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Corneal Transplant Rejection Following Durvalumab Therapy in a Patient With NSCLC: A Case Report. 一名 NSCLC 患者接受 Durvalumab 治疗后出现角膜移植排斥反应:病例报告。
IF 3.2 4区 医学 Q3 IMMUNOLOGY Pub Date : 2024-07-30 DOI: 10.1097/CJI.0000000000000536
Luise Froessl, Puja Panwar, Subir Bhatia, Jonathan Dowell

We report the case of corneal transplant rejection in a 77-year-old male receiving durvalumab as consolidative therapy for stage IIIB non-small cell lung cancer (NSCLC). Following successful chemoradiation and initiation of durvalumab, the patient underwent a right corneal transplant for corneal dystrophy. Six months after an initially stable post-transplant course, he developed progressive visual decline culminating in graft failure 1 year later despite treatment with prednisone eye drops. This case adds to the limited evidence implicating immune checkpoint inhibitors (ICIs) in corneal graft rejection, emphasizing the need for multidisciplinary evaluation and close monitoring of corneal transplant recipients undergoing ICI therapy.

我们报告了一例角膜移植排斥反应病例,患者是一名 77 岁的男性,因ⅢB 期非小细胞肺癌(NSCLC)接受度伐单抗巩固治疗。化疗成功并开始使用度伐单抗后,患者因角膜营养不良接受了右眼角膜移植手术。在移植后最初病情稳定的六个月后,他出现了进行性视力下降,尽管使用了泼尼松滴眼液治疗,但一年后移植手术最终还是失败了。本病例补充了免疫检查点抑制剂(ICIs)与角膜移植排斥反应有关的有限证据,强调了对接受 ICI 治疗的角膜移植受者进行多学科评估和密切监测的必要性。
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引用次数: 0
NUSAP1 Promotes Immunity and Apoptosis by the SHCBP1/JAK2/STAT3 Phosphorylation Pathway to Induce Dendritic Cell Generation in Hepatocellular Carcinoma. NUSAP1 通过 SHCBP1/JAK2/STAT3 磷酸化途径促进免疫和凋亡,从而诱导肝细胞癌树突状细胞的生成
IF 3.2 4区 医学 Q3 IMMUNOLOGY Pub Date : 2024-07-09 DOI: 10.1097/CJI.0000000000000531
Guojie Chen, WenYa Li, Ruomu Ge, Ting Guo, Yuhan Zhang, Chenglin Zhou, Mei Lin

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and is associated with high morbidity and mortality rates. The aims of this study were to investigate the immune-promoting action of nucleolar and spindle-associated protein 1 (NUSAP1) and identify an immunotherapy target for HCC. The Cancer Genome Atlas (TCGA) was used to analyze interaction molecules and immune correlation. The interaction between NUSAP1 and SHC binding and spindle associated 1 (SHCBP1) was examined. The role of the SHCBP1/Janus kinase 2/signal transducer and activator of transcription 3 (SHCBP1/JAK2/STAT3) pathway in this process was explored. After co-culture with HCC cell lines, the differentiation of peripheral blood mononuclear cells (PBMCs) into dendritic cells (DC) was evaluated by measuring the expression of surface factors CD1a and CD86. Pathological tissues from 50 patients with HCC were collected to validate the results of cell experiments. The expression levels of CD1a and CD86 in tissues were also determined. The results show that NUSAP1 interacted with SHCBP1 and was positively correlated with DC. In HCC cell lines, an interaction was observed between NUSAP1 and SHCBP1. It was verified that NUSAP1 inhibited the JAK2/STAT3 phosphorylation pathway by blocking SHCBP1. After co-culture, the levels of CD1a and CD86 in PBMC were elevated. In the clinical specimens, CD1a and CD86 expression levels were significantly higher in the high-NUSAP1 group versus the low-NUSAP1 group. In Summary, NUSAP1 enhanced immunity by inhibiting the SHCBP1/JAK2/STAT3 phosphorylation pathway and promoted DC generation and HCC apoptosis. NUSAP1 may be a target of immunotherapy for HCC.

肝细胞癌(HCC)是最常见的肝癌类型,发病率和死亡率都很高。本研究的目的是研究细胞核和纺锤体相关蛋白1(NUSAP1)的免疫促进作用,并确定HCC的免疫治疗靶点。癌症基因组图谱(TCGA)用于分析相互作用分子和免疫相关性。研究人员考察了NUSAP1与SHC结合和纺锤体相关1(SHCBP1)之间的相互作用。研究还探讨了SHCBP1/破伤风激酶2/信号转导和转录激活因子3(SHCBP1/JAK2/STAT3)通路在这一过程中的作用。在与 HCC 细胞系共培养后,通过测量表面因子 CD1a 和 CD86 的表达,评估了外周血单核细胞(PBMC)向树突状细胞(DC)的分化情况。为了验证细胞实验的结果,研究人员收集了 50 名 HCC 患者的病理组织。同时还测定了组织中 CD1a 和 CD86 的表达水平。结果显示,NUSAP1与SHCBP1相互作用,并与DC呈正相关。在 HCC 细胞系中,NUSAP1 与 SHCBP1 之间存在相互作用。研究证实,NUSAP1 通过阻断 SHCBP1 抑制了 JAK2/STAT3 磷酸化途径。共培养后,PBMC 中的 CD1a 和 CD86 水平升高。在临床标本中,高 NUSAP1 组的 CD1a 和 CD86 表达水平明显高于低 NUSAP1 组。综上所述,NUSAP1 通过抑制 SHCBP1/JAK2/STAT3 磷酸化通路增强免疫力,促进 DC 生成和 HCC 细胞凋亡。NUSAP1可能是治疗HCC的免疫疗法靶点。
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引用次数: 0
Comprehensive Molecular Analyses of an M2-Like Tumor-Associated Macrophage for Predicting the Prognosis and Immunotherapy in Breast Cancer. 用于预测乳腺癌预后和免疫疗法的 M2 类肿瘤相关巨噬细胞的综合分子分析。
IF 3.9 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-07-01 Epub Date: 2024-04-30 DOI: 10.1097/CJI.0000000000000517
Kexin Chang, QingFang Yue, Long Jin, Pengyu Fan, Yi Liu, Fei Cao, Yuan Zhang

The involvement of M2-like tumor-associated macrophages (TAMs) in the advancement and treatment of cancer has been widely documented. This study aimed to develop a new signature associated with M2-like TAMs to predict the prognosis and treatment response in individuals diagnosed with breast cancer (BC). Weighted gene co-expression network analysis (WGCNA) was used to identity for M2-like TAM-related modular genes. The M2-like TAM-related modular subtype was identified using unsupervised clustering. WGCNA identified 722 M2-like TAM genes, 204 of which were associated with recurrence-free survival (RFS). Patients in cluster 1 exhibited upregulated cancer-related pathways, a higher proportion of triple-negative breast cancer (TNBC) subtypes, lower expression of immune checkpoints, and worse prognosis. Cluster 2 was characterized by upregulated immune-related pathways, a higher proportion of luminal A subtypes, and higher expression of immune checkpoints. A prognostic signature was created and confirmed using an independent dataset. A well-built nomogram can accurately forecast the survival outcomes for every individual. Furthermore, patients classified as low-risk exhibited a more favorable outlook, elevated tumor microenvironment (TME) score, and superior reaction to immunotherapy. In conclusion, we discovered 2 different types of M2-like TAMs and developed a prognostic signature revealing the diversity of M2-like TAMs in BC and their correlation with immune status and prognosis. This feature can predict the prognosis and immunotherapeutic effects of BC and offer novel concepts and approaches for tailoring BC treatment.

M2样肿瘤相关巨噬细胞(TAMs)参与癌症的发展和治疗已被广泛记录。本研究旨在开发一种与M2样肿瘤相关巨噬细胞相关的新特征,以预测乳腺癌(BC)患者的预后和治疗反应。研究采用加权基因共表达网络分析(WGCNA)来识别与M2样TAM相关的模块基因。通过无监督聚类确定了M2样TAM相关模块亚型。WGCNA 确定了 722 个 M2-like TAM 基因,其中 204 个基因与无复发生存率(RFS)相关。群组1的患者表现出癌症相关通路上调、三阴性乳腺癌(TNBC)亚型比例较高、免疫检查点表达较低以及预后较差等特征。群组2的特点是免疫相关通路上调、管腔A亚型比例较高以及免疫检查点表达较高。我们创建了一个预后特征,并通过一个独立的数据集进行了确认。建立良好的提名图可以准确预测每个人的生存结果。此外,被归类为低风险的患者前景更乐观,肿瘤微环境(TME)评分更高,对免疫疗法的反应更佳。总之,我们发现了两种不同类型的M2样TAMs,并建立了一个预后特征,揭示了M2样TAMs在BC中的多样性及其与免疫状态和预后的相关性。这一特征可以预测 BC 的预后和免疫治疗效果,并为定制 BC 治疗提供了新的概念和方法。
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引用次数: 0
Rapid Life-Saving Response to Anti-PD-1 in a Solid Organ Transplant Recipient With Metastatic Cutaneous Squamous Cell Carcinoma: A Case Report and Review. 一名转移性皮肤鳞状细胞癌实体器官移植受者对抗PD-1的快速救命反应:病例报告与综述
IF 3.9 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-07-01 Epub Date: 2024-03-27 DOI: 10.1097/CJI.0000000000000514
John P Antonelli, Myiah Quach, Aparna Mahajan, Jennifer Pleva, Vincent T Ma

Summary: Anti-programmed cell death protein 1 (PD-1) therapy is considered effective in the treatment of metastatic or locally advanced cutaneous squamous cell carcinoma but the use of these agents in solid organ transplant recipients (SOTRs) is often taken with caution. While anti-tumor effects without graft rejection have been reported, studies have shown high rates of fatal graft rejection with immune checkpoint therapy. In this case report, we present an SOTR patient with life-threatening, acute hypoxic respiratory failure due to rapidly progressive metastatic cutaneous squamous cell carcinoma with lung and pleural involvement. Modification of their immunosuppressive regimen and treatment with front-line anti-PD-1 inhibitor, pembrolizumab, led to rapid clinical response with near complete resolution of metastatic pulmonary disease and no long-term evidence of graft rejection. Our case report shows that front-line treatment with PD-1 inhibitors can be safely administered in SOTR patients with rapid metastatic disease control.

摘要:抗程序性细胞死亡蛋白1(PD-1)疗法被认为是治疗转移性或局部晚期皮肤鳞状细胞癌的有效方法,但在实体器官移植受者(SOTR)中使用这些药物往往需要谨慎。虽然有报道称免疫检查点疗法具有抗肿瘤效果,但不会出现移植物排斥反应,而研究显示免疫检查点疗法的致命性移植物排斥反应发生率很高。在本病例报告中,我们介绍了一名因快速进展的转移性皮肤鳞状细胞癌并累及肺部和胸膜而出现急性缺氧性呼吸衰竭、危及生命的 SOTR 患者。修改免疫抑制方案并使用一线抗PD-1抑制剂pembrolizumab治疗后,患者的临床反应迅速,转移性肺部疾病几乎完全缓解,且没有长期的移植物排斥证据。我们的病例报告表明,SOTR 患者可以安全地使用 PD-1 抑制剂进行一线治疗,并迅速控制转移性疾病。
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引用次数: 0
Extracorporeal Photopheresis as a Treatment Option for Immune-Related Adverse Events: Two Case Reports and a Prospective Study. 体外光子疗法作为免疫相关不良事件的一种治疗方案:两个病例报告和一项前瞻性研究。
IF 3.2 4区 医学 Q3 IMMUNOLOGY Pub Date : 2024-07-01 Epub Date: 2024-03-14 DOI: 10.1097/CJI.0000000000000510
Theresa Ruf, Farnaz Rahimi, David Anz, Amanda Tufman, Suzanna Salzer, Sarah Zierold, Dirk Tomsitz, Lars E French, Lucie Heinzerling

The wide use of immune checkpoint inhibitors has increased the frequency of immune-related adverse events (irAEs). While many are managed with corticosteroids or hormone substitution, up to 14.9% of irAEs are steroid-refractory or steroid-dependent and thus require second-line treatment. These should reduce irAE-related morbidity and mortality and induce a few side effects of their own while maintaining the antitumor response. There is little comparative data on second-line therapies for irAEs. Two cases of irAEs could not be sufficiently managed with corticosteroids and subsequently received treatment with extracorporeal photopheresis (ECP), including one patient with immune-related erosive oral lichen planus and one patient with immune-related colitis. In both cases, the irAE resolved with ECP in combination with immunosuppressive drugs, that is 4 weeks and 10 weeks after the start of ECP, respectively. To investigate this approach, a prospective clinical study that compares ECP and other second-line therapies for the treatment of steroid-refractory and steroid-dependent irAEs with regard to immunophenotype and therapy response has been designed. ECP could be a treatment option for steroid-refractory and steroid-dependent irAEs, given its good safety profile and lack of adverse effects on antitumor response. Comparative prospective studies are needed to generate an evidence base.

免疫检查点抑制剂的广泛使用增加了免疫相关不良事件(irAEs)的发生频率。虽然许多不良反应可通过皮质类固醇或激素替代治疗来控制,但高达 14.9% 的 irAEs 是类固醇难治性或类固醇依赖性的,因此需要二线治疗。这些治疗应能降低与虹膜AE相关的发病率和死亡率,并在维持抗肿瘤反应的同时产生一些自身的副作用。关于虹膜睫状体异常二线疗法的比较数据很少。有两例虹膜睫状体异常无法通过皮质类固醇得到充分控制,随后接受了体外光动力疗法(ECP)治疗,其中包括一名免疫相关侵蚀性口腔扁平苔藓患者和一名免疫相关结肠炎患者。在这两例患者中,ECP与免疫抑制剂联合使用后,虹膜急性睫状体炎分别在ECP开始4周和10周后得到缓解。为了研究这种方法,我们设计了一项前瞻性临床研究,对 ECP 和其他二线疗法治疗类固醇难治性和类固醇依赖性虹膜急性结肠炎的免疫表型和治疗反应进行比较。ECP 具有良好的安全性,且对抗肿瘤反应无不良影响,因此可作为类固醇难治性和类固醇依赖性虹膜异位症的治疗选择。需要进行前瞻性比较研究,以形成证据基础。
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引用次数: 0
Effects of CTLA-4 Single Nucleotide Polymorphisms on Toxicity of Ipilimumab-Containing Regimens in Patients With Advanced Stage Melanoma. CTLA-4单核苷酸多态性对晚期黑色素瘤患者接受含伊匹单抗治疗方案毒性的影响
IF 3.9 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-06-01 Epub Date: 2024-02-06 DOI: 10.1097/CJI.0000000000000506
Karlijn de Joode, Alfonso Rojas Mora, Ron H N van Schaik, Alfred Zippelius, Astrid van der Veldt, Camille Léa Gerard, Heinz Läubli, Olivier Michielin, Roger von Moos, Markus Joerger, Mitchell P Levesque, Stefanie Aeppli, Johanna Mangana, Cristina Mangas, Nadine Trost, Stefan Meyer, Sandra Leoni Parvex, Ron Mathijssen, Yannis Metaxas

Single nucleotide polymorphisms (SNPs) in the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) gene, an inhibitor of T-cell priming, are associated with auto and alloimmunity. Studies implied a role for these SNPs as surrogate markers for immunotherapy-outcome in patients with melanoma. However, no predictive SNPs are defined to date. We analyzed different CTLA-4 SNPs in a large multicenter cohort of patients with ipilimumab-treated melanoma and investigated possible correlations with treatment-related outcomes. Archival blood and/or tumor tissue samples were collected from 361 patients with advanced-stage ipilimumab-treated (±nivolumab) in 6 Swiss and Dutch hospitals. Matrix-assisted laser desorption/ionization-time of flight mass spectrometry based DNA genotyping was performed for 10 different CTLA-4 SNPs: 49A>G, CT60G>A, Jo27T>C, Jo30G>A, Jo31G>T, -658C>T, -1722T>C, -1661A>G, 318C>T, and C>T rs1863800. Associations between different allele genotypes and occurrence of grade ≥3 adverse events (AEs) and survival were tested using univariable logistic regressions or Cox proportional hazard models. 262/361 (73%) patients could be analyzed; 65% of those were males, the median age was 58 years, 39% showed a partial or complete response, and 65% had ≥1 AEs. A TT-genotype of -1722T>C SNP was significantly associated with a lower incidence of grade ≥3 AEs ( P = 0.049), whereas the GG-genotype of CT60G>A correlated with a higher incidence of grade ≥3 AEs ( P = 0.026). The TT-genotype of Jo27T>C SNP ( P = 0.056) and GG-genotype of Jo31G>T ( P = 0.046) were associated with overall survival. CTLA-4 SNPs might predict treatment-related outcomes in patients with melanoma receiving ipilimumab. Confirmatory studies are needed to fully exploit those findings as predictive biomarkers for ipilimumab AEs.

细胞毒性 T 淋巴细胞相关蛋白 4(CTLA-4)是一种 T 细胞启动抑制因子,其基因中的单核苷酸多态性(SNPs)与自身免疫和异体免疫有关。研究表明,这些 SNPs 可作为黑色素瘤患者免疫疗法结果的替代标记。然而,迄今为止还没有确定具有预测作用的 SNPs。我们分析了伊匹单抗治疗的黑色素瘤患者大型多中心队列中的不同 CTLA-4 SNPs,并研究了它们与治疗相关结果之间可能存在的关联。在瑞士和荷兰的6家医院收集了361名接受过ipilimumab治疗(±nivolumab)的晚期患者的存档血液和/或肿瘤组织样本。对10个不同的CTLA-4 SNPs进行了基于基质辅助激光解吸/电离飞行时间质谱的DNA基因分型:49A>G、CT60G>A、Jo27T>C、Jo30G>A、Jo31G>T、-658C>T、-1722T>C、-1661A>G、318C>T和C>T rs1863800。采用单变量逻辑回归或 Cox 比例危险模型检验了不同等位基因基因型与≥3 级不良事件(AEs)发生率和生存率之间的关系。262/361(73%)名患者接受了分析;其中65%为男性,中位年龄为58岁,39%的患者出现了部分或完全应答,65%的患者出现了≥1级不良反应。-1722T>C SNP的TT基因型与较低的≥3级AEs发生率显著相关(P = 0.049),而CT60G>A的GG基因型与较高的≥3级AEs发生率相关(P = 0.026)。Jo27T>C SNP的TT基因型(P = 0.056)和Jo31G>T的GG基因型(P = 0.046)与总生存率相关。CTLA-4 SNPs可预测接受伊匹单抗治疗的黑色素瘤患者的治疗相关结果。要充分利用这些发现作为伊匹单抗AEs的预测性生物标志物,还需要进行确证研究。
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引用次数: 0
The Effectiveness of Adjuvant PD-1 Inhibitors in Patients With Surgically Resected Stage III/IV Acral Melanoma. PD-1抑制剂对手术切除的III/IV期口腔黑色素瘤患者的辅助治疗效果。
IF 3.9 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-06-01 Epub Date: 2024-03-11 DOI: 10.1097/CJI.0000000000000508
Haci Arak, Suna Erkiliç, Şendağ Yaslikaya, Eda Eylemer Mocan, Gökmen Aktaş, Melek Özdemir, Hüseyin Salih Semiz, Saadettin Kiliçkap, Faruk Recep Özalp, Özlem Nuray Sever, Goncagül Akdağ, Ahmet Burak Ağaoğlu, Melike Özçelik, Murat Sari, Murat Arcagök, Hicran Anik, Şaziye Burçak Yayla, Nadiye Sever, Fatma Pinar Açar, İsmail Bayrakçi, Serdar Turhal, Murat Ayhan, Tülay Kuş

Our aim was to assess the efficacy of adjuvant programmed cell death protein-1 (PD-1) inhibitors and compare the other adjuvant treatments in patients with surgically resected stage III or IV acral melanoma. This study is a multicenter, retrospective analysis. We included 114 patients with stage III or IV acral malignant melanoma who underwent surgery within the past 10 years. We analyzed the effect of adjuvant programmed cell death protein-1 inhibitors on disease-free survival (DFS). The mean follow-up was 40 months, during which 69 (59.5%) patients experienced recurrence. Among the participants, 64 (56.1%) received systemic adjuvant therapy. Specifically, 48.4% received anti-PD-1 therapy, 29.7% received interferon, 14.1% received tezozolomide, and 7.8% received B-Raf proto-oncogene/mitogen-activated protein kinase inhibitors. Patients who received adjuvant therapy had a median DFS of 24 (10.9-37.2) months, whereas those who did not receive adjuvant therapy had a median DFS of 15 (9.8-20.2) months. Multivariate analysis for DFS revealed that the receipt of adjuvant therapy and lymph node metastasis stage were independent significant parameters ( P = 0.021, P = 0.018, respectively). No statistically significant difference was observed for DFS between programmed cell death protein-1 inhibitor treatment and other adjuvant treatments. Regarding overall survival (OS), patients who received adjuvant treatment had a median OS of 71 (30.4-111.7) months, whereas those who did not receive adjuvant treatment had a median OS of 38 (16.7-59.3; P = 0.023) months. In addition, there were no significant differences in OS observed between various adjuvant treatment agents ( P = 0.122). In our study, we have shown that adjuvant therapy had a positive effect on both DFS and OS in patients with stages III-IV acral melanoma who underwent curative intent surgery. Notably, we found no significant differences between anti-PD-1 therapy and other adjuvant therapies.

我们的目的是评估程序性细胞死亡蛋白-1(PD-1)抑制剂的辅助疗效,并比较其他辅助疗法对手术切除的III期或IV期尖锐湿疣患者的疗效。本研究是一项多中心回顾性分析。我们纳入了114名在过去10年内接受过手术的III期或IV期口角恶性黑色素瘤患者。我们分析了程序性细胞死亡蛋白-1抑制剂辅助治疗对无病生存期(DFS)的影响。平均随访时间为 40 个月,期间有 69 例(59.5%)患者复发。其中,64人(56.1%)接受了全身辅助治疗。具体来说,48.4%的患者接受了抗PD-1治疗,29.7%的患者接受了干扰素治疗,14.1%的患者接受了替佐唑胺治疗,7.8%的患者接受了B-Raf原癌基因/介原激活蛋白激酶抑制剂治疗。接受辅助治疗的患者的中位生存期为24(10.9-37.2)个月,而未接受辅助治疗的患者的中位生存期为15(9.8-20.2)个月。DFS的多变量分析显示,接受辅助治疗和淋巴结转移分期是独立的重要参数(分别为P = 0.021和P = 0.018)。在DFS方面,程序性细胞死亡蛋白-1抑制剂治疗与其他辅助治疗之间没有统计学差异。在总生存期(OS)方面,接受辅助治疗的患者的中位OS为71(30.4-111.7)个月,而未接受辅助治疗的患者的中位OS为38(16.7-59.3;P = 0.023)个月。此外,不同辅助治疗药物的中位生存期也无明显差异(P = 0.122)。在我们的研究中,我们发现辅助治疗对接受治愈性手术的 III-IV 期盲灶黑色素瘤患者的 DFS 和 OS 均有积极影响。值得注意的是,我们发现抗PD-1疗法与其他辅助疗法之间没有明显差异。
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引用次数: 0
Nonclinical Investigation of Cytokine Mitigation Strategies for T-cell-Engaging Bispecifics in the Cynomolgus Macaque. 犬科猕猴T细胞激活双特异性药物细胞因子缓解策略的非临床研究
IF 3.9 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-06-01 Epub Date: 2024-04-02 DOI: 10.1097/CJI.0000000000000512
Cris Kamperschroer, Magali Guffroy, Amy Shen, Melba Dokmanovich, Makeida Stubbs, Lynn M O'Donnell

Summary: T-cell-directed cancer therapies such as T-cell-engaging bispecifics (TCBs) are commonly associated with cytokine release syndrome and associated clinical signs that can limit their tolerability and therapeutic benefit. Strategies for reducing cytokine release are therefore needed. Here, we report on studies performed in cynomolgus monkeys to test different approaches for mitigating cytokine release with TCBs. A "priming dose" as well as subcutaneous dosing reduced cytokine release compared with intravenous dosing but did not affect the intended T-cell response to the bispecific. As another strategy, cytokines or cytokine responses were blocked with an anti-IL-6 antibody, dexamethasone, or a JAK1/TYK2-selective inhibitor, and the effects on toxicity as well as T-cell responses to a TCB were evaluated. The JAK1/TYK2 inhibitor and dexamethasone prevented CRS-associated clinical signs on the day of TCB administration, but the anti-IL-6 had little effect. All interventions allowed for functional T-cell responses and expected damage to target-bearing tissues, but the JAK1/TYK2 inhibitor prevented the upregulation of activation markers on T cells, suggesting the potential for suppression of T-cell responses. Our results suggest that short-term prophylactic dexamethasone treatment may be an effective option for blocking cytokine responses without affecting desired T-cell responses to TCBs.

摘要:T细胞定向癌症疗法,如T细胞激活双特异性药物(TCBs),通常与细胞因子释放综合征和相关临床症状有关,这可能会限制其耐受性和治疗效果。因此需要减少细胞因子释放的策略。在此,我们报告了在眼镜猴身上进行的研究,这些研究测试了使用细胞因子抑制剂减少细胞因子释放的不同方法。与静脉注射相比,"启动剂量 "和皮下注射可减少细胞因子的释放,但不会影响T细胞对双特异性的预期反应。另一种策略是用抗 IL-6 抗体、地塞米松或 JAK1/TYK2 选择性抑制剂阻断细胞因子或细胞因子反应,并评估其对毒性以及 T 细胞对 TCB 反应的影响。JAK1/TYK2抑制剂和地塞米松能防止在注射TCB当天出现CRS相关临床症状,但抗IL-6的效果甚微。所有干预措施都能使T细胞产生功能性反应,并对靶组织造成预期损伤,但JAK1/TYK2抑制剂能阻止T细胞活化标志物的上调,这表明它有可能抑制T细胞反应。我们的研究结果表明,短期预防性地塞米松治疗可能是阻断细胞因子反应而不影响T细胞对TCB的预期反应的有效选择。
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引用次数: 0
TIGIT Blockade Reshapes the Tumor Microenvironment Based on the Single-cell RNA-Sequencing Analysis. 基于单细胞 RNA 序列分析的 TIGIT 阻断疗法重塑了肿瘤微环境
IF 3.9 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-06-01 Epub Date: 2024-03-28 DOI: 10.1097/CJI.0000000000000511
Yanyan Lang, Hao Huang, Hongwei Jiang, Shaoxian Wu, Yaping Chen, Bin Xu, Yingting Liu, Dawei Zhu, Xiao Zheng, Lujun Chen, Jingting Jiang

Summary: Immune checkpoint blockade therapy is a pivotal approach in treating malignant tumors. TIGIT has emerged as a focal point of interest among the diverse targets for tumor immunotherapy. Nonetheless, there is still a lack of comprehensive understanding regarding the immune microenvironment alterations following TIGIT blockade treatment. To bridge this knowledge gap, we performed single-cell sequencing on mice both before and after the administration of anti-TIGIT therapy. Our analysis revealed that TIGIT was predominantly expressed on T cells and natural killer (NK) cells. The blockade of TIGIT exhibited inhibitory effects on Treg cells by downregulating the expression of Foxp3 and reducing the secretion of immunosuppressive cytokines. In addition, TIGIT blockade facilitated the activation of NK cells, leading to an increase in cell numbers, and promoted cDC1 maturation through the secretion of XCL1 and Flt3L. This activation, in turn, stimulated the TCR signaling of CD8 + T cells, thereby enhancing their antitumor effect. Consequently, anti-TIGIT therapy demonstrated substantial potential for cancer immunotherapy. Our research provided novel insights into future therapeutic strategies targeting TIGIT for patients with cancer.

免疫检查点阻断疗法是治疗恶性肿瘤的关键方法。在肿瘤免疫疗法的各种靶点中,TIGIT已成为人们关注的焦点。然而,人们对TIGIT阻断治疗后免疫微环境的改变仍缺乏全面的了解。为了弥补这一知识空白,我们在小鼠接受抗TIGIT治疗前后对其进行了单细胞测序。我们的分析表明,TIGIT 主要在 T 细胞和自然杀伤(NK)细胞上表达。通过下调 Foxp3 的表达和减少免疫抑制细胞因子的分泌,阻断 TIGIT 对 Treg 细胞有抑制作用。此外,阻断 TIGIT 还能促进 NK 细胞的活化,使细胞数量增加,并通过分泌 XCL1 和 Flt3L 促进 cDC1 的成熟。这种活化反过来又刺激了 CD8+T 细胞的 TCR 信号转导,从而增强了它们的抗肿瘤效果。因此,抗TIGIT疗法在癌症免疫疗法中展现了巨大的潜力。我们的研究为未来针对癌症患者的TIGIT治疗策略提供了新的见解。
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引用次数: 0
Site-specific Antibody-Nitric Oxide Conjugate HN02 Possesses Improved Antineoplastic and Safety Properties. 位点特异性抗体-一氧化氮共轭物 HN02 具有更好的抗肿瘤性和安全性。
IF 3.9 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-06-01 Epub Date: 2024-03-27 DOI: 10.1097/CJI.0000000000000507
Tianyue Cheng, Jiajun Xie, Xun Yuan, Minji Guo, Jianbing Wu, Min Wang, Zhangjian Huang, Juan Zhang

Antibody-drug conjugates (ADCs) combine the high specificity of antibodies with the cytotoxicity of payloads and have great potential in pan-cancer immunotherapy. However, the current payloads for clinical uses have limited the therapeutic window due to their uncontrollable off-site toxicity. There is unmet needs to develop more potent ADC payloads with better safety and efficacy profiles. Nitric oxide (NO) is a special molecule that has low toxicity itself, which can kill tumor cells effectively when highly concentrated, has broad application prospects. Previously, we prepared for the first time an antibody-nitric oxide conjugate (ANC)-HN01, which showed inhibitory activity against hepatocellular carcinoma. However, the random conjugation method made HN01 highly heterogeneous and unstable. Here, we used site-specific conjugation-based engineered cysteine sites (CL-V211C) of anti-CD24 antibody to prepare a second-generation ANC with a drug-to-antibody ratio of 2. The homogeneous ANC, HN02 was stable in human plasma, shown in vitro bystander effect to neighboring cells and antiproliferative activity to CD24-targeted tumor cells. Compared with HN01, HN02 significantly prolonged the survival of tumor-bearing mice. In summary, we developed a stable and homogeneous site-specific conjugated ANC, which showed good antitumor activity and improved safety profile both in vitro and in vivo. This study provides new insight into the development of next generation of ADC candidates.

抗体药物共轭物(ADCs)结合了抗体的高特异性和有效载荷的细胞毒性,在泛癌症免疫疗法中具有巨大潜力。然而,目前用于临床的有效载荷因其不可控的异位毒性而限制了治疗窗口。开发安全性更高、疗效更好的强效 ADC 有效载荷的需求尚未得到满足。一氧化氮(NO)是一种特殊分子,本身毒性低,高浓度时能有效杀死肿瘤细胞,具有广阔的应用前景。此前,我们首次制备了抗体-一氧化氮共轭物(ANC)-HN01,对肝细胞癌具有抑制活性。然而,随机共轭方法使得 HN01 具有高度异质性和不稳定性。在这里,我们利用抗 CD24 抗体的半胱氨酸位点(CL-V211C)进行位点特异性共轭,制备出药物与抗体比为 2 的第二代 ANC。均一的 ANC HN02 在人血浆中稳定,体外对邻近细胞有旁观效应,对 CD24 靶向的肿瘤细胞有抗增殖活性。与 HN01 相比,HN02 能显著延长肿瘤小鼠的生存期。总之,我们开发出了一种稳定、均质的位点特异性共轭 ANC,它在体外和体内均表现出良好的抗肿瘤活性和更高的安全性。这项研究为开发新一代 ADC 候选药物提供了新的思路。
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Journal of Immunotherapy
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