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Correction to: Development of nomograms to predict therapeutic response and prognosis of non-small cell lung cancer patients treated with anti-PD-1 antibody. 更正:开发用于预测接受抗 PD-1 抗体治疗的非小细胞肺癌患者的治疗反应和预后的提名图。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-05 DOI: 10.1007/s00262-024-03812-4
Shijin Yuan, Yan Xia, Lihong Shen, Liuqing Ye, Lisha Li, Lifen Chen, Xinyou Xie, Haizhou Lou, Jun Zhang
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引用次数: 0
Enhanced anti-tumor efficacy of electroporation (EP)-mediated DNA vaccine boosted by allogeneic lymphocytes in pre-established tumor models. 电穿孔(EP)介导的 DNA 疫苗在已建立的肿瘤模型中增强了异体淋巴细胞的抗肿瘤疗效。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-03 DOI: 10.1007/s00262-024-03838-8
Sanyuan Shi, Luchen Zhang, Anjie Zheng, Fang Xie, Samuel Kesse, Yang Yang, Jinliang Peng, Yuhong Xu

Background: Tumor-reactive T cells play a crucial role in anti-tumor responses, but T cells induced by DNA vaccination are time-consuming processes and exhibit limited anti-tumor efficacy. Therefore, we evaluated the anti-tumor effectiveness of reactive T cells elicited by electroporation (EP)-mediated DNA vaccine targeting epidermal growth factor receptor variant III (pEGFRvIII plasmid), in conjunction with adoptive cell therapy (ACT), involving the transfer of lymphocytes from a pEGFRvIII EP-vaccinated healthy donor.

Methods: The validation of the established pEGFRvIII plasmid and EGFRvIII-positive cell model was confirmed through immunofluorescence and western blot analysis. Flow cytometry and cytotoxicity assays were performed to evaluate the functionality of antigen-specific reactive T cells induced by EP-mediated pEGFRvIII vaccines, ACT, or their combination. The anti-tumor effectiveness of EP-mediated pEGFRvIII vaccines alone or combined with ACT was evaluated in the B16F10-EGFRvIII tumor model.

Results: EP-mediated pEGFRvIII vaccines elicited serum antibodies and a robust cellular immune response in both healthy and tumor-bearing mice. However, this response only marginally inhibited early-stage tumor growth in established tumor models. EP-mediated pEGFRvIII vaccination followed by adoptive transfer of lymphocytes from vaccinated healthy donors led to notable anti-tumor efficacy, attributed to the synergistic action of antigen-specific CD4+ Th1 cells supplemented by ACT and antigen-specific CD8+ T cells elicited by the EP-mediated DNA vaccination.

Conclusions: Our preclinical studies results demonstrate an enhanced anti-tumor efficacy of EP-mediated DNA vaccination boosted with adoptively transferred, vaccinated healthy donor-derived allogeneic lymphocytes.

背景:肿瘤反应性 T 细胞在抗肿瘤反应中起着至关重要的作用,但 DNA 疫苗接种诱导的 T 细胞需要耗费大量时间,且抗肿瘤效果有限。因此,我们评估了电穿孔(EP)介导的针对表皮生长因子受体变异体 III 的 DNA 疫苗(pEGFRvIII 质粒)诱导的反应性 T 细胞的抗肿瘤效果,同时还评估了采用细胞疗法(ACT),即从接种了 pEGFRvIII EP 疫苗的健康供体中转移淋巴细胞:方法:通过免疫荧光和 Western 印迹分析确认了已建立的 pEGFRvIII 质粒和 EGFRvIII 阳性细胞模型。流式细胞术和细胞毒性试验评估了 EP 介导的 pEGFRvIII 疫苗、ACT 或它们的组合诱导的抗原特异性反应 T 细胞的功能。在B16F10-EGFRvIII肿瘤模型中评估了EP介导的pEGFRvIII疫苗单独使用或与ACT联合使用的抗肿瘤效果:结果:EP介导的 pEGFRvIII 疫苗可在健康小鼠和肿瘤小鼠体内激发血清抗体和强大的细胞免疫反应。然而,在已建立的肿瘤模型中,这种反应只能在一定程度上抑制早期肿瘤的生长。EP介导的pEGFRvIII疫苗接种后,再采用接种过疫苗的健康供体的淋巴细胞进行转移,可获得显著的抗肿瘤疗效,这归功于ACT补充的抗原特异性CD4+ Th1细胞和EP介导的DNA疫苗接种激发的抗原特异性CD8+ T细胞的协同作用:我们的临床前研究结果表明,EP介导的DNA疫苗接种与被收养转移、接种健康供体来源的异体淋巴细胞协同作用,可增强抗肿瘤疗效。
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引用次数: 0
Exploring the impact of durvalumab on biliary tract cancer: insights from real-world clinical data. 探索杜伐单抗对胆道癌的影响:真实世界临床数据的启示。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-03 DOI: 10.1007/s00262-024-03842-y
Patrick Reimann, Ilektra-Antonia Mavroeidi, Jonathan Burghofer, Hossein Taghizadeh, Gerald Webersinke, Stefan Kasper, Georg Schreil, Darius Morariu, Andreas Reichinger, Hideo Andreas Baba, Patrick Kirchweger, Martin Schuler, Angela Djanani, Gerald W Prager, Holger Rumpold, Magdalena Benda, Eva-Maria Schneider, Sylvia Mink, Thomas Winder, Bernhard Doleschal

Introduction: This study assesses the effectiveness of durvalumab with platinum and gemcitabine for biliary tract cancers (BTC). It aims to confirm the TOPAZ-1 trial results in a real-world context and explore the link between BTC molecular profiles and patient outcomes.

Methods: A retrospective analysis was conducted on 102 BTC patients treated with durvalumab, platinum, and gemcitabine at five cancer centers in Austria and one in Germany from 2022 to 2024. Molecular profiling used targeted DNA and RNA assays. Clinical endpoints, including progression-free survival (PFS) and overall survival (OS), were assessed using log-rank tests and Cox regression, with correlations to second-line molecular-targeted therapies.

Results: Among 102 patients, 60.8% had intrahepatic cholangiocarcinoma. The treatment achieved a disease control rate of 71.57% and an overall response rate of 35.11%. Median PFS was 6.51 months, and OS was 13.61 months. Patients under 65 had significantly better OS. Alterations in chromatin remodeling or homologous recombination repair genes were not predictive of survival benefit (HR: 0.45; p = 0.851 and HR: 1.63; p = 0.26, respectively). Patients with molecular-informed second-line therapy showed a trend toward survival benefit (HR: 0.23; p = 0.052).

Conclusion: This study confirms the phase 3 trial results of durvalumab with platinum and gemcitabine, providing a substantial real-world dataset with detailed molecular characterization. No specific patient subgroup showed a markedly better response to durvalumab based on conventional NGS panels. Further research is needed to explore the link between immunotherapy responses and molecular subgroups.

简介本研究评估了杜伐单抗与铂类和吉西他滨治疗胆道癌(BTC)的有效性。其目的是在现实世界中证实 TOPAZ-1 试验的结果,并探索 BTC 分子特征与患者预后之间的联系:方法:在2022年至2024年期间,在奥地利的五家癌症中心和德国的一家癌症中心对102名接受了德伐卢单抗、铂类和吉西他滨治疗的BTC患者进行了回顾性分析。分子分析采用了靶向 DNA 和 RNA 检测方法。采用对数秩检验和考克斯回归评估临床终点,包括无进展生存期(PFS)和总生存期(OS),以及与二线分子靶向疗法的相关性:102名患者中,60.8%患有肝内胆管癌。治疗的疾病控制率为 71.57%,总反应率为 35.11%。中位 PFS 为 6.51 个月,OS 为 13.61 个月。65岁以下患者的OS明显更好。染色质重塑或同源重组修复基因的改变并不能预测生存获益(HR:0.45;p = 0.851 和 HR:1.63;p = 0.26)。接受分子信息二线治疗的患者有生存获益的趋势(HR:0.23;p = 0.052):这项研究证实了杜伐单抗与铂类和吉西他滨的3期试验结果,提供了一个具有详细分子特征的大量真实世界数据集。根据传统的 NGS 面板,没有特定的患者亚组对度伐卢单抗的反应明显更好。要探索免疫疗法反应与分子亚组之间的联系,还需要进一步的研究。
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引用次数: 0
Dose-escalation, tolerability, and efficacy of intratumoral and subcutaneous injection of hemagglutinating virus of Japan envelope (HVJ-E) against chemotherapy-resistant malignant pleural mesothelioma: a clinical trial. 瘤内和皮下注射日本血凝病毒包膜(HVJ-E)对化疗耐药恶性胸膜间皮瘤的剂量递增、耐受性和疗效:一项临床试验。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-03 DOI: 10.1007/s00262-024-03815-1
Kazuma Sakura, Muneyoshi Kuroyama, Yasushi Shintani, Soichiro Funaki, Shinji Atagi, Yoshihisa Kadota, Kozo Kuribayashi, Takashi Kijima, Takashi Nakano, Toshihiro Nakajima, Masao Sasai, Meinoshin Okumura, Yasufumi Kaneda

The hemagglutinating virus of Japan envelope (HVJ-E) is an inactivated Sendai virus particle with antitumor effect and inducing antitumor immunity. However, its dosage and efficacy have not been verified. We conducted a phase I clinical study on chemotherapy-resistant malignant pleural mesothelioma (MPM) aiming to determine the recommended dosage for a phase II study through dose-limiting toxicity and evaluate HVJ-E's preliminary efficacy. HVJ-E was administered intratumorally and subcutaneously to the patients with chemotherapy-resistant MPM. While no serious adverse events occurred, known adverse events of HVJ-E were observed. In the preliminary antitumor efficacy using modified response evaluation criteria in solid tumors (RECIST) criteria, three low-dose patients exhibited progressive disease, while all high-dose patients achieved stable disease, yielding disease control rates (DCRs) of 0% and 100%, respectively. Furthermore, the dose-dependent effect of HVJ-E revealed on DCR modified by RECIST and the baseline changes in target lesion size (by CT and SUL-peak; p < 0.05). Comparing targeted lesions receiving intratumoral HVJ-E with non-injected ones, while no clear difference existed at the end of the study, follow-up cases suggested stronger antitumor effects with intratumoral administration. Our findings suggest that HVJ-E could be safely administered to patients with chemotherapy-resistant MPM at both study doses. HVJ-E exhibited some antitumor activity against chemotherapy-resistant MPM, and higher doses tended to have stronger antitumor effects than lower doses. Consequently, a phase II clinical trial with higher HVJ-E doses has been conducted for MPM treatment. Trial registration number: UMIN Clinical Trials Registry (#UMIN000019345).

日本血凝病毒包膜(HVJ-E)是一种灭活的仙台病毒颗粒,具有抗肿瘤作用,可诱导抗肿瘤免疫。然而,其剂量和疗效尚未得到验证。我们对化疗耐药的恶性胸膜间皮瘤(MPM)进行了 I 期临床研究,旨在通过剂量限制毒性确定 II 期研究的推荐剂量,并评估 HVJ-E 的初步疗效。HVJ-E 经瘤内和皮下给药给耐化疗 MPM 患者。虽然没有发生严重不良事件,但观察到了 HVJ-E 的已知不良事件。在采用改良的实体瘤反应评价标准(RECIST)进行的初步抗肿瘤疗效研究中,有三名低剂量患者的病情出现进展,而所有高剂量患者的病情均趋于稳定,疾病控制率(DCR)分别为0%和100%。此外,HVJ-E对RECIST标准修改后的DCR和靶病灶大小的基线变化(通过CT和SUL-peak;p
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引用次数: 0
INTASYL self-delivering RNAi decreases TIGIT expression, enhancing NK cell cytotoxicity: a potential application to increase the efficacy of NK adoptive cell therapy against cancer. INTASYL 自传递 RNAi 可降低 TIGIT 的表达,增强 NK 细胞的细胞毒性:这是一种提高 NK 采用细胞疗法抗癌疗效的潜在应用。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-03 DOI: 10.1007/s00262-024-03835-x
Melissa Maxwell, Dingxue Yan, Brianna Rivest, Andrew Boone, James Cardia, Elfriede Noessner

Natural killer (NK) cells are frontline defenders against cancer and are capable of recognizing and eliminating tumor cells without prior sensitization or antigen presentation. Due to their unique HLA mismatch tolerance, they are ideal for adoptive cell therapy (ACT) because of their ability to minimize graft-versus-host-disease risk. The therapeutic efficacy of NK cells is limited in part by inhibitory immune checkpoint receptors, which are upregulated upon interaction with cancer cells and the tumor microenvironment. Overexpression of inhibitory receptors reduces NK cell-mediated cytotoxicity by impairing the ability of NK cells to secrete effector cytokines and cytotoxic granules. T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT), a well-known checkpoint receptor involved in T-cell exhaustion, has recently been implicated in the exhaustion of NK cells. Overcoming TIGIT-mediated inhibition of NK cells may allow for a more potent antitumor response following ACT. Here, we describe a novel approach to TIGIT inhibition using self-delivering RNAi compounds (INTASYL™) that incorporates the features of RNAi and antisense technology. INTASYL compounds demonstrate potent activity and stability, are rapidly and efficiently taken up by cells, and can be easily incorporated into cell product manufacturing. INTASYL PH-804, which targets TIGIT, suppresses TIGIT mRNA and protein expression in NK cells, resulting in increased cytotoxic capacity and enhanced tumor cell killing in vitro. Delivering PH-804 to NK cells before ACT has emerged as a promising strategy to counter TIGIT inhibition, thereby improving the antitumor response. This approach offers the potential for more potent off-the-shelf products for adoptive cell therapy, particularly for hematological malignancies.

自然杀伤(NK)细胞是抗癌的前线卫士,能够识别并消灭肿瘤细胞,而无需事先进行致敏或抗原递呈。由于其独特的 HLA 错配耐受性,它们是采用细胞疗法 (ACT) 的理想选择,因为它们能够最大限度地降低移植物抗宿主疾病的风险。NK 细胞的疗效部分受到抑制性免疫检查点受体的限制,这些受体在与癌细胞和肿瘤微环境相互作用时会上调。抑制性受体的过度表达会损害 NK 细胞分泌效应细胞因子和细胞毒性颗粒的能力,从而降低 NK 细胞介导的细胞毒性。具有免疫球蛋白和 ITIM 结构域的 T 细胞免疫受体(TIGIT)是众所周知的参与 T 细胞衰竭的检查点受体,最近也被认为与 NK 细胞的衰竭有关。克服 TIGIT 介导的 NK 细胞抑制可能使 ACT 后的抗肿瘤反应更有效。在这里,我们介绍了一种利用自传递 RNAi 化合物(INTASYL™)抑制 TIGIT 的新方法,该方法结合了 RNAi 和反义技术的特点。INTASYL 化合物具有强大的活性和稳定性,能快速、高效地被细胞吸收,并能方便地融入细胞产品生产中。INTASYL PH-804 以 TIGIT 为靶标,可抑制 NK 细胞中 TIGIT mRNA 和蛋白的表达,从而提高细胞毒性能力,增强体外杀伤肿瘤细胞的能力。在 ACT 前向 NK 细胞释放 PH-804 已成为对抗 TIGIT 抑制从而改善抗肿瘤反应的一种有前途的策略。这种方法有望为采用细胞疗法,特别是血液恶性肿瘤的治疗提供更有效的现成产品。
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引用次数: 0
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 4.6 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
Multi-omics analysis and response prediction of PD-1 monoclonal antibody containing regimens in patients with relapsed/refractory diffuse large B-cell lymphoma. 对复发/难治性弥漫大B细胞淋巴瘤患者使用含PD-1单克隆抗体治疗方案的多组学分析和反应预测
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-03 DOI: 10.1007/s00262-024-03840-0
Xinrui Chen, Yan Qin, Xuemin Xue, Zucheng Xie, Tongji Xie, Liling Huang, Haohua Zhu, Lina Gao, Jiangtao Li, Jianliang Yang, Lin Gui, Sheng Yang, Haizhu Chen, Xiaoli Feng, Yuankai Shi

Patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) show varied responses to PD-1 monoclonal antibody (mAb) containing regimens. The mechanisms and predictive biomarkers for the efficacy of this regimen are unclear. This study retrospectively collected r/r DLBCL patients who received PD-1 mAb and rituximab regimens as salvage therapy. Clinical and genomic features were collected, and mechanisms were explored by multiplex immunofluorescence and digital spatial profiling. An artificial neural network (ANN) model was constructed to predict the response. Between October 16th, 2018 and May 4th, 2023, 50 r/r DLBCL patients were collected, 29 were response patients and 21 were non-response patients. CREBBP (p = 0.029) and TP53 (p = 0.015) alterations were statistically higher in non-response patients. Patients with PD-L1 CPS ≥ 5 were correlated with a longer overall survival (OS) than those with PD-L1 CPS < 5 (median OS: not reached vs. 9.7 months, hazard ratio [HR]: 3.8, 95% confidence interval [CI] 0.64-22.44, p = 0.016). Immune-related pathways were activated in response patients. The proportion and spatial organization of tumor-infiltrating immune cells affect the response. PD-L1 CPS level, age, and alterations of TP53, MYD88, CREBBP, EP300, GNA13 were used to build an ANN predictive model that showed high prediction efficiency (training set area under curve [AUC] of 0.97 and test set AUC of 0.94). The proportion and spatial distribution of tumor-infiltrating immune cells may be related to the function of immune-related pathways, thereby influencing the efficacy of PD-1 mAb containing regimens. The ANN predictive model showed potential value in predicting the responses of r/r DLBCL patients received PD-1 mAb and rituximab regimens.

复发/难治(r/r)弥漫大B细胞淋巴瘤(DLBCL)患者对含PD-1单克隆抗体(mAb)治疗方案的反应各不相同。这种疗法的疗效机制和预测性生物标志物尚不清楚。本研究回顾性收集了接受PD-1 mAb和利妥昔单抗方案作为挽救疗法的r/r DLBCL患者。研究收集了临床和基因组特征,并通过多重免疫荧光和数字空间图谱分析探讨了其机制。构建了一个人工神经网络(ANN)模型来预测反应。2018年10月16日至2023年5月4日期间,共收集了50例r/r DLBCL患者,其中29例为应答患者,21例为非应答患者。据统计,非应答患者的CREBBP(p = 0.029)和TP53(p = 0.015)改变率较高。与PD-L1 CPS≥5的患者相比,PD-L1 CPS≥5的患者总生存期(OS)更长。
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引用次数: 0
Therapeutic antibodies in oncology: an immunopharmacological overview. 肿瘤学中的治疗性抗体:免疫药理学概述。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-10-03 DOI: 10.1007/s00262-024-03814-2
Karen Toledo-Stuardo, Carolina H Ribeiro, Fabiola González-Herrera, Douglas J Matthies, María Soledad Le Roy, Claudio Dietz-Vargas, Yesenia Latorre, Ivo Campos, Yuneisy Guerra, Samantha Tello, Valeria Vásquez-Sáez, Pedro Novoa, Nicolás Fehring, Mauricio González, Jose Rodríguez-Siza, Gonzalo Vásquez, Pamela Méndez, Claudia Altamirano, María Carmen Molina

The biotechnological development of monoclonal antibodies and their immunotherapeutic use in oncology have grown exponentially in the last decade, becoming the first-line therapy for some types of cancer. Their mechanism of action is based on the ability to regulate the immune system or by interacting with targets that are either overexpressed in tumor cells, released into the extracellular milieu or involved in processes that favor tumor growth. In addition, the intrinsic characteristics of each subclass of antibodies provide specific effector functions against the tumor by activating antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis, among other mechanisms. The rational design and engineering of monoclonal antibodies have improved their pharmacokinetic and pharmacodynamic features, thus optimizing the therapeutic regimens administered to cancer patients and improving their clinical outcomes. The selection of the immunoglobulin G subclass, modifications to its crystallizable region (Fc), and conjugation of radioactive substances or antineoplastic drugs may all improve the antitumor effects of therapeutic antibodies. This review aims to provide insights into the immunological and pharmacological aspects of therapeutic antibodies used in oncology, with a rational approach at molecular modifications that can be introduced into these biological tools, improving their efficacy in the treatment of cancer.

近十年来,单克隆抗体的生物技术发展及其在肿瘤学中的免疫治疗应用呈指数增长,已成为某些类型癌症的一线疗法。单克隆抗体的作用机制基于其调节免疫系统的能力,或与肿瘤细胞中过度表达、释放到细胞外环境中或参与肿瘤生长过程的靶点相互作用。此外,每个亚类抗体的固有特性都能通过激活抗体依赖性细胞毒性、补体依赖性细胞毒性和抗体依赖性细胞吞噬作用等机制,对肿瘤发挥特定的效应功能。单克隆抗体的合理设计和工程化改善了其药代动力学和药效学特征,从而优化了癌症患者的治疗方案,提高了临床疗效。免疫球蛋白 G 亚类的选择、对其可结晶区(Fc)的修饰以及与放射性物质或抗肿瘤药物的结合都可以提高治疗性抗体的抗肿瘤效果。本综述旨在深入探讨肿瘤学中使用的治疗性抗体的免疫学和药理学方面的问题,并通过合理的方法对这些生物工具进行分子修饰,从而提高它们在治疗癌症方面的疗效。
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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 4.6 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 4.6 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
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Cancer Immunology, Immunotherapy
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