首页 > 最新文献

Clinical Cancer Research最新文献

英文 中文
Beyond the Burden: Elevating Immunotherapy in Colorectal Cancer. 超越负担:提高结直肠癌的免疫治疗。
IF 11.5 1区 医学 Q1 ONCOLOGY Pub Date : 2026-01-13 DOI: 10.1158/1078-0432.ccr-25-4251
Christine M Parseghian,Madhulika Eluri
Colorectal cancers treated with targeted therapies frequently acquire numerous subclonal genomic alterations. Tumor mutation burden (TMB) is under investigation as a biomarker for predicting response to immunotherapy in microsatellite-stable metastatic colorectal cancer. Here, we contextualize a recent study evaluating high plasma TMB post-targeted therapy and its implications for immunotherapy.
用靶向疗法治疗的结直肠癌经常获得许多亚克隆基因组改变。肿瘤突变负荷(TMB)作为预测微卫星稳定转移性结直肠癌免疫治疗应答的生物标志物正在研究中。在这里,我们介绍了最近一项评估高血浆TMB靶向治疗后及其对免疫治疗的影响的研究。
{"title":"Beyond the Burden: Elevating Immunotherapy in Colorectal Cancer.","authors":"Christine M Parseghian,Madhulika Eluri","doi":"10.1158/1078-0432.ccr-25-4251","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-4251","url":null,"abstract":"Colorectal cancers treated with targeted therapies frequently acquire numerous subclonal genomic alterations. Tumor mutation burden (TMB) is under investigation as a biomarker for predicting response to immunotherapy in microsatellite-stable metastatic colorectal cancer. Here, we contextualize a recent study evaluating high plasma TMB post-targeted therapy and its implications for immunotherapy.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"29 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145955934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Integrative Clinical and Molecular Evaluation of Renal Cell Carcinoma with Merlin Protein Deficiency and Biallelic Loss of NF2. 肾癌伴Merlin蛋白缺乏和NF2双等位基因缺失的临床与分子综合评价。
IF 11.5 1区 医学 Q1 ONCOLOGY Pub Date : 2026-01-12 DOI: 10.1158/1078-0432.ccr-25-2871
Emre Yekedüz,Weiwei Bian,Stephanie E Siegmund,Marc Machaalani,Jad El Masri,Mustafa Saleh,Eddy Saad,Liliana Ascione,Razane El Hajj Chehade,Clara Steiner,Pablo Moura Barrios,Stephanie A Berg,Bradley McGregor,Charlene Mantia,Praful Ravi,Wenxin Xu,Michelle S Hirsch,Toni K Choueiri,Michael Serzan
PURPOSEIn renal cell carcinoma (RCC), loss of the NF2 tumor suppressor gene encoding the merlin protein is associated with aggressive clinical behavior. However, data regarding the clinical course and additional molecular features in the context of contemporary systemic therapies remains limited.METHODSClinical outcomes were evaluated in patients with RCC exhibiting merlin loss by immunohistochemistry in one academic cohort. Integrative genomic analyses were performed, including targeted DNA sequencing via the institutional OncoPanel assay and RNA sequencing data from The Cancer Genome Atlas (TCGA).RESULTSIn the institutional cohort (n=33), most patients had biphasic hyalinizing psammomatous RCC (66.6%) and metastatic disease (78.8%). Among 23 patients receiving systemic therapy, those treated with non-immunotherapy (IO)-based regimens (n=5) had numerically longer overall survival (24.5 vs 16.5 months, p=0.2) and progression-free survival (9.8 vs 5 months, p=0.5) compared to IO-based therapies (n=18), though differences were not statistically significant. Genomic analysis (n=17) revealed frequent truncating mutations of NF2 (82.3%) and recurrent alterations in chromatin remodeling and DNA damage-response signaling genes with prominent deletions in tumor suppressor genes such as CDKN2A/B. Transcriptomic profiling of NF2-inactivated tumors from TCGA (n=13) demonstrated enrichment of cellular proliferation and concurrent suppression of metabolic and immune pathways, suggesting an aggressive phenotype compared to clear cell RCC without NF2 inactivation (n=529).CONCLUSIONSBiallelic NF2 inactivation and merlin protein deficiency drives an aggressive RCC phenotype marked by immune dysfunction, high proliferation, and frequent cell cycle and DNA damage-response signaling alterations. Limited treatment response to immunotherapy highlights the need for molecularly tailored therapies.
目的:在肾细胞癌(RCC)中,编码merlin蛋白的NF2肿瘤抑制基因的缺失与侵袭性临床行为有关。然而,关于临床过程和其他分子特征的数据在当代全身治疗的背景下仍然有限。方法采用免疫组化方法对一个学术队列中表现为梅林丢失的肾细胞癌患者的临床结果进行评估。进行了综合基因组分析,包括通过机构OncoPanel测定的靶向DNA测序和来自癌症基因组图谱(TCGA)的RNA测序数据。结果在机构队列中(33例),大多数患者患有双期透明性沙质癌(66.6%)和转移性疾病(78.8%)。在接受全身治疗的23例患者中,与基于免疫治疗的治疗(n=18)相比,接受非免疫治疗(IO)方案治疗的患者(n=5)的总生存期(24.5 vs 16.5个月,p=0.2)和无进展生存期(9.8 vs 5个月,p=0.5)更长,但差异无统计学意义。基因组分析(n=17)显示NF2频繁截断突变(82.3%),染色质重塑和DNA损伤反应信号基因复发性改变,肿瘤抑制基因如CDKN2A/B显著缺失。来自TCGA的NF2失活肿瘤的转录组学分析(n=13)显示细胞增殖富集,代谢和免疫途径同时受到抑制,表明与未NF2失活的透明细胞RCC相比,其表型具有侵袭性(n=529)。结论双等位基因NF2失活和merlin蛋白缺乏驱动侵袭性RCC表型,其特征是免疫功能障碍、高增殖、频繁的细胞周期和DNA损伤反应信号改变。有限的治疗反应免疫疗法突出需要分子定制治疗。
{"title":"Integrative Clinical and Molecular Evaluation of Renal Cell Carcinoma with Merlin Protein Deficiency and Biallelic Loss of NF2.","authors":"Emre Yekedüz,Weiwei Bian,Stephanie E Siegmund,Marc Machaalani,Jad El Masri,Mustafa Saleh,Eddy Saad,Liliana Ascione,Razane El Hajj Chehade,Clara Steiner,Pablo Moura Barrios,Stephanie A Berg,Bradley McGregor,Charlene Mantia,Praful Ravi,Wenxin Xu,Michelle S Hirsch,Toni K Choueiri,Michael Serzan","doi":"10.1158/1078-0432.ccr-25-2871","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2871","url":null,"abstract":"PURPOSEIn renal cell carcinoma (RCC), loss of the NF2 tumor suppressor gene encoding the merlin protein is associated with aggressive clinical behavior. However, data regarding the clinical course and additional molecular features in the context of contemporary systemic therapies remains limited.METHODSClinical outcomes were evaluated in patients with RCC exhibiting merlin loss by immunohistochemistry in one academic cohort. Integrative genomic analyses were performed, including targeted DNA sequencing via the institutional OncoPanel assay and RNA sequencing data from The Cancer Genome Atlas (TCGA).RESULTSIn the institutional cohort (n=33), most patients had biphasic hyalinizing psammomatous RCC (66.6%) and metastatic disease (78.8%). Among 23 patients receiving systemic therapy, those treated with non-immunotherapy (IO)-based regimens (n=5) had numerically longer overall survival (24.5 vs 16.5 months, p=0.2) and progression-free survival (9.8 vs 5 months, p=0.5) compared to IO-based therapies (n=18), though differences were not statistically significant. Genomic analysis (n=17) revealed frequent truncating mutations of NF2 (82.3%) and recurrent alterations in chromatin remodeling and DNA damage-response signaling genes with prominent deletions in tumor suppressor genes such as CDKN2A/B. Transcriptomic profiling of NF2-inactivated tumors from TCGA (n=13) demonstrated enrichment of cellular proliferation and concurrent suppression of metabolic and immune pathways, suggesting an aggressive phenotype compared to clear cell RCC without NF2 inactivation (n=529).CONCLUSIONSBiallelic NF2 inactivation and merlin protein deficiency drives an aggressive RCC phenotype marked by immune dysfunction, high proliferation, and frequent cell cycle and DNA damage-response signaling alterations. Limited treatment response to immunotherapy highlights the need for molecularly tailored therapies.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"39 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145949629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Sym024 interacts with a unique epitope on the CD73 homodimer, favoring effective bivalent binding to improve anti-PD1 therapy. Sym024与CD73二聚体上的一个独特表位相互作用,有利于有效的二价结合,以改善抗pd1治疗。
IF 10.2 1区 医学 Q1 ONCOLOGY Pub Date : 2026-01-09 DOI: 10.1158/1078-0432.CCR-25-2406
Janus S Jakobsen, Michael M Grandal, Randi W Hansen, Harsh Bansia, Emily Armbruster, Isabelle Theret, Niels Jørgen Ø Skartved, Rikke Hald, Maria C Melander, Anne Worsaae, Matteo Riva, Kristian Reckzeh, Laurent Vuillard, Johan Lantto, Amedee des Georges, Camilla Fröhlich

Purpose: Adenosine signaling may be a central immune suppressive mechanism in several cancers, and blockade of the rate-limiting CD73 AMP-to-adenosine enzyme has been demonstrated to improve clinical efficacy of PD(L)-1 immune therapy. However, deep inhibition of CD73 activity could prove difficult in tumor environments with a constant AMP supply and high CD73 levels. Here, we sought to identify, characterize, and benchmark a novel antagonistic anti-CD73 antibody, Sym024 (S95024), and to structurally decode its mode of action.

Experimental design: Sym024, selected via functional antibody repertoire screening, was tested against benchmark anti-CD73 antibodies in primary cell, cell line in vitro binding, CD73 enzymatic activity, and T cell activation assays. Its in vivo tumor growth inhibition was examined in transplanted human or mouse tumors in immunocompetent or immunodeficient mice, and intra-tumoral enzymatic inhibition and immune cell recruitment were assessed. We investigated Sym024-CD73 interaction using surface plasmon resonance, cryo-electron microscopy, site-directed mutagenesis, and population level complex formation through size-exclusion-chromatography with light scatter mass detection. Preclinical safety and pharmacokinetics were assessed in monkeys.

Results: Sym024 effectively blocked CD73 across a large range of enzyme expression levels, comparing favorably to benchmark anti-CD73 antibodies; it improved the efficacy of PD-1 blockade in vitro as well as in vivo. Our structural data indicate that a unique one-to-one Sym024-CD73 interaction engenders this comprehensive inhibition. No pre-clinical safety flags were observed, and the pharmacokinetics profile of Sym024 supported a standard clinical dosing regimen.

Conclusions: The comprehensive CD73 inhibition exhibited by Sym024 may improve the efficacy of anti-PD(L)-1/anti-CD73 combination treatment.

目的:腺苷信号可能是多种癌症的中枢免疫抑制机制,阻断限速的CD73 amp -to-腺苷酶已被证明可以提高PD(L)-1免疫治疗的临床疗效。然而,在恒定的AMP供应和高CD73水平的肿瘤环境中,CD73活性的深度抑制可能被证明是困难的。在这里,我们试图鉴定,表征和基准一种新的拮抗cd73抗体,Sym024 (S95024),并结构解码其作用模式。实验设计:通过功能性抗体库筛选筛选Sym024,在原代细胞、细胞系体外结合、CD73酶活性和T细胞活化试验中对基准抗CD73抗体进行测试。在免疫正常或免疫缺陷小鼠移植的人或小鼠肿瘤中检测其体内肿瘤生长抑制作用,并评估肿瘤内酶抑制和免疫细胞募集。我们使用表面等离子体共振、冷冻电子显微镜、定点诱变和光散射质量检测的尺寸-排斥色谱法研究了Sym024-CD73的相互作用。在猴子身上进行了临床前安全性和药代动力学评估。结果:Sym024在很大的酶表达水平范围内有效阻断CD73,优于基准抗CD73抗体;提高了PD-1阻断剂在体内和体外的疗效。我们的结构数据表明,一种独特的一对一的Sym024-CD73相互作用产生了这种全面的抑制。没有观察到临床前安全标志,Sym024的药代动力学特征支持标准的临床给药方案。结论:Sym024对CD73的综合抑制作用可能提高抗pd (L)-1/抗CD73联合治疗的疗效。
{"title":"Sym024 interacts with a unique epitope on the CD73 homodimer, favoring effective bivalent binding to improve anti-PD1 therapy.","authors":"Janus S Jakobsen, Michael M Grandal, Randi W Hansen, Harsh Bansia, Emily Armbruster, Isabelle Theret, Niels Jørgen Ø Skartved, Rikke Hald, Maria C Melander, Anne Worsaae, Matteo Riva, Kristian Reckzeh, Laurent Vuillard, Johan Lantto, Amedee des Georges, Camilla Fröhlich","doi":"10.1158/1078-0432.CCR-25-2406","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-25-2406","url":null,"abstract":"<p><strong>Purpose: </strong>Adenosine signaling may be a central immune suppressive mechanism in several cancers, and blockade of the rate-limiting CD73 AMP-to-adenosine enzyme has been demonstrated to improve clinical efficacy of PD(L)-1 immune therapy. However, deep inhibition of CD73 activity could prove difficult in tumor environments with a constant AMP supply and high CD73 levels. Here, we sought to identify, characterize, and benchmark a novel antagonistic anti-CD73 antibody, Sym024 (S95024), and to structurally decode its mode of action.</p><p><strong>Experimental design: </strong>Sym024, selected via functional antibody repertoire screening, was tested against benchmark anti-CD73 antibodies in primary cell, cell line in vitro binding, CD73 enzymatic activity, and T cell activation assays. Its in vivo tumor growth inhibition was examined in transplanted human or mouse tumors in immunocompetent or immunodeficient mice, and intra-tumoral enzymatic inhibition and immune cell recruitment were assessed. We investigated Sym024-CD73 interaction using surface plasmon resonance, cryo-electron microscopy, site-directed mutagenesis, and population level complex formation through size-exclusion-chromatography with light scatter mass detection. Preclinical safety and pharmacokinetics were assessed in monkeys.</p><p><strong>Results: </strong>Sym024 effectively blocked CD73 across a large range of enzyme expression levels, comparing favorably to benchmark anti-CD73 antibodies; it improved the efficacy of PD-1 blockade in vitro as well as in vivo. Our structural data indicate that a unique one-to-one Sym024-CD73 interaction engenders this comprehensive inhibition. No pre-clinical safety flags were observed, and the pharmacokinetics profile of Sym024 supported a standard clinical dosing regimen.</p><p><strong>Conclusions: </strong>The comprehensive CD73 inhibition exhibited by Sym024 may improve the efficacy of anti-PD(L)-1/anti-CD73 combination treatment.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145931479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
TAPISTRY: A Phase II Study of Atezolizumab in Patients with Tumor Mutational Burden-High Tumors. TAPISTRY: Atezolizumab在肿瘤突变负担高的肿瘤患者中的II期研究
IF 10.2 1区 医学 Q1 ONCOLOGY Pub Date : 2026-01-09 DOI: 10.1158/1078-0432.CCR-25-3336
David M Thomas, Jeong Eun Kim, Fabrice Barlesi, Uwe M Martens, Maciej Krzakowski, Rafal Dziadziuszko, Jae Ho Jeong, Gennaro Daniele, Timothy R Wilson, Felice Wu, Brian P Simmons, Sid Patel, Maria Sbirnac, Monika Kaul, Shirish M Gadgeel

Purpose: Patients with tumor mutational burden (TMB)-high tumors can derive benefit from atezolizumab, though previous studies have used inconsistent TMB cutoffs. We report data for atezolizumab in patients with TMB-high solid tumors from the phase II, TAPISTRY multicohort trial, using TMB cutoffs of ≥13 and ≥16 mutations/megabase (mut/Mb).

Methods: Patients with PD-L1 inhibitor-naïve,TMB-high (≥13 mut/Mb) advanced/metastatic solid tumors received atezolizumab every 21 days (1200 mg adults, 15 mg/kg [up to 1200 mg/kg] children).

Primary endpoint: independent review committee (IRC)-assessed objective response rate (ORR) for TMB ≥16 mut/Mb. Secondary endpoints (using TMB ≥13 mut/Mb) included IRC-assessed ORR, duration of response (DOR), progression-free survival (PFS), and safety.

Results: As of November 9, 2023 (median survival follow-up: 9.8 months), 148 patients received treatment. Median age was 63 years, 31.8% of patients had >2 prior therapy lines, and the most common tumor types were colorectal (29.1%), breast (8.8%), and gastroesophageal (8.8%). IRC-assessed ORR was 22.3% (95% CI, 15.0-31.2) with TMB ≥16 mut/Mb (n=112), and 20.2% (95% CI, 13.6-28.1) with TMB ≥13 mut/Mb (n=129). Median IRC-assessed DOR was not estimable. Median IRC-assessed PFS was 2.8 (95% CI, 1.7-5.4) and 2.7 (95% CI, 1.5-4.2) months using TMB ≥16 and ≥13 mut/Mb, respectively. Adverse events (AEs) were reported in 93.2% of patients, of which 53.4% were treatment-related (no grade 5) and 40.5% were grade ≥3.

Conclusion: Atezolizumab led to moderate antitumor activity in various TMB-high solid tumors. Safety was consistent with previous reports.

Clinical trial number: NCT04589845.

目的:肿瘤突变负荷(TMB)高的肿瘤患者可以从atezolizumab中获益,尽管先前的研究使用了不一致的TMB截止值。我们报告了来自TAPISTRY II期多队列试验的atezolizumab在TMB高实体瘤患者中的数据,使用TMB截止值≥13和≥16个突变/兆基(mut/Mb)。方法:PD-L1 inhibitor-naïve、tmb高(≥13 mut/Mb)晚期/转移性实体瘤患者每21天接受一次atezolizumab治疗(成人1200mg,儿童15mg /kg[高达1200mg /kg])。主要终点:独立审查委员会(IRC)评估的TMB≥16mut /Mb的客观缓解率(ORR)。次要终点(使用TMB≥13 mut/Mb)包括irc评估的ORR、反应持续时间(DOR)、无进展生存期(PFS)和安全性。结果:截至2023年11月9日(中位生存期随访9.8个月),148例患者接受治疗。中位年龄为63岁,31.8%的患者既往接受过bbb2治疗,最常见的肿瘤类型为结直肠(29.1%)、乳腺(8.8%)和胃食管(8.8%)。TMB≥16 mut/Mb (n=112)时,irc评估的ORR为22.3% (95% CI, 15.0-31.2), TMB≥13 mut/Mb (n=129)时,irc评估的ORR为20.2% (95% CI, 13.6-28.1)。irc评估的DOR中位数无法估计。当TMB≥16和≥13 mut/Mb时,irc评估的中位PFS分别为2.8 (95% CI, 1.7-5.4)和2.7 (95% CI, 1.5-4.2)个月。93.2%的患者报告了不良事件(ae),其中53.4%与治疗相关(无5级),40.5%为≥3级。结论:Atezolizumab对多种高tmb实体瘤具有中等抗肿瘤活性。安全性与之前的报告一致。临床试验号:NCT04589845。
{"title":"TAPISTRY: A Phase II Study of Atezolizumab in Patients with Tumor Mutational Burden-High Tumors.","authors":"David M Thomas, Jeong Eun Kim, Fabrice Barlesi, Uwe M Martens, Maciej Krzakowski, Rafal Dziadziuszko, Jae Ho Jeong, Gennaro Daniele, Timothy R Wilson, Felice Wu, Brian P Simmons, Sid Patel, Maria Sbirnac, Monika Kaul, Shirish M Gadgeel","doi":"10.1158/1078-0432.CCR-25-3336","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-25-3336","url":null,"abstract":"<p><strong>Purpose: </strong>Patients with tumor mutational burden (TMB)-high tumors can derive benefit from atezolizumab, though previous studies have used inconsistent TMB cutoffs. We report data for atezolizumab in patients with TMB-high solid tumors from the phase II, TAPISTRY multicohort trial, using TMB cutoffs of ≥13 and ≥16 mutations/megabase (mut/Mb).</p><p><strong>Methods: </strong>Patients with PD-L1 inhibitor-naïve,TMB-high (≥13 mut/Mb) advanced/metastatic solid tumors received atezolizumab every 21 days (1200 mg adults, 15 mg/kg [up to 1200 mg/kg] children).</p><p><strong>Primary endpoint: </strong>independent review committee (IRC)-assessed objective response rate (ORR) for TMB ≥16 mut/Mb. Secondary endpoints (using TMB ≥13 mut/Mb) included IRC-assessed ORR, duration of response (DOR), progression-free survival (PFS), and safety.</p><p><strong>Results: </strong>As of November 9, 2023 (median survival follow-up: 9.8 months), 148 patients received treatment. Median age was 63 years, 31.8% of patients had >2 prior therapy lines, and the most common tumor types were colorectal (29.1%), breast (8.8%), and gastroesophageal (8.8%). IRC-assessed ORR was 22.3% (95% CI, 15.0-31.2) with TMB ≥16 mut/Mb (n=112), and 20.2% (95% CI, 13.6-28.1) with TMB ≥13 mut/Mb (n=129). Median IRC-assessed DOR was not estimable. Median IRC-assessed PFS was 2.8 (95% CI, 1.7-5.4) and 2.7 (95% CI, 1.5-4.2) months using TMB ≥16 and ≥13 mut/Mb, respectively. Adverse events (AEs) were reported in 93.2% of patients, of which 53.4% were treatment-related (no grade 5) and 40.5% were grade ≥3.</p><p><strong>Conclusion: </strong>Atezolizumab led to moderate antitumor activity in various TMB-high solid tumors. Safety was consistent with previous reports.</p><p><strong>Clinical trial number: </strong>NCT04589845.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145931511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Differential Immunological Effects of Short-Course and Long-Course Radiotherapy in Locally Advanced Rectal Cancer. 局部晚期直肠癌短期与长期放疗的差异免疫效应。
IF 10.2 1区 医学 Q1 ONCOLOGY Pub Date : 2026-01-09 DOI: 10.1158/1078-0432.CCR-25-2733
Lily V S Hillson, Ross K McMahon, Norman J Galbraith, Ashley K McCulloch, Chia Yew Kong, Walaiphorn Woraharn, Lydia Melissourgou-Syka, Kathryn A F Pennel, Jean A Quinn, Leia Jones, Raheleh Amirkhah, Natalie Fisher, Noori Maka, Aula Ammar, Phimmada Hatthakarnkul, Liang Tang, Annabelle Smith, Simon Milling, Alec C McDonald, Harikrishnan Nair, Paul G Horgan, Colin W Steele, Janet S Graham, Philip D Dunne, Joanne Edwards, Sean M O'Cathail, Campbell S Roxburgh

Purpose: Two dominant neoadjuvant radiotherapy (RT) regimens are in common use for locally advanced rectal cancer (LARC): long-course radiotherapy (LCRT;25x1.8Gy) with concomitant chemotherapy and short-course radiotherapy (SCRT;5x5Gy) typically followed by systemic chemotherapy. This study uses serial sampling to investigate the evolution of systemic and local immune responses to different radiotherapy regimens in LARC.

Experimental design: We conducted a serial sampling study involving patients receiving radiotherapy for LARC, in which longitudinal blood and tumor biospecimens were collected at baseline, and at 2, 6, and 12 weeks after treatment initiation. Leukocyte concentrations via full blood count and a multiplex cytokine ELISA of plasma samples measured systemic changes. Multiplex immunofluorescence (CD8 and FOXP3) and RNA-sequencing of tumor biopsies were used to assess local changes.

Results: Circulating lymphocyte concentrations tended to increase in SCRT patients and decrease in LCRT patients between week 2 and week 6 and were significantly lower in LCRT patients compared to SCRT patients at week 6 (p<0.0001) and week 12 (p=0.019). Additionally, we report higher densities of CD8+ and FOXP3+ tumoral lymphocytes from SCRT patients compared to LCRT patients at week 2 (CD8 p=0.053, FOXP3 p=0.023) and week 6 (CD8 p=0.035, FOXP3 p=0.0016).

Conclusions: SCRT is less lympho-depleting and induces more frequent increases in intra-tumoral T cell infiltration compared to LCRT. These results are relevant to the field of radiation-immune-oncology combination studies in LARC. Furthermore, these findings may underpin early trial results, where higher rates of response to radiotherapy-immune checkpoint inhibitor combinations have been reported with SCRT-based regimens.

目的:两种主要的新辅助放疗(RT)方案通常用于局部晚期直肠癌(LARC):长期放疗(LCRT;25x1.8Gy)伴随化疗和短期放疗(SCRT;5x5Gy),通常随后进行全身化疗。本研究采用连续抽样研究LARC对不同放疗方案的全身和局部免疫反应的演变。实验设计:我们对接受LARC放疗的患者进行了系列抽样研究,在基线、治疗开始后2周、6周和12周收集纵向血液和肿瘤生物标本。白细胞浓度通过全血细胞计数和血浆样品的多重细胞因子ELISA测量全身变化。采用多重免疫荧光(CD8和FOXP3)和肿瘤活检的rna测序来评估局部变化。结果:在第2周至第6周,循环淋巴细胞浓度在SCRT患者中有升高的趋势,而在LCRT患者中有降低的趋势,并且在第6周,与SCRT患者相比,LCRT患者的循环淋巴细胞浓度显著降低(结论:与LCRT相比,SCRT的淋巴细胞消耗更少,肿瘤内T细胞浸润的增加更频繁。这些结果与LARC放射-免疫-肿瘤联合研究领域有关。此外,这些发现可能支持早期试验结果,其中放疗-免疫检查点抑制剂联合使用基于scrt的方案的应答率更高。
{"title":"Differential Immunological Effects of Short-Course and Long-Course Radiotherapy in Locally Advanced Rectal Cancer.","authors":"Lily V S Hillson, Ross K McMahon, Norman J Galbraith, Ashley K McCulloch, Chia Yew Kong, Walaiphorn Woraharn, Lydia Melissourgou-Syka, Kathryn A F Pennel, Jean A Quinn, Leia Jones, Raheleh Amirkhah, Natalie Fisher, Noori Maka, Aula Ammar, Phimmada Hatthakarnkul, Liang Tang, Annabelle Smith, Simon Milling, Alec C McDonald, Harikrishnan Nair, Paul G Horgan, Colin W Steele, Janet S Graham, Philip D Dunne, Joanne Edwards, Sean M O'Cathail, Campbell S Roxburgh","doi":"10.1158/1078-0432.CCR-25-2733","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-25-2733","url":null,"abstract":"<p><strong>Purpose: </strong>Two dominant neoadjuvant radiotherapy (RT) regimens are in common use for locally advanced rectal cancer (LARC): long-course radiotherapy (LCRT;25x1.8Gy) with concomitant chemotherapy and short-course radiotherapy (SCRT;5x5Gy) typically followed by systemic chemotherapy. This study uses serial sampling to investigate the evolution of systemic and local immune responses to different radiotherapy regimens in LARC.</p><p><strong>Experimental design: </strong>We conducted a serial sampling study involving patients receiving radiotherapy for LARC, in which longitudinal blood and tumor biospecimens were collected at baseline, and at 2, 6, and 12 weeks after treatment initiation. Leukocyte concentrations via full blood count and a multiplex cytokine ELISA of plasma samples measured systemic changes. Multiplex immunofluorescence (CD8 and FOXP3) and RNA-sequencing of tumor biopsies were used to assess local changes.</p><p><strong>Results: </strong>Circulating lymphocyte concentrations tended to increase in SCRT patients and decrease in LCRT patients between week 2 and week 6 and were significantly lower in LCRT patients compared to SCRT patients at week 6 (p<0.0001) and week 12 (p=0.019). Additionally, we report higher densities of CD8+ and FOXP3+ tumoral lymphocytes from SCRT patients compared to LCRT patients at week 2 (CD8 p=0.053, FOXP3 p=0.023) and week 6 (CD8 p=0.035, FOXP3 p=0.0016).</p><p><strong>Conclusions: </strong>SCRT is less lympho-depleting and induces more frequent increases in intra-tumoral T cell infiltration compared to LCRT. These results are relevant to the field of radiation-immune-oncology combination studies in LARC. Furthermore, these findings may underpin early trial results, where higher rates of response to radiotherapy-immune checkpoint inhibitor combinations have been reported with SCRT-based regimens.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145931526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Population analysis and immunologic landscape of melanoma in people living with HIV 艾滋病毒感染者黑色素瘤的人群分析和免疫景观
IF 11.5 1区 医学 Q1 ONCOLOGY Pub Date : 2026-01-08 DOI: 10.1158/1078-0432.ccr-25-3148
Lindsay N. Barger, Derek Wang, Ashley L. Saravia, Valeria Mezzano, Gyles Ward, Cynthia Loomis, Carly Feldman, Madalina Tuluc, Rino S. Seedor, Peter J. Gaskill, Anna E. Coghill, Gita Suneja, Iman Dehzangi, Jennifer L. Hope, George Jour, Gabriele Romano
Purpose: To dissect the clinical and immunological features of people living with HIV (PLWH) diagnosed with melanoma, who have consistently shown worse outcomes than HIV-negative individuals (PLw/oH) with the same cancer. Experimental Design: We analyzed electronic health records from 1,087 PLWH and 394,437 PLw/oH with melanoma. Demographic and clinical characteristics were compared. Spatial immune transcriptomics (72 immune-related genes) was performed on melanoma tumor samples (n=11), with downstream validation using multiplex immunofluorescence (n=15 PLWH, n=14 PLw/oH). Results: PLWH were diagnosed at a younger age, had greater representation of Hispanic and Black individuals, and showed reduced survival. They also had a markedly increased risk of brain metastases. PLWH experienced significant delays in initiating immune checkpoint inhibitor (ICI) therapy and had worse post-ICI survival, even after balancing covariates. Spatial transcriptomics revealed a more immunosuppressive tumor microenvironment in PLWH, with increased transcription of immune checkpoints (PD1, LAG3) and reduced antigen-presentation markers (HLA-DRB, B2M), with distinct spatial distributions in tumors and surrounding microenvironments. Multiplex immunofluorescence demonstrated features of an exhausted CD8⁺ T cell compartment, including enrichment of PD1intLAG3⁻ and PD1intLAG3⁺ subpopulations, and a significant accumulation of myeloid-derived suppressor cells (CD11b⁺ HLA-DR⁻ CD33⁺). Conclusions: Melanoma in PLWH is associated with distinct clinical and immunological features, including delayed ICI treatment, reduced survival, and an immunosuppressive microenvironment with exhausted CD8⁺ T cells and expanded myeloid-derived suppressor cells. These findings suggest that chronic HIV infection may impair antitumor immunity in melanoma. Targeting the pathways identified here may improve therapeutic responses and outcomes in this population.
目的:剖析诊断为黑色素瘤的HIV感染者(PLWH)的临床和免疫学特征,这些患者的预后一直比患有相同癌症的HIV阴性个体(PLw/oH)更差。实验设计:我们分析了1,087名PLWH和394,437名黑色素瘤PLw/oH患者的电子健康记录。比较人口学特征和临床特征。在黑色素瘤样本(n=11)上进行空间免疫转录组学(72个免疫相关基因),并使用多重免疫荧光(n=15 PLWH, n=14 PLw/oH)进行下游验证。结果:PLWH在年轻时被诊断出来,在西班牙裔和黑人个体中有更大的代表性,并且生存率降低。他们发生脑转移的风险也明显增加。即使在平衡协变量后,PLWH在启动免疫检查点抑制剂(ICI)治疗方面也有明显的延迟,并且ICI后生存率更差。空间转录组学显示,PLWH的肿瘤微环境具有更强的免疫抑制性,免疫检查点(PD1、LAG3)的转录增加,抗原呈递标志物(HLA-DRB、B2M)的转录减少,在肿瘤和周围微环境中的空间分布明显。多重免疫荧光显示出CD8 + T细胞耗竭的特征,包括PD1intLAG3⁻和PD1intLAG3⁺亚群的富集,以及髓源性抑制细胞的显著积累(CD11b + HLA-DR⁻CD33 +)。结论:PLWH中的黑色素瘤具有明显的临床和免疫学特征,包括ICI治疗延迟、生存率降低、CD8 + T细胞耗尽和骨髓源性抑制细胞扩增的免疫抑制微环境。这些发现提示慢性HIV感染可能损害黑色素瘤的抗肿瘤免疫。针对这里确定的途径可能会改善这一人群的治疗反应和结果。
{"title":"Population analysis and immunologic landscape of melanoma in people living with HIV","authors":"Lindsay N. Barger, Derek Wang, Ashley L. Saravia, Valeria Mezzano, Gyles Ward, Cynthia Loomis, Carly Feldman, Madalina Tuluc, Rino S. Seedor, Peter J. Gaskill, Anna E. Coghill, Gita Suneja, Iman Dehzangi, Jennifer L. Hope, George Jour, Gabriele Romano","doi":"10.1158/1078-0432.ccr-25-3148","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-3148","url":null,"abstract":"Purpose: To dissect the clinical and immunological features of people living with HIV (PLWH) diagnosed with melanoma, who have consistently shown worse outcomes than HIV-negative individuals (PLw/oH) with the same cancer. Experimental Design: We analyzed electronic health records from 1,087 PLWH and 394,437 PLw/oH with melanoma. Demographic and clinical characteristics were compared. Spatial immune transcriptomics (72 immune-related genes) was performed on melanoma tumor samples (n=11), with downstream validation using multiplex immunofluorescence (n=15 PLWH, n=14 PLw/oH). Results: PLWH were diagnosed at a younger age, had greater representation of Hispanic and Black individuals, and showed reduced survival. They also had a markedly increased risk of brain metastases. PLWH experienced significant delays in initiating immune checkpoint inhibitor (ICI) therapy and had worse post-ICI survival, even after balancing covariates. Spatial transcriptomics revealed a more immunosuppressive tumor microenvironment in PLWH, with increased transcription of immune checkpoints (PD1, LAG3) and reduced antigen-presentation markers (HLA-DRB, B2M), with distinct spatial distributions in tumors and surrounding microenvironments. Multiplex immunofluorescence demonstrated features of an exhausted CD8⁺ T cell compartment, including enrichment of PD1intLAG3⁻ and PD1intLAG3⁺ subpopulations, and a significant accumulation of myeloid-derived suppressor cells (CD11b⁺ HLA-DR⁻ CD33⁺). Conclusions: Melanoma in PLWH is associated with distinct clinical and immunological features, including delayed ICI treatment, reduced survival, and an immunosuppressive microenvironment with exhausted CD8⁺ T cells and expanded myeloid-derived suppressor cells. These findings suggest that chronic HIV infection may impair antitumor immunity in melanoma. Targeting the pathways identified here may improve therapeutic responses and outcomes in this population.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"18 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145920236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
DESTINY-Breast08: a phase 1b study of trastuzumab deruxtecan in combination with other anticancer therapies in patients with HER2-low metastatic breast cancer DESTINY-Breast08:曲妥珠单抗与其他抗癌药物联合治疗her2低转移性乳腺癌的1b期研究
IF 11.5 1区 医学 Q1 ONCOLOGY Pub Date : 2026-01-08 DOI: 10.1158/1078-0432.ccr-25-0874
Komal Jhaveri, Sherene Loi, Erika Hamilton, Peter Schmid, Carey K. Anders, Laura Testa, Hans Wildiers, Ling-Ming Tseng, Yen-Shen Lu, Yeon Hee Park, Seock-Ah Im, Shin-Cheh Chen, Robyn R. Young, Caron Lloyd, Magdalena Wrona, Cuihong Zhang, Danielle Carroll, Fabrice Andre
Purpose: Establish the safety, tolerability, and preliminary activity of trastuzumab deruxtecan (T-DXd) in combination with other anticancer therapies in human epidermal growth factor receptor 2 (HER2)-low metastatic breast cancer (mBC). Experimental Design: DESTINY-Breast08 was a two-part, open-label, multicenter, phase 1b study. Patients with locally confirmed HER2-low mBC received T-DXd plus capecitabine, durvalumab+paclitaxel, capivasertib, anastrozole, or fulvestrant. Eligibility criteria for hormone receptor status varied across modules and between study parts. Primary objectives were safety/tolerability and determining recommended phase 2 doses (RP2Ds); secondary endpoints included objective response rate (ORR, per investigator). Results; In the dose-finding phase, 37 patients were assigned to a module. RP2Ds were determined for T-DXd plus capecitabine, capivasertib, anastrozole, or fulvestrant. For strategic reasons, T-DXd+durvalumab+paclitaxel was not pursued beyond the dose-finding phase (n=3). In the dose-expansion phase, 101 patients were assigned to a module. For T-DXd+capecitabine, grade (G)≥3 adverse events (AEs) occurred in 55.0% (11/20) of patients; ORR: 60.0%. For T-DXd+capivasertib, G≥3 AEs occurred in 67.5% (27/40) of patients; ORR: 60.0%. For T-DXd+anastrozole, G≥3 AEs occurred in 47.6% (10/21) of patients; ORR: 71.4%. For T-DXd+fulvestrant, G≥3 AEs occurred in 55.0% (11/20) of patients; ORR: 40.0%. Adjudicated drug-related interstitial lung disease/pneumonitis events were reported for T-DXd+capecitabine (3/20; G2, n=2; G5, n=1), T-DXd+capivasertib (8/40; all G≤2), and T-DXd+fulvestrant (5/20; all G2). Conclusions: Safety results were generally consistent with known individual profiles for T-DXd and combination drugs. T-DXd plus capecitabine, capivasertib, anastrozole, or fulvestrant demonstrated preliminary clinical activity in patients with HER2-low mBC.
目的:建立曲妥珠单抗德鲁西替康(T-DXd)联合其他抗癌疗法治疗人表皮生长因子受体2 (HER2)-低转移性乳腺癌(mBC)的安全性、耐受性和初步活性。实验设计:DESTINY-Breast08是一项两部分、开放标签、多中心、1b期研究。局部确诊her2低mBC的患者接受T-DXd联合卡培他滨、杜伐单抗+紫杉醇、卡维塞替、阿那曲唑或氟维司汀治疗。激素受体状态的合格标准因模块和研究部分而异。主要目标是安全性/耐受性和确定推荐的2期剂量(RP2Ds);次要终点包括客观缓解率(ORR,每个研究者)。结果;在剂量寻找阶段,37名患者被分配到一个模块。测定T-DXd联合卡培他滨、卡培他滨、阿那曲唑或氟维司汀的rp2d。出于战略原因,T-DXd+durvalumab+紫杉醇没有在剂量寻找阶段之后继续进行(n=3)。在剂量扩大阶段,101名患者被分配到一个模块。对于T-DXd+卡培他滨,55.0%(11/20)的患者发生(G)级≥3级不良事件(ae);奥尔:60.0%。对于T-DXd+capivasertib, 67.5%(27/40)的患者发生G≥3 ae;奥尔:60.0%。T-DXd+阿那曲唑组G≥3 ae发生率为47.6% (10/21);奥尔:71.4%。对于T-DXd+氟维司汀,55.0%(11/20)的患者发生G≥3 ae;奥尔:40.0%。报告了T-DXd+卡培他滨(3/20;G2, n=2; G5, n=1)、T-DXd+capivasertib(8/40;所有G≤2)和T-DXd+氟维司汀(5/20;所有G2)的药物相关性肺间质性疾病/肺炎事件。结论:安全性结果与已知的T-DXd和联合用药的个体特征基本一致。T-DXd联合卡培他滨、capivasertib、阿那曲唑或氟维司汀在her2低mBC患者中显示出初步的临床活性。
{"title":"DESTINY-Breast08: a phase 1b study of trastuzumab deruxtecan in combination with other anticancer therapies in patients with HER2-low metastatic breast cancer","authors":"Komal Jhaveri, Sherene Loi, Erika Hamilton, Peter Schmid, Carey K. Anders, Laura Testa, Hans Wildiers, Ling-Ming Tseng, Yen-Shen Lu, Yeon Hee Park, Seock-Ah Im, Shin-Cheh Chen, Robyn R. Young, Caron Lloyd, Magdalena Wrona, Cuihong Zhang, Danielle Carroll, Fabrice Andre","doi":"10.1158/1078-0432.ccr-25-0874","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0874","url":null,"abstract":"Purpose: Establish the safety, tolerability, and preliminary activity of trastuzumab deruxtecan (T-DXd) in combination with other anticancer therapies in human epidermal growth factor receptor 2 (HER2)-low metastatic breast cancer (mBC). Experimental Design: DESTINY-Breast08 was a two-part, open-label, multicenter, phase 1b study. Patients with locally confirmed HER2-low mBC received T-DXd plus capecitabine, durvalumab+paclitaxel, capivasertib, anastrozole, or fulvestrant. Eligibility criteria for hormone receptor status varied across modules and between study parts. Primary objectives were safety/tolerability and determining recommended phase 2 doses (RP2Ds); secondary endpoints included objective response rate (ORR, per investigator). Results; In the dose-finding phase, 37 patients were assigned to a module. RP2Ds were determined for T-DXd plus capecitabine, capivasertib, anastrozole, or fulvestrant. For strategic reasons, T-DXd+durvalumab+paclitaxel was not pursued beyond the dose-finding phase (n=3). In the dose-expansion phase, 101 patients were assigned to a module. For T-DXd+capecitabine, grade (G)≥3 adverse events (AEs) occurred in 55.0% (11/20) of patients; ORR: 60.0%. For T-DXd+capivasertib, G≥3 AEs occurred in 67.5% (27/40) of patients; ORR: 60.0%. For T-DXd+anastrozole, G≥3 AEs occurred in 47.6% (10/21) of patients; ORR: 71.4%. For T-DXd+fulvestrant, G≥3 AEs occurred in 55.0% (11/20) of patients; ORR: 40.0%. Adjudicated drug-related interstitial lung disease/pneumonitis events were reported for T-DXd+capecitabine (3/20; G2, n=2; G5, n=1), T-DXd+capivasertib (8/40; all G≤2), and T-DXd+fulvestrant (5/20; all G2). Conclusions: Safety results were generally consistent with known individual profiles for T-DXd and combination drugs. T-DXd plus capecitabine, capivasertib, anastrozole, or fulvestrant demonstrated preliminary clinical activity in patients with HER2-low mBC.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"664 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145920274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
SARC031: A Phase 2 Trial of Selumetinib and Sirolimus for Patients with Unresectable or Metastatic Malignant Peripheral Nerve Sheath Tumors (MPNST) SARC031:塞鲁美替尼和西罗莫司治疗不可切除或转移性恶性周围神经鞘肿瘤(MPNST)的2期临床试验
IF 11.5 1区 医学 Q1 ONCOLOGY Pub Date : 2026-01-08 DOI: 10.1158/1078-0432.ccr-25-2887
AeRang Kim, Karla V. Ballman, Pamela L. Wolters, Rachel S. Heise, Jack F. Shern, R. Taylor. Sundby, Liza Lindenberg, Min-Jung Lee, Shraddha Rastogi, Nahoko Sato, Shirin Shahsavari, Angela C. Hirbe, Brian A. Van Tine, Christian F. Meyer, Christine Pratilas, Natalie B. Collins, Geraldine O'Sullivan Coyne, Alice P. Chen, Eva Dombi, Roshan L. Shrestha, Andrea M. Gross, Denise Reinke, Karen Cichowski, Brigitte C. Widemann
Purpose: Combined mTOR and MEK inhibition, critical components of the RAS effector pathway underlying the pathogenesis of NF1 related tumors caused regression in a malignant peripheral nerve sheath tumor (MPNST) transgenic mouse model. The primary objective was to determine the clinical benefit rate in patients with unresectable/metastatic MPNST. Experimental Design: The study design was a multi-institutional open label Simon 2 stage phase 2 study of the MEK inhibitor selumetinib and mTOR inhibitor sirolimus. Patients ≥12 years with histologically confirmed MPNST received selumetinib 50mg twice daily and sirolimus 4mg once daily, in continuous 28-day cycles. Correlative studies evaluated patient-reported pain, immune signature in peripheral blood, and cell-free DNA (cfDNA). Results: 21 heavily pretreated patients (7F; median age 41 y (range 16-72), 14 with NF1) with advanced disease enrolled at 5 participating sites. Clinical benefit was observed in only 1/7 in stage 1 and 1/14 in stage 2. The median number of cycles was 2 (range 1-6). Most common adverse events (AEs) were grade ≤2 gastrointestinal toxicity, acneiform rash, hypertriglyceridemia, mucositis, and transaminase elevation. Unlike the preclinical model, early 18FDG-PET scan performed during cycle 1 demonstrated partial metabolic responses in 5 patients (24%) but did not correlate with objective responses post cycle 2. cfDNA was able to detect MPNST with the potential to be a biomarker of response. Conclusion: The combination was safe with manageable and expected AEs, but did not meet study parameters for further evaluation in MPNST. Correlative studies were informative and may guide future therapeutic trials of MPNST.
目的:在恶性周围神经鞘肿瘤(MPNST)转基因小鼠模型中,mTOR和MEK联合抑制是NF1相关肿瘤发病机制中RAS效应通路的关键成分。主要目的是确定不可切除/转移性MPNST患者的临床获益率。实验设计:该研究设计是一项多机构开放标签Simon 2期2期研究,研究MEK抑制剂selumetinib和mTOR抑制剂sirolimus。≥12岁组织学证实的MPNST患者接受selumetinib 50mg,每日2次,西罗莫司4mg,每日1次,连续28天为一个周期。相关研究评估了患者报告的疼痛、外周血免疫特征和无细胞DNA (cfDNA)。结果:21例重度预处理患者(7F,中位年龄41岁(16-72岁),14例NF1)在5个参与地点入选。临床获益在1期只有1/7,在2期只有1/14。周期数中位数为2(范围1-6)。最常见的不良事件(ae)为≤2级胃肠道毒性、痤疮样皮疹、高甘油三酯血症、粘膜炎和转氨酶升高。与临床前模型不同,在第1周期进行的早期18FDG-PET扫描显示5例患者(24%)有部分代谢反应,但与第2周期后的客观反应无关。cfDNA能够检测MPNST,有可能成为反应的生物标志物。结论:联合用药安全,不良反应可控且预期,但不符合进一步评价MPNST的研究参数。相关研究提供了信息,并可能指导未来MPNST的治疗试验。
{"title":"SARC031: A Phase 2 Trial of Selumetinib and Sirolimus for Patients with Unresectable or Metastatic Malignant Peripheral Nerve Sheath Tumors (MPNST)","authors":"AeRang Kim, Karla V. Ballman, Pamela L. Wolters, Rachel S. Heise, Jack F. Shern, R. Taylor. Sundby, Liza Lindenberg, Min-Jung Lee, Shraddha Rastogi, Nahoko Sato, Shirin Shahsavari, Angela C. Hirbe, Brian A. Van Tine, Christian F. Meyer, Christine Pratilas, Natalie B. Collins, Geraldine O'Sullivan Coyne, Alice P. Chen, Eva Dombi, Roshan L. Shrestha, Andrea M. Gross, Denise Reinke, Karen Cichowski, Brigitte C. Widemann","doi":"10.1158/1078-0432.ccr-25-2887","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-2887","url":null,"abstract":"Purpose: Combined mTOR and MEK inhibition, critical components of the RAS effector pathway underlying the pathogenesis of NF1 related tumors caused regression in a malignant peripheral nerve sheath tumor (MPNST) transgenic mouse model. The primary objective was to determine the clinical benefit rate in patients with unresectable/metastatic MPNST. Experimental Design: The study design was a multi-institutional open label Simon 2 stage phase 2 study of the MEK inhibitor selumetinib and mTOR inhibitor sirolimus. Patients ≥12 years with histologically confirmed MPNST received selumetinib 50mg twice daily and sirolimus 4mg once daily, in continuous 28-day cycles. Correlative studies evaluated patient-reported pain, immune signature in peripheral blood, and cell-free DNA (cfDNA). Results: 21 heavily pretreated patients (7F; median age 41 y (range 16-72), 14 with NF1) with advanced disease enrolled at 5 participating sites. Clinical benefit was observed in only 1/7 in stage 1 and 1/14 in stage 2. The median number of cycles was 2 (range 1-6). Most common adverse events (AEs) were grade ≤2 gastrointestinal toxicity, acneiform rash, hypertriglyceridemia, mucositis, and transaminase elevation. Unlike the preclinical model, early 18FDG-PET scan performed during cycle 1 demonstrated partial metabolic responses in 5 patients (24%) but did not correlate with objective responses post cycle 2. cfDNA was able to detect MPNST with the potential to be a biomarker of response. Conclusion: The combination was safe with manageable and expected AEs, but did not meet study parameters for further evaluation in MPNST. Correlative studies were informative and may guide future therapeutic trials of MPNST.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"84 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145920235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
From Biology to Bedside: Challenges and Strategies in Developing Combination Cancer Therapies in Early-Phase Trials 从生物学到床边:早期癌症联合治疗的挑战和策略
IF 11.5 1区 医学 Q1 ONCOLOGY Pub Date : 2026-01-08 DOI: 10.1158/1078-0432.ccr-25-1356
Niamh Coleman, R. Donald Harvey, David S. Hong, Patricia M. LoRusso
Recent advances in next-generation sequencing and molecular profiling have significantly expanded our understanding of the tumor mutational landscape, leading to a substantial increase in the number of novel targeted agents. Small molecules have transformed the standard of care for many patients with oncogene-driven cancers. However, single-agent therapies have several limitations, including the development of primary (intrinsic) or secondary (acquired) resistance, which often results in non-durable antitumor responses. Additionally, targeting a single alteration can lead to the upregulation of additional alterations, thereby minimizing activity. The development of novel rational combination strategies is essential to overcome compensatory escape mechanisms, intrinsic and acquired resistance, and other challenges, such as intratumoral heterogeneity and clonal evolution. In this article, we summarize key aspects of early-phase clinical trials of combination therapy, including regulatory, biological, and logistical considerations—such as biomarker integration, real-time molecular profiling, and adaptive trial infrastructure—that shape the future of combination strategies in early-phase oncology trials. We discuss recent successes with combination therapy in the clinic and discuss some current challenges in developing combination trials. Finally, we expand upon previously published guidance and, in the context of Project Optimus, propose recommendations for designing and conducting early-phase clinical trials of combination therapies.
新一代测序和分子图谱的最新进展极大地扩展了我们对肿瘤突变景观的理解,导致了新型靶向药物数量的大幅增加。小分子已经改变了许多癌基因驱动型癌症患者的治疗标准。然而,单药治疗有一些局限性,包括原发性(内在)或继发性(获得性)耐药性的发展,这通常导致非持久的抗肿瘤反应。此外,针对单个改变可能导致其他改变的上调,从而使活动最小化。开发新的合理组合策略对于克服代偿性逃避机制、内在和获得性抵抗以及其他挑战(如肿瘤内异质性和克隆进化)至关重要。在本文中,我们总结了联合治疗早期临床试验的关键方面,包括监管、生物学和后勤方面的考虑,如生物标志物整合、实时分子谱分析和适应性试验基础设施,这些因素塑造了早期肿瘤试验中联合策略的未来。我们讨论了近期联合治疗在临床中的成功,并讨论了目前在开展联合试验中面临的一些挑战。最后,我们扩展了先前发表的指南,并在Optimus项目的背景下,提出了设计和实施联合疗法早期临床试验的建议。
{"title":"From Biology to Bedside: Challenges and Strategies in Developing Combination Cancer Therapies in Early-Phase Trials","authors":"Niamh Coleman, R. Donald Harvey, David S. Hong, Patricia M. LoRusso","doi":"10.1158/1078-0432.ccr-25-1356","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-1356","url":null,"abstract":"Recent advances in next-generation sequencing and molecular profiling have significantly expanded our understanding of the tumor mutational landscape, leading to a substantial increase in the number of novel targeted agents. Small molecules have transformed the standard of care for many patients with oncogene-driven cancers. However, single-agent therapies have several limitations, including the development of primary (intrinsic) or secondary (acquired) resistance, which often results in non-durable antitumor responses. Additionally, targeting a single alteration can lead to the upregulation of additional alterations, thereby minimizing activity. The development of novel rational combination strategies is essential to overcome compensatory escape mechanisms, intrinsic and acquired resistance, and other challenges, such as intratumoral heterogeneity and clonal evolution. In this article, we summarize key aspects of early-phase clinical trials of combination therapy, including regulatory, biological, and logistical considerations—such as biomarker integration, real-time molecular profiling, and adaptive trial infrastructure—that shape the future of combination strategies in early-phase oncology trials. We discuss recent successes with combination therapy in the clinic and discuss some current challenges in developing combination trials. Finally, we expand upon previously published guidance and, in the context of Project Optimus, propose recommendations for designing and conducting early-phase clinical trials of combination therapies.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"45 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145920237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Phase 3 Trial of Pegylated Liposomal Doxorubicin for Patients with Advanced and Refractory Desmoid Tumors 聚乙二醇脂质体阿霉素治疗晚期难治性硬纤维瘤的3期临床试验
IF 11.5 1区 医学 Q1 ONCOLOGY Pub Date : 2026-01-08 DOI: 10.1158/1078-0432.ccr-25-3128
Huaiyuan Xu, Jinxin Hu, Yun Zhang, Aihua Zhuang, Yingchun Zhang, Jibin Li, Hao Wu, Guohui Song, Chuanquan Deng, Hongmin Chen, Weiqing Chen, Chuangzhong Deng, Anqi Wang, Huixiong Feng, Jinchang Lu, Qinglian Tang, Xiaojun Zhu, Jin Wang
Purpose: To evaluate the efficacy and safety of pegylated liposomal doxorubicin (PLD) in the treatment of desmoid tumors (DTs). Patients and Methods: In this investigator-initiated, double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) patients with advanced or refractory DTs to receive either PLD (50 mg/m² intravenously) or placebo every 4 weeks for 6 cycles. Crossover from placebo to PLD was permitted upon disease progression. The primary endpoint was progression-free survival (PFS). The secondary endpoints were objective response and safety. Results: From November 2020 to March 2023, a total of 73 patients were assigned to receive PLD (49 patients) or placebo (24 patients). With a median follow-up of 16.1 months, PLD had a significantly longer PFS over placebo (not reached vs. 4.3 months), with a hazard ratio (HR) of 0.05 (95% CI, 0.01-0.17; P&lt;0.001). The 2-year PFS rates were 90.4% with the PLD group and 19.6% with placebo. PFS benefit favored PLD across most prespecified subgroups. The confirmed objective response was observed in 19 (40.4%) patients in the PLD group and 1 (4.3%) in the placebo group (P=0.002). Common grade 3 or higher adverse events with PLD included neutrophil count decreased (10.6%), mucositis oral (6.4%), and white-cell decreased (4.3%). Significant between-group differences in certain patient-reported toxicities were observed (P&lt;0.05). Conclusions: PLD significantly prolonged PFS and induced durable responses than placebo, with a favorable safety profile, for patients with progressive or symptomatic desmoid tumors.
目的:评价聚乙二醇化脂质体阿霉素(PLD)治疗硬纤维瘤(DTs)的疗效和安全性。患者和方法:在这项研究者发起的双盲三期试验中,我们随机分配(以2:1的比例)晚期或难治性DTs患者接受PLD (50mg /m²静脉注射)或安慰剂,每4周接受6个周期。在疾病进展时,允许从安慰剂过渡到PLD。主要终点为无进展生存期(PFS)。次要终点是客观反应和安全性。结果:从2020年11月到2023年3月,共有73例患者被分配接受PLD(49例)或安慰剂(24例)。中位随访时间为16.1个月,PLD的PFS明显长于安慰剂(未达到vs. 4.3个月),风险比(HR)为0.05 (95% CI, 0.01-0.17; P<0.001)。PLD组的2年PFS为90.4%,安慰剂组为19.6%。PFS在大多数预先指定的子组中都有利于PLD。PLD组有19例(40.4%)患者客观缓解,安慰剂组有1例(4.3%)患者客观缓解(P=0.002)。PLD常见的3级或以上不良事件包括中性粒细胞计数下降(10.6%),口腔粘膜炎(6.4%)和白细胞下降(4.3%)。在某些患者报告的毒性方面,组间存在显著差异(P<0.05)。结论:对于进行性或症状性硬纤维瘤患者,与安慰剂相比,PLD显著延长了PFS,并诱导了持久的反应,具有良好的安全性。
{"title":"Phase 3 Trial of Pegylated Liposomal Doxorubicin for Patients with Advanced and Refractory Desmoid Tumors","authors":"Huaiyuan Xu, Jinxin Hu, Yun Zhang, Aihua Zhuang, Yingchun Zhang, Jibin Li, Hao Wu, Guohui Song, Chuanquan Deng, Hongmin Chen, Weiqing Chen, Chuangzhong Deng, Anqi Wang, Huixiong Feng, Jinchang Lu, Qinglian Tang, Xiaojun Zhu, Jin Wang","doi":"10.1158/1078-0432.ccr-25-3128","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-3128","url":null,"abstract":"Purpose: To evaluate the efficacy and safety of pegylated liposomal doxorubicin (PLD) in the treatment of desmoid tumors (DTs). Patients and Methods: In this investigator-initiated, double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) patients with advanced or refractory DTs to receive either PLD (50 mg/m² intravenously) or placebo every 4 weeks for 6 cycles. Crossover from placebo to PLD was permitted upon disease progression. The primary endpoint was progression-free survival (PFS). The secondary endpoints were objective response and safety. Results: From November 2020 to March 2023, a total of 73 patients were assigned to receive PLD (49 patients) or placebo (24 patients). With a median follow-up of 16.1 months, PLD had a significantly longer PFS over placebo (not reached vs. 4.3 months), with a hazard ratio (HR) of 0.05 (95% CI, 0.01-0.17; P&amp;lt;0.001). The 2-year PFS rates were 90.4% with the PLD group and 19.6% with placebo. PFS benefit favored PLD across most prespecified subgroups. The confirmed objective response was observed in 19 (40.4%) patients in the PLD group and 1 (4.3%) in the placebo group (P=0.002). Common grade 3 or higher adverse events with PLD included neutrophil count decreased (10.6%), mucositis oral (6.4%), and white-cell decreased (4.3%). Significant between-group differences in certain patient-reported toxicities were observed (P&amp;lt;0.05). Conclusions: PLD significantly prolonged PFS and induced durable responses than placebo, with a favorable safety profile, for patients with progressive or symptomatic desmoid tumors.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"263 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145920276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
期刊
Clinical Cancer Research
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1