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Clinical features associated with immune checkpoint inhibitor nephritis: a single-center clinical case series. 与免疫检查点抑制剂肾炎相关的临床特征:单中心临床病例系列。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-08-06 DOI: 10.1007/s00262-024-03775-6
Ramya Muddasani, Neel Talwar, Isa Mambetsariev, Jeremy Fricke, Mercury Lin, Daniel Schmolze, Andrew Yue, Amna Rizvi, Ravi Salgia

Background: Acute kidney injury (AKI) has been well described as a complication of immune checkpoint inhibitor therapy. We present a series of patients, the majority with lung adenocarcinoma, who developed AKI while actively receiving immune checkpoint inhibitors.

Methods: This is a retrospectively analyzed clinical case series of six patients treated at City of Hope Comprehensive Cancer Center. Data were collected on gender, age, ethnicity, comorbidities, concomitant medications, type of malignancy, treatments, and renal function. All patients underwent renal biopsy for classification of the mechanism of AKI. Comprehensive genomic profiling (CGP) was performed on tumor tissue for all patients.

Results: Patterns of AKI included acute interstitial nephritis and acute tubular necrosis. Contributing factors included the use of concomitant medications known to contribute to AKI. All but two patients had full resolution of the AKI with the use of steroids. There were several mutations found on CGP that was notable including an Exon 20 insertion as well as multiple NF1 and TP53 mutations. There was high PD-L1 expression on tumor tissue noted in two out of six patients. In addition to AKI, a subset of patients had proteinuria with biopsies revealing corresponding glomerular lesions of minimal change disease and focal and segmental glomerulosclerosis.

Conclusions: Our case series demonstrates that AKI from immune checkpoint inhibitors has a variable presentation that may require an individualized treatment approach. Further studies are needed to identify biomarkers that may help identify those at risk and guide the management of this condition.

背景:急性肾损伤(AKI)作为免疫检查点抑制剂治疗的一种并发症已被广泛描述。我们介绍了一系列在积极接受免疫检查点抑制剂治疗期间出现急性肾损伤的患者,其中大部分患者为肺腺癌患者:这是一个回顾性分析的临床病例系列,涉及在希望之城综合癌症中心接受治疗的六名患者。收集的数据包括性别、年龄、种族、合并症、伴随药物、恶性肿瘤类型、治疗方法和肾功能。所有患者都接受了肾活检,以便对 AKI 的机制进行分类。对所有患者的肿瘤组织进行了全面基因组分析(CGP):结果:AKI的模式包括急性间质性肾炎和急性肾小管坏死。诱发因素包括同时使用已知会导致 AKI 的药物。除两名患者外,所有患者在使用类固醇后都完全缓解了AKI。CGP上发现了几个值得注意的突变,包括一个外显子20插入以及多个NF1和TP53突变。六名患者中有两名患者的肿瘤组织中出现了 PD-L1 高表达。除了 AKI 外,部分患者还出现蛋白尿,活检显示相应的肾小球病变,包括微小病变、局灶性和节段性肾小球硬化:我们的系列病例表明,免疫检查点抑制剂引起的 AKI 表现各异,可能需要个体化的治疗方法。还需要进一步研究来确定生物标志物,以帮助识别高危人群并指导该病症的治疗。
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引用次数: 0
Hypofractionated radiotherapy plus PD-1 antibody and SOX chemotherapy as second-line therapy in metastatic pancreatic cancer: a single-arm, phase II clinical trial. 转移性胰腺癌二线治疗中的低分次放疗加 PD-1 抗体和 SOX 化疗:单臂 II 期临床试验。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-08-06 DOI: 10.1007/s00262-024-03744-z
Qin Wang, Fan Tong, Li Qiao, Liang Qi, Yi Sun, Yahui Zhu, Jiayao Ni, Juan Liu, Weiwei Kong, Baorui Liu, Juan Du

Purpose: To assess the efficacy and safety of concurrent hypofractionated radiotherapy plus anti-PD-1 antibody and SOX chemotherapy in the treatment of metastatic pancreatic cancer (mPC) after failure of first-line chemotherapy.

Methods: Patients with pathologically confirmed mPC who failed standard first-line chemotherapy were enrolled. The patients were treated with a regimen of hypofractionated radiotherapy, SOX chemotherapy, and immune checkpoint inhibitors at our institution. We collected the patients' clinical information and outcome measurements. The median progression-free survival (mPFS) was the primary endpoint of the study, followed by disease control rate (DCR), objective response rate (ORR), median overall survival (mOS) and safety. Exploratory analyses included biomarkers related to the benefits.

Results: Between February 24, 2021, and August 30, 2023, twenty-five patients were enrolled in the study, and twenty-three patients who received at least one dose of the study agent had objective efficacy evaluation. The mPFS was 5.48 months, the mOS was 6.57 months, and the DCR and ORR were 69.5% and 30.4%, respectively. Among the seven patients who achieved a PR, the median duration of the response was 7.41 months. On-treatment decreased serum CA19-9 levels were associated with better overall survival. Besides, pretreatment inflammatory markers were associated with tumor response and survival.

Conclusions: Clinically meaningful antitumor activity and favorable safety profiles were demonstrated after treatment with these combination therapies in patients with refractory mPC. On-treatment decreased serum CA19-9 levels and pretreatment inflammatory markers platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), lactate dehydrogenase (LDH) might be biomarkers related to clinical benefits.

Clinical trial registration: https://www.chictr.org.cn/showproj.html?proj=130211 , identifier: ChiCTR2100049799, date of registration: 2021-08-09.

目的:评估低分次放疗联合抗PD-1抗体和SOX化疗治疗一线化疗失败后的转移性胰腺癌(mPC)的有效性和安全性:入选患者均为病理确诊的转移性胰腺癌患者,且一线化疗失败。这些患者在我院接受了低分次放疗、SOX化疗和免疫检查点抑制剂治疗。我们收集了患者的临床信息和疗效测量结果。中位无进展生存期(mPFS)是研究的主要终点,其次是疾病控制率(DCR)、客观反应率(ORR)、中位总生存期(mOS)和安全性。探索性分析包括与获益相关的生物标志物:2021年2月24日至2023年8月30日期间,共有25名患者入组研究,23名接受了至少一剂研究药物的患者进行了客观疗效评估。mPFS为5.48个月,mOS为6.57个月,DCR和ORR分别为69.5%和30.4%。在获得 PR 的 7 名患者中,中位反应持续时间为 7.41 个月。治疗时血清CA19-9水平的降低与较好的总生存率相关。此外,治疗前的炎症标志物与肿瘤反应和生存期有关:结论:对于难治性mPC患者,这些联合疗法具有临床意义的抗肿瘤活性和良好的安全性。治疗时血清CA19-9水平的降低和治疗前炎症标志物血小板与淋巴细胞比值(PLR)、淋巴细胞与单核细胞比值(LMR)、乳酸脱氢酶(LDH)可能是与临床获益相关的生物标志物。临床试验注册:https://www.chictr.org.cn/showproj.html?proj=130211 ,标识符:ChiCTR2100049799:ChiCTR2100049799,注册日期:2021-08-09。
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引用次数: 0
Safety and clinical activity of JNJ-78306358, a human leukocyte antigen-G (HLA-G) x CD3 bispecific antibody, for the treatment of advanced stage solid tumors. 用于治疗晚期实体瘤的人类白细胞抗原-G (HLA-G) x CD3 双特异性抗体 JNJ-78306358 的安全性和临床活性。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-08-06 DOI: 10.1007/s00262-024-03790-7
Ravit Geva, Maria Vieito, Jorge Ramon, Ruth Perets, Manuel Pedregal, Elena Corral, Bernard Doger, Emiliano Calvo, Jorge Bardina, Elena Garralda, Regina J Brown, James G Greger, Shujian Wu, Douglas Steinbach, Tsun-Wen Sheena Yao, Yu Cao, Josh Lauring, Ruchi Chaudhary, Jaymala Patel, Bharvin Patel, Victor Moreno

Background: JNJ-78306358 is a bispecific antibody that redirects T cells to kill human leukocyte antigen-G (HLA-G)-expressing tumor cells. This dose escalation study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of JNJ-78306358 in patients with advanced solid tumors.

Methods: Adult patients with metastatic/unresectable solid tumors with high prevalence of HLA-G expression were enrolled. Dose escalation was initiated with once-weekly subcutaneous administration with step-up dosing to mitigate cytokine release syndrome (CRS).

Results: Overall, 39 heavily pretreated patients (colorectal cancer: n = 23, ovarian cancer: n = 10, and renal cell carcinoma: n = 6) were dosed in 7 cohorts. Most patients (94.9%) experienced ≥ 1 treatment-emergent adverse events (TEAEs); 87.2% had ≥ 1 related TEAEs. About half of the patients (48.7%) experienced CRS, which were grade 1/2. Nine patients (23.1%) received tocilizumab for CRS. No grade 3 CRS was observed. Dose-limiting toxicities (DLTs) of increased transaminases, pneumonitis and recurrent CRS requiring a dose reduction were reported in 4 patients, coinciding with CRS. No treatment-related deaths reported. No objective responses were noted, but 2 patients had stable disease > 40 weeks. JNJ-78306358 stimulated peripheral T cell activation and cytokine release. Anti-drug antibodies were observed in 45% of evaluable patients with impact on exposure. Approximately half of archival tumor samples (48%) had expression of HLA-G by immunohistochemistry.

Conclusion: JNJ-78306358 showed pharmacodynamic effects with induction of cytokines and T cell activation. JNJ-78306358 was associated with CRS-related toxicities including increased transaminases and pneumonitis which limited its dose escalation to potentially efficacious levels. Trial registration number ClinicalTrials.gov (No. NCT04991740).

背景:JNJ-78306358是一种双特异性抗体,它能引导T细胞杀死表达人类白细胞抗原-G(HLA-G)的肿瘤细胞。这项剂量递增研究评估了 JNJ-78306358 在晚期实体瘤患者中的安全性、药代动力学、药效学和初步抗肿瘤活性:方法:研究人员招募了患有转移性/不可切除实体瘤且HLA-G表达率较高的成年患者。开始剂量升级,每周一次皮下注射,同时加大剂量以减轻细胞因子释放综合征(CRS):共有 39 名重度预处理患者(结直肠癌:23 人;卵巢癌:10 人;肾细胞癌:6 人)在 7 个队列中接受了治疗。大多数患者(94.9%)发生了≥1次治疗突发不良事件(TEAEs);87.2%发生了≥1次相关TEAEs。约半数患者(48.7%)出现了CRS,均为1/2级。9名患者(23.1%)因CRS接受了托珠单抗治疗。未观察到 3 级 CRS。有4名患者报告了转氨酶升高、肺炎和复发性CRS等剂量限制性毒性(DLTs),需要减少剂量,并与CRS同时发生。没有与治疗相关的死亡报告。未发现客观反应,但有 2 名患者病情稳定超过 40 周。JNJ-78306358 可刺激外周 T 细胞活化和细胞因子释放。在 45% 的可评估患者中观察到了抗药性抗体,并对暴露产生了影响。约有一半的存档肿瘤样本(48%)通过免疫组化表达了 HLA-G:结论:JNJ-78306358 具有诱导细胞因子和 T 细胞活化的药效学效应。JNJ-78306358与CRS相关毒性有关,包括转氨酶升高和肺炎,这限制了其剂量升级到潜在有效水平。试验注册号为 ClinicalTrials.gov(NCT04991740 号)。
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引用次数: 0
GP100 expression is variable in intensity in melanoma. 黑色素瘤中 GP100 的表达强度不一。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-08-06 DOI: 10.1007/s00262-024-03776-5
Jacqueline E Mann, Nitzan Hasson, David G Su, Adebowale J Adeniran, Keiran S M Smalley, Dijana Djureinovic, Lucia B Jilaveanu, David A Schoenfeld, Harriet M Kluger

Drugs or cellular products that bind to gp100 are being investigated for treatment of cutaneous melanoma. The relative specificity of gp100 expression in melanocytes makes it an attractive target to harness for therapeutic intent. For example, Tebentafusp, a bispecific gp100 peptide-HLA-directed CD3 T cell engager, has generated significant enthusiasm in recent years due to its success in improving outcomes for uveal melanoma and is being studied in cutaneous melanoma. However, the extent and intensity of gp100 expression in advanced cutaneous melanoma has not been well studied. Here, we interrogated a large cohort of primary and metastatic melanomas for gp100 expression by immunohistochemistry. Expression in metastatic samples was globally higher and almost uniformly positive, however the degree of intensity was variable. Using a quantitative immunofluorescence method, we confirmed the variability in expression. As gp100-binding drugs are assessed in clinical trials, the association between activity of the drugs and the level of gp100 expression should be studied in order to potentially improve patient selection.

目前正在研究与 gp100 结合的药物或细胞产品,以治疗皮肤黑色素瘤。gp100在黑色素细胞中表达的相对特异性使其成为一个极具吸引力的治疗靶点。例如,Tebentafusp是一种双特异性gp100肽-HLA定向CD3 T细胞吸引剂,近年来由于成功改善了葡萄膜黑色素瘤的治疗效果而引起了极大的反响,目前正在皮肤黑色素瘤领域进行研究。然而,gp100 在晚期皮肤黑色素瘤中的表达范围和强度还没有得到很好的研究。在这里,我们用免疫组化方法检测了一大批原发性和转移性黑色素瘤的gp100表达情况。转移瘤样本中gp100的表达量总体较高,几乎呈均匀的阳性,但强度不一。我们使用定量免疫荧光方法证实了表达的差异性。随着临床试验中对gp100结合药物的评估,应研究药物活性与gp100表达水平之间的关联,以便改进对患者的选择。
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引用次数: 0
TIGIT expression in renal cell carcinoma infiltrating T cells is variable and inversely correlated with PD-1 and LAG3. 肾细胞癌浸润 T 细胞中 TIGIT 的表达是可变的,并且与 PD-1 和 LAG3 成反比。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-08-06 DOI: 10.1007/s00262-024-03773-8
Oscar Perales, Lucia Jilaveanu, Adebowale Adeniran, David G Su, Michael Hurwitz, David A Braun, Harriet M Kluger, David A Schoenfeld

Purpose: Immune checkpoint inhibitors have revolutionized the treatment of renal cell carcinoma (RCC), but many patients do not respond to therapy and the majority develop resistant disease over time. Thus, there is increasing need for alternative immunomodulating agents. The co-inhibitory molecule T-cell immunoglobulin and ITIM domain (TIGIT) may play a role in resistance to approved immune checkpoint inhibitors and is being investigated as a potential therapeutic target. The purpose of this study was to quantify TIGIT positivity in tumor-infiltrating T cells in RCC.

Methods: We employed tissue microarrays containing specimens from primary RCC tumors, adjacent normal renal tissue, and RCC metastases to quantify TIGIT within tumor-infiltrating CD3+ T cells using quantitative immunofluorescent analysis. We also compared these results to TIGIT+ CD3+ levels in four other tumor types (melanoma, non-small cell lung, cervical, and head and neck cancers).

Results: We did not observe significant differences in TIGIT positivity between primary RCC tumors and patient-matched metastatic samples. We found that the degree of TIGIT positivity in RCC is comparable to that in lung cancer but lower than that in melanoma, cervical, and head and neck cancers. Correlation analysis comparing TIGIT positivity to previously published, patient-matched spatial proteomic data by our group revealed a negative association between TIGIT and the checkpoint proteins PD-1 and LAG3.

Conclusion: Our findings support careful evaluation of TIGIT expression on T cells in primary or metastatic RCC specimens for patients who may be treated with TIGIT-targeting antibodies, as increased TIGIT positivity might be associated with a greater likelihood of response to therapy.

目的:免疫检查点抑制剂彻底改变了肾细胞癌(RCC)的治疗方法,但许多患者对治疗没有反应,而且大多数患者随着时间的推移会出现耐药性。因此,人们越来越需要替代性免疫调节药物。共抑制分子T细胞免疫球蛋白和ITIM结构域(TIGIT)可能在已获批准的免疫检查点抑制剂的耐药性中发挥作用,目前正将其作为潜在的治疗靶点进行研究。本研究的目的是量化RCC中肿瘤浸润T细胞的TIGIT阳性率:我们采用了包含原发性 RCC 肿瘤、邻近正常肾组织和 RCC 转移灶标本的组织芯片,使用定量免疫荧光分析法定量检测了肿瘤浸润 CD3+ T 细胞中的 TIGIT。我们还将这些结果与其他四种肿瘤类型(黑色素瘤、非小细胞肺癌、宫颈癌和头颈癌)中的 TIGIT+ CD3+ 水平进行了比较:结果:我们没有观察到原发性 RCC 肿瘤与患者匹配的转移样本在 TIGIT 阳性率上存在明显差异。我们发现 TIGIT 在 RCC 中的阳性程度与肺癌相当,但低于黑色素瘤、宫颈癌和头颈癌。将 TIGIT 阳性与我们小组之前发表的、与患者匹配的空间蛋白质组数据进行相关性分析后发现,TIGIT 与检查点蛋白 PD-1 和 LAG3 呈负相关:我们的研究结果支持对原发性或转移性RCC标本中T细胞上的TIGIT表达进行仔细评估,因为TIGIT阳性率的增加可能与治疗反应的可能性增大有关。
{"title":"TIGIT expression in renal cell carcinoma infiltrating T cells is variable and inversely correlated with PD-1 and LAG3.","authors":"Oscar Perales, Lucia Jilaveanu, Adebowale Adeniran, David G Su, Michael Hurwitz, David A Braun, Harriet M Kluger, David A Schoenfeld","doi":"10.1007/s00262-024-03773-8","DOIUrl":"10.1007/s00262-024-03773-8","url":null,"abstract":"<p><strong>Purpose: </strong>Immune checkpoint inhibitors have revolutionized the treatment of renal cell carcinoma (RCC), but many patients do not respond to therapy and the majority develop resistant disease over time. Thus, there is increasing need for alternative immunomodulating agents. The co-inhibitory molecule T-cell immunoglobulin and ITIM domain (TIGIT) may play a role in resistance to approved immune checkpoint inhibitors and is being investigated as a potential therapeutic target. The purpose of this study was to quantify TIGIT positivity in tumor-infiltrating T cells in RCC.</p><p><strong>Methods: </strong>We employed tissue microarrays containing specimens from primary RCC tumors, adjacent normal renal tissue, and RCC metastases to quantify TIGIT within tumor-infiltrating CD3<sup>+</sup> T cells using quantitative immunofluorescent analysis. We also compared these results to TIGIT<sup>+</sup> CD3<sup>+</sup> levels in four other tumor types (melanoma, non-small cell lung, cervical, and head and neck cancers).</p><p><strong>Results: </strong>We did not observe significant differences in TIGIT positivity between primary RCC tumors and patient-matched metastatic samples. We found that the degree of TIGIT positivity in RCC is comparable to that in lung cancer but lower than that in melanoma, cervical, and head and neck cancers. Correlation analysis comparing TIGIT positivity to previously published, patient-matched spatial proteomic data by our group revealed a negative association between TIGIT and the checkpoint proteins PD-1 and LAG3.</p><p><strong>Conclusion: </strong>Our findings support careful evaluation of TIGIT expression on T cells in primary or metastatic RCC specimens for patients who may be treated with TIGIT-targeting antibodies, as increased TIGIT positivity might be associated with a greater likelihood of response to therapy.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"73 10","pages":"192"},"PeriodicalIF":4.6,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11303630/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892923","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
Predicting recurrent glioblastoma clinical outcome to immune checkpoint inhibition and low-dose bevacizumab with tumor in situ fluid circulating tumor DNA analysis. 利用肿瘤原位液循环肿瘤DNA分析预测免疫检查点抑制剂和小剂量贝伐单抗对复发性胶质母细胞瘤的临床疗效
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-08-06 DOI: 10.1007/s00262-024-03774-7
Guangzhong Guo, Ziyue Zhang, Jiubing Zhang, Dayang Wang, Sensen Xu, Guanzheng Liu, Yushuai Gao, Jie Mei, Zhaoyue Yan, Ruijiao Zhao, Meiyun Wang, Tianxiao Li, Xingyao Bu

Objective: Most recurrent glioblastoma (rGBM) patients do not benefit from immune checkpoint inhibition, emphasizing the necessity for response biomarkers. This study evaluates whether tumor in situ fluid (TISF) circulating tumor DNA (ctDNA) could serve as a biomarker for response to low-dose bevacizumab (Bev) plus anti-PD-1 therapy in rGBM patients, aiming to enhance systemic responses to immunotherapy.

Methods: In this phase II trial, 32 GBM patients with first recurrence after standard therapy were enrolled and then received tislelizumab plus low-dose Bev each cycle. TISF samples were analyzed for ctDNA using a 551-gene panel before each treatment.

Results: The median progression-free survival (mPFS) and overall survival (mOS) were 8.2 months (95% CI, 5.2-11.1) and 14.3 months (95% CI, 6.5-22.1), respectively. The 12-month OS was 43.8%, and the objective response rate was 56.3%. Patients with more than 20% reduction in the mutant allele fraction and tumor mutational burden after treatment were significantly associated with better prognosis compared to baseline TISF-ctDNA. Among detectable gene mutations, patients with MUC16 mutation, EGFR mutation & amplification, SRSF2 amplification, and H3F3B amplification were significantly associated with worse prognosis.

Conclusions: Low-dose Bev plus anti-PD-1 therapy significantly improves OS in rGBM patients, offering guiding significance for future individualized treatment strategies. TISF-ctDNA can monitor rGBM patients' response to combination therapy and guide treatment.

Clinical trial registration: This trial is registered with ClinicalTrials.gov, NCT05540275.

目的:大多数复发性胶质母细胞瘤(rGBM)患者不能从免疫检查点抑制剂中获益,这就强调了反应生物标志物的必要性。本研究评估了肿瘤原位液(TISF)循环肿瘤DNA(ctDNA)是否可作为rGBM患者对小剂量贝伐单抗(Bev)加抗PD-1疗法反应的生物标志物,旨在增强免疫疗法的全身反应:在这项II期试验中,32名经标准治疗后首次复发的GBM患者入组,然后每个周期接受替赛珠单抗加小剂量贝伐单抗治疗。每次治疗前,使用 551 个基因面板对 TISF 样本进行 ctDNA 分析:中位无进展生存期(mPFS)和总生存期(mOS)分别为8.2个月(95% CI,5.2-11.1)和14.3个月(95% CI,6.5-22.1)。12个月的OS为43.8%,客观反应率为56.3%。与基线TISF-ctDNA相比,治疗后突变等位基因比例和肿瘤突变负荷减少20%以上的患者预后明显较好。在可检测到的基因突变中,MUC16突变、表皮生长因子受体(EGFR)突变和扩增、SRSF2扩增和H3F3B扩增的患者与较差的预后明显相关:小剂量Bev加抗PD-1治疗可明显改善rGBM患者的OS,对未来的个体化治疗策略具有指导意义。TISF-ctDNA可以监测rGBM患者对联合治疗的反应,指导治疗:本试验已在 ClinicalTrials.gov 登记,编号为 NCT05540275。
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引用次数: 0
ALK5/VEGFR2 dual inhibitor TU2218 alone or in combination with immune checkpoint inhibitors enhances immune-mediated antitumor effects. ALK5/VEGFR2 双抑制剂 TU2218 单独使用或与免疫检查点抑制剂联合使用可增强免疫介导的抗肿瘤效果。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-08-06 DOI: 10.1007/s00262-024-03777-4
Nam-Hoon Kim, Jihyun Lee, Seung-Hyun Kim, Seong-Ho Kang, Sowon Bae, Chan-Hee Yu, Jeongmin Seo, Hun-Taek Kim

Transforming growth factor β (TGFβ) is present in blood of patients who do not respond to anti-programmed cell death (ligand) 1 [PD-(L)1] treatment, and through synergy with vascular endothelial growth factor (VEGF), it helps to create an environment that promotes tumor immune evasion and immune tolerance. Therefore, simultaneous inhibition of TGFβ/VEGF is more effective than targeting TGFβ alone. In this study, the dual inhibitory mechanism of TU2218 was identified through in vitro analysis mimicking the tumor microenvironment, and its antitumor effects were analyzed using mouse syngeneic tumor models. TU2218 directly restored the activity of damaged cytotoxic T lymphocytes (CTLs) and natural killer cells inhibited by TGFβ and suppressed the activity and viability of regulatory T cells. The inactivation of endothelial cells induced by VEGF stimulation was completely ameliorated by TU2218, an effect not observed with vactosertib, which inhibits only TGFβ signaling. The combination of TU2218 and anti-PD1 therapy had a significantly greater antitumor effect than either drug alone in the poorly immunogenic B16F10 syngeneic tumor model. The mechanism of tumor reduction was confirmed by flow cytometry, which showed upregulated VCAM-1 expression in vascular cells and increased influx of CD8 + CTLs into the tumor. As another strategy, combination of anti-CTLA4 therapy and TU2218 resulted in high complete regression (CR) rates in CT26 and WEHI-164 tumor models. In particular, immunological memory generated by the combination of anti-CTLA4 and TU2218 in the CT26 model prevented the development of tumors after additional tumor cell transplantation, suggesting that the TU2218-based combination has therapeutic potential in immunotherapy.

抗程序性细胞死亡(配体)1[PD-(L)1]治疗无效的患者血液中存在转化生长因子β(TGFβ),它通过与血管内皮生长因子(VEGF)协同作用,有助于创造一种促进肿瘤免疫逃避和免疫耐受的环境。因此,同时抑制 TGFβ/VEGF 比单独靶向 TGFβ 更为有效。本研究通过模拟肿瘤微环境的体外分析确定了TU2218的双重抑制机制,并利用小鼠合成肿瘤模型分析了其抗肿瘤效果。TU2218能直接恢复被TGFβ抑制的受损细胞毒性T淋巴细胞(CTL)和自然杀伤细胞的活性,并抑制调节性T细胞的活性和活力。TU2218能完全改善血管内皮细胞受血管内皮生长因子刺激引起的内皮细胞失活,而只抑制TGFβ信号传导的vactosertib则没有这种效果。在免疫原性较差的 B16F10 合成肿瘤模型中,TU2218 和抗 PD1 联合治疗的抗肿瘤效果明显高于单独使用其中一种药物。流式细胞术证实了肿瘤缩小的机制,它显示了血管细胞中 VCAM-1 表达的上调和 CD8 + CTLs 流入肿瘤的增加。作为另一种策略,在 CT26 和 WEHI-164 肿瘤模型中,联合使用抗 CTLA4 疗法和 TU2218 可实现较高的完全消退率(CR)。特别是,在CT26模型中,抗CTLA4和TU2218联合疗法产生的免疫记忆阻止了肿瘤细胞移植后肿瘤的发展,这表明基于TU2218的联合疗法在免疫疗法中具有治疗潜力。
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引用次数: 0
Conversion of anti-tissue factor antibody sequences to chimeric antigen receptor and bi-specific T-cell engager format. 将抗组织因子抗体序列转换为嵌合抗原受体和双特异性 T 细胞吞噬格式。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-08-06 DOI: 10.1007/s00262-024-03778-3
S C Saunderson, J C Halpin, G M Y Tan, P Shrivastava, A D McLellan

Background: The efficacy of antibody-targeted therapy of solid cancers is limited by the lack of consistent tumour-associated antigen expression. However, tumour-associated antigens shared with non-malignant cells may still be targeted using conditionally activated-antibodies, or by chimeric antigen receptor (CAR) T cells or CAR NK cells activated either by the tumour microenvironment or following 'unlocking' via multiple antigen-recognition. In this study, we have focused on tissue factor (TF; CD142), a type I membrane protein present on a range of solid tumours as a basis for future development of conditionally-activated BiTE or CAR T cells. TF is frequently upregulated on multiple solid tumours providing a selective advantage for growth, immune evasion and metastasis, as well as contributing to the pathology of thrombosis via the extrinsic coagulation pathway.

Methods: Two well-characterised anti-TF monoclonal antibodies (mAb) were cloned into expression or transposon vectors to produce single chain (scFv) BiTE for assessment as CAR and CD28-CD3-based CAR or CD3-based BiTE. The affinities of both scFv formats for TF were determined by surface plasmon resonance. Jurkat cell line-based assays were used to confirm the activity of the BiTE or CAR constructs.

Results: The anti-TF mAb hATR-5 and TF8-5G9 mAb were shown to maintain their nanomolar affinities following conversion into a single chain (scFv) format and could be utilised as CD28-CD3-based CAR or CD3-based BiTE format.

Conclusion: Because of the broad expression of TF on a range of solid cancers, anti-TF antibody formats provide a useful addition for the development of conditionally activated biologics for antibody and cellular-based therapy.

背景:由于缺乏一致的肿瘤相关抗原表达,抗体靶向治疗实体瘤的疗效受到限制。不过,与非恶性细胞共有的肿瘤相关抗原仍可通过条件激活抗体或由肿瘤微环境激活的嵌合抗原受体(CAR)T细胞或通过多重抗原识别 "解锁 "后激活的CAR NK细胞进行靶向治疗。在这项研究中,我们重点研究了组织因子(TF;CD142),这是一种存在于多种实体瘤上的 I 型膜蛋白,是未来开发条件激活型 BiTE 或 CAR T 细胞的基础。TF在多种实体瘤上经常上调,为肿瘤的生长、免疫逃避和转移提供了选择性优势,并通过外凝血途径促成了血栓形成的病理过程:方法:将两种特性良好的抗血小板单克隆抗体(mAb)克隆到表达载体或转座子载体中,以产生单链(scFv)BiTE,用于评估CAR和基于CD28-CD3的CAR或基于CD3的BiTE。两种 scFv 格式对 TF 的亲和力都是通过表面等离子共振测定的。用基于 Jurkat 细胞系的检测来确认 BiTE 或 CAR 构建物的活性:结果:抗TF mAb hATR-5和TF8-5G9 mAb在转化为单链(scFv)形式后保持了纳摩尔级的亲和力,可用作基于CD28-CD3的CAR或基于CD3的BiTE形式:结论:由于TF在一系列实体瘤中广泛表达,抗TF抗体格式为开发条件激活生物制剂提供了有用的补充,可用于基于抗体和细胞的治疗。
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引用次数: 0
Anlotinib reversed resistance to PD-1 inhibitors in recurrent and metastatic head and neck cancers: a real-world retrospective study. 安罗替尼逆转复发性和转移性头颈部癌症患者对PD-1抑制剂的耐药性:一项真实世界的回顾性研究。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-08-06 DOI: 10.1007/s00262-024-03784-5
Jianyun Jiang, Bin Wu, Ying Sun, Jun Xiang, Chunying Shen, Xiayun He, Hongmei Ying, Zuguang Xia

Patients with recurrent or metastatic head and neck cancers (R/M HNCs) are prone to developing resistance after immunotherapy. This retrospective real-world study aims to investigate whether the addition of anlotinib can reverse resistance to PD-1 inhibitors (PD-1i) and evaluate the efficacy and safety of this combination in R/M HNCs. Main outcomes included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety. Potential biomarkers included PD-L1 expression, lipid index, and genomic profiling. Twenty-one patients with R/M HNCs were included, including 11 nasopharyngeal carcinoma (NPC), five head and neck squamous cell carcinoma (HNSCC), three salivary gland cancers (SGC), and two nasal cavity or paranasal sinus cancers (NC/PNC). Among all patients, ORR was 47.6% (95% CI: 28.6-66.7), with 2 (9.5%) complete response; DCR was 100%. At the median follow-up of 17.1 months, the median PFS and OS were 14.3 months (95% CI: 5.9-NR) and 16.7 months (95% CI:8.4-NR), respectively. The median DOR was 11.2 months (95% CI: 10.1-NR). As per different diseases, the ORR was 45.5% for NPC, 60.0% for HNSCC, 66.7% for SGC, and 50.0% for NC/PNC. Most treatment-related adverse events (TRAEs) were grade 1 or 2 (88.9%). The most common grades 3-4 TRAE was hypertension (28.6%), and two treatment-related deaths occurred due to bleeding. Therefore, adding anlotinib to the original PD-1i could reverse PD-1 blockade resistance, with a favorable response rate, prolonged survival, and acceptable toxicity, indicating the potential as a second-line and subsequent therapy choice in R/M HNCs.

复发性或转移性头颈癌(R/M HNCs)患者在接受免疫疗法后容易产生耐药性。这项回顾性真实世界研究旨在探讨安罗替尼是否能逆转PD-1抑制剂(PD-1i)的耐药性,并评估这种联合疗法在R/M HNCs中的疗效和安全性。主要结果包括客观反应率(ORR)、疾病控制率(DCR)、无进展生存期(PFS)、总生存期(OS)、反应持续时间(DOR)和安全性。潜在的生物标记物包括 PD-L1 表达、血脂指数和基因组图谱分析。共纳入21例R/M HNCs患者,包括11例鼻咽癌(NPC)、5例头颈部鳞状细胞癌(HNSCC)、3例唾液腺癌(SGC)和2例鼻腔或副鼻窦癌(NC/PNC)。在所有患者中,ORR 为 47.6%(95% CI:28.6-66.7),其中 2 例(9.5%)完全应答;DCR 为 100%。中位随访时间为 17.1 个月,中位 PFS 和 OS 分别为 14.3 个月(95% CI:5.9-NR)和 16.7 个月(95% CI:8.4-NR)。中位DOR为11.2个月(95% CI:10.1-NR)。就不同疾病而言,鼻咽癌的ORR为45.5%,HNSCC为60.0%,SGC为66.7%,NC/PNC为50.0%。大多数治疗相关不良事件(TRAE)为 1 级或 2 级(88.9%)。最常见的3-4级TRAE是高血压(28.6%),有两例治疗相关死亡是由于出血。因此,在原有的PD-1i基础上添加安罗替尼可逆转PD-1阻断耐药,且反应率良好、生存期延长、毒性可接受,这表明安罗替尼有望成为R/M HNCs的二线和后续治疗选择。
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引用次数: 0
CD27 signaling inhibits tumor growth and metastasis via CD8 + T cell-independent mechanisms in the B16-F10 melanoma model. 在 B16-F10 黑色素瘤模型中,CD27 信号通过与 CD8 + T 细胞无关的机制抑制肿瘤生长和转移。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-08-06 DOI: 10.1007/s00262-024-03780-9
Eswara Rao Puppala, Long Wu, Xiaoxuan Fan, Xuefang Cao

CD27 belongs to the tumor necrosis factor receptor superfamily and acts as a co-stimulatory molecule, modulating T and B cell responses. CD27 stimulation enhances T cell survival and effector functions, thus providing opportunities to develop therapeutic strategies. The current study aims to investigate the role of endogenous CD27 signaling in tumor growth and metastasis. CD8 + T cell-specific CD27 knockout (CD8Cre-CD27fl) mice were developed, while global CD27 knockout (KO) mice were also used in our studies. Flow cytometry analyses confirmed that CD27 was deleted specifically from CD8 + T cells without affecting CD4 + T cells, B cells, and HSPCs in the CD8Cre-CD27fl mice, while CD27 was deleted from all cell types in global CD27 KO mice. Tumor growth and metastasis studies were performed by injecting B16-F10 melanoma cells subcutaneously (right flank) or intravenously into the mice. We have found that global CD27 KO mice succumbed to significantly accelerated tumor growth compared to WT controls. In addition, global CD27 KO mice showed a significantly higher burden of metastatic tumor nests in the lungs compared to WT controls. However, there was no significant difference in tumor growth curves, survival, metastatic tumor nest counts between the CD8Cre-CD27fl mice and WT controls. These results suggest that endogenous CD27 signaling inhibits tumor growth and metastasis via CD8 + T cell-independent mechanisms in this commonly used melanoma model, presumably through stimulating antitumor activities of other types of immune cells.

CD27 属于肿瘤坏死因子受体超家族,是一种协同刺激分子,可调节 T 细胞和 B 细胞的反应。CD27 刺激可增强 T 细胞的存活和效应功能,从而为开发治疗策略提供机会。本研究旨在探讨内源性 CD27 信号在肿瘤生长和转移中的作用。我们培育了CD8 + T细胞特异性CD27基因敲除(CD8Cre-CD27fl)小鼠,同时还使用了全基因CD27基因敲除(KO)小鼠。流式细胞术分析证实,在CD8Cre-CD27fl小鼠中,CD27特异性地从CD8 + T细胞中删除,而不影响CD4 + T细胞、B细胞和HSPCs,而在全基因CD27 KO小鼠中,CD27从所有细胞类型中删除。通过向小鼠皮下(右翼)或静脉注射 B16-F10 黑色素瘤细胞,进行了肿瘤生长和转移研究。我们发现,与 WT 对照组相比,CD27 KO 小鼠的肿瘤生长速度明显加快。此外,与 WT 对照组相比,CD27 KO 小鼠肺部转移性肿瘤巢的负担明显增加。然而,CD8Cre-CD27fl小鼠与WT对照组在肿瘤生长曲线、存活率、转移瘤巢数量等方面没有明显差异。这些结果表明,在这种常用的黑色素瘤模型中,内源性 CD27 信号通过 CD8 + T 细胞依赖性机制抑制肿瘤生长和转移,可能是通过刺激其他类型免疫细胞的抗肿瘤活性。
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引用次数: 0
期刊
Cancer Immunology, Immunotherapy
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