不良事件报告。基线CA19-9水平正常的患者具有更高的ORR(p = 0.011)、更长的PFS(11.5个月对4.6个月;HR 0.47;p=0.005)和OS(21.0个月对9.7个月;HR 0.43;p=0.003)。IDH1突变与ORR增加相关(60.0%对8.9%,P=0.016):结论:伦伐替尼联合托瑞帕利单抗是治疗晚期ICC的一种有效且耐受性良好的无化疗方案。基线CA19-9水平和IDH1突变可作为与治疗相关的预测性生物标志物。
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引用次数: 0
GPCRs: emerging targets for novel T cell immune checkpoint therapy. GPCR:新型 T 细胞免疫检查点疗法的新兴靶点。
IF 5.4 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-03 DOI: 10.1007/s00262-024-03801-7
Kaitlyn Dickinson, Elliott J Yee, Isaac Vigil, Richard D Schulick, Yuwen Zhu

Although immune checkpoint blockade (ICB) has become the mainstay of treatment for advanced solid organ malignancies, success in revitalizing the host anticancer immune response remains limited. G-protein coupled receptors (GPCRs) are a broad family of cell-surface proteins that have been regarded as main players in regulating the immune system, namely by mediating the activity of T lymphocytes. Among the most novel immunoregulatory GPCRs include GPR171, lysophosphatidic acid receptors (LPARs), GPR68, cannabinoid receptor 2 (CB2), and prostaglandin E receptors, many of which have shown promise in mediating antitumor response via activation of cytotoxic T cells, inhibiting immunosuppressive lymphocytes, and facilitating immune cell infiltration within the tumor microenvironment across multiple types of cancers. This paper reviews our current understanding of some of the most novel GPCRs-their expression patterns, evolving roles within the immune system and cancer, potential therapeutic applications, and perspective for future investigation.

尽管免疫检查点阻断疗法(ICB)已成为晚期实体器官恶性肿瘤的主要治疗方法,但在重振宿主抗癌免疫反应方面取得的成功仍然有限。G 蛋白偶联受体(GPCRs)是一个广泛的细胞表面蛋白家族,一直被认为是调节免疫系统的主要角色,即通过介导 T 淋巴细胞的活性。最新颖的免疫调节GPCR包括GPR171、溶血磷脂酸受体(LPARs)、GPR68、大麻素受体2(CB2)和前列腺素E受体,其中许多都有望通过激活细胞毒性T细胞、抑制免疫抑制淋巴细胞和促进免疫细胞在多种类型癌症的肿瘤微环境中浸润来介导抗肿瘤反应。本文回顾了我们目前对一些最新型 GPCRs 的了解--它们的表达模式、在免疫系统和癌症中不断演变的作用、潜在的治疗应用以及未来研究的前景。
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引用次数: 0
期刊
Cancer Immunology, Immunotherapy
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