Pub Date : 2026-03-12DOI: 10.1158/1078-0432.CCR-25-3525
Kazutaka Fukumura, Peixin Jiang, Debra Nana Yeboa, Akshara Singareeka Raghavendra, Maria A Gubbiotti, Clark R Andersen, Sherise D Ferguson, Dzifa Yawa Duose, Yujin Kudo, Banu Arun, Alexandre Reuben, Jason T Huse, Nuhad K Ibrahim
Purpose: Brain metastasis (BM) is a deadly complication of systemic malignancy, which has been associated with defective cellular immunity. We sought to characterize the foundational elements and clinical relevance BM-associated immunosuppression using integrated molecular profiling in primary patient material.
Experimental design: Retrospective patient tissue cohorts of breast (N=153) and lung (N=153) cancer BM were stratified by histopathological scoring of tumor-infiltrating lymphocytes (TILs) and clinical outcome, with a large subset of breast cancer samples further analyzed by T-cell receptor (TCR) and RNA sequencing. An ongoing clinical trial comparing pre-operative (pre-op) and post-operative (post-op) stereotactic radiosurgery (SRS)/stereotactic radiotherapy (SRT) in BM management was then leveraged to dissect radiation-induced immune responses by TCR and RNA sequencing.
Results: Patients with high-grade histopathological TIL infiltration and enriched TCR diversity demonstrated favorable prognoses in breast and lung cancer BM. Moreover, SRS/SRT treatment enhanced TCR diversity in the BM microenvironment, along with signatures of antigen processing and presentation. Finally, integrated analysis demonstrated that IR appeared to reactivate immune microenvironmental signatures normally suppressed in BM and upregulate immune signaling pathways correlated with favorable outcome in breast cancer BM patients.
Conclusions: Our findings demonstrate that high TCR diversity in BM associates with favorable prognosis, pointing to therapeutically tractable targets within the immune microenvironment. Moreover, we show in a prospective clinical trial that IR enhances T cell-mediated immune responses, upregulating antigen-presentation and enhancing TCR diversity in BM. These results argue for increased therapeutic investigations of radiation-induced immunomodulatory effects in BM, potentially in association with immune checkpoint inhibition.
{"title":"Ionizing radiation enhances prognostically significant cellular immunity programs in the brain metastasis microenvironment.","authors":"Kazutaka Fukumura, Peixin Jiang, Debra Nana Yeboa, Akshara Singareeka Raghavendra, Maria A Gubbiotti, Clark R Andersen, Sherise D Ferguson, Dzifa Yawa Duose, Yujin Kudo, Banu Arun, Alexandre Reuben, Jason T Huse, Nuhad K Ibrahim","doi":"10.1158/1078-0432.CCR-25-3525","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-25-3525","url":null,"abstract":"<p><strong>Purpose: </strong>Brain metastasis (BM) is a deadly complication of systemic malignancy, which has been associated with defective cellular immunity. We sought to characterize the foundational elements and clinical relevance BM-associated immunosuppression using integrated molecular profiling in primary patient material.</p><p><strong>Experimental design: </strong>Retrospective patient tissue cohorts of breast (N=153) and lung (N=153) cancer BM were stratified by histopathological scoring of tumor-infiltrating lymphocytes (TILs) and clinical outcome, with a large subset of breast cancer samples further analyzed by T-cell receptor (TCR) and RNA sequencing. An ongoing clinical trial comparing pre-operative (pre-op) and post-operative (post-op) stereotactic radiosurgery (SRS)/stereotactic radiotherapy (SRT) in BM management was then leveraged to dissect radiation-induced immune responses by TCR and RNA sequencing.</p><p><strong>Results: </strong>Patients with high-grade histopathological TIL infiltration and enriched TCR diversity demonstrated favorable prognoses in breast and lung cancer BM. Moreover, SRS/SRT treatment enhanced TCR diversity in the BM microenvironment, along with signatures of antigen processing and presentation. Finally, integrated analysis demonstrated that IR appeared to reactivate immune microenvironmental signatures normally suppressed in BM and upregulate immune signaling pathways correlated with favorable outcome in breast cancer BM patients.</p><p><strong>Conclusions: </strong>Our findings demonstrate that high TCR diversity in BM associates with favorable prognosis, pointing to therapeutically tractable targets within the immune microenvironment. Moreover, we show in a prospective clinical trial that IR enhances T cell-mediated immune responses, upregulating antigen-presentation and enhancing TCR diversity in BM. These results argue for increased therapeutic investigations of radiation-induced immunomodulatory effects in BM, potentially in association with immune checkpoint inhibition.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2026-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147431328","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}
Pub Date : 2026-03-11DOI: 10.1158/1078-0432.CCR-26-0032
Javier Martin-Broto, Javier Martinez-Trufero, Roberto Diaz-Beveridge, Antonio Gutierrez, Irene Carrasco, Carlos Lopez-Jimenez, Ana Sebio, Enrique González-Billalabeitia, Rafael Ramos, Cleofe Romagosa, Jose Merino, Javier Fernandez-Jara, Laura Hernandez-Vargas, Maria Dolores Garmendia, Josefina Cruz-Jurado, Claudia Valverde, Jose L Mondaza-Hernandez, Maria A Carrera, Patricio Ledesma, Nadia Hindi, David S Moura
Purpose: This single-arm, phase Ib trial aimed to evaluate the safety and preliminary efficacy of epirubicin, ifosfamide, and nivolumab as first-line treatment for advanced UPS.
Experimental design: Adult patients with a centrally confirmed diagnosis of advanced undifferentiated pleomorphic sarcoma were eligible. Patients received epirubicin 60 mg/m² (days 1-2), ifosfamide 3 g/m² (days 1-3) every 21 days for up to six cycles, and nivolumab 360 mg flat dose IV (day 3/ each cycle), followed by maintenance nivolumab for one year. The primary endpoint was the determination of the recommended phase II dose (RP2D).
Results: Sixteen patients were enrolled with no dose-limiting toxicities observed; the RP2D was established at full-dose epirubicin, ifosfamide, and nivolumab 360 mg. Grade 3-4 treatment-related adverse events included neutropenia (62.5%) and anemia (43.8%). The ORR was 68.8%, with 94% of patients experiencing tumor shrinkage. Median PFS was 9.9 months (95% CI, 7.0-12.7), and median OS was not reached.
Conclusion: The combination of epirubicin, ifosfamide, and nivolumab is a safe, feasible, and highly active treatment for advanced UPS.
{"title":"Safety and Efficacy of Epirubicin, Ifosfamide, and Nivolumab as First-line treatment for patients with Undifferentiated Pleomorphic Sarcoma.","authors":"Javier Martin-Broto, Javier Martinez-Trufero, Roberto Diaz-Beveridge, Antonio Gutierrez, Irene Carrasco, Carlos Lopez-Jimenez, Ana Sebio, Enrique González-Billalabeitia, Rafael Ramos, Cleofe Romagosa, Jose Merino, Javier Fernandez-Jara, Laura Hernandez-Vargas, Maria Dolores Garmendia, Josefina Cruz-Jurado, Claudia Valverde, Jose L Mondaza-Hernandez, Maria A Carrera, Patricio Ledesma, Nadia Hindi, David S Moura","doi":"10.1158/1078-0432.CCR-26-0032","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-26-0032","url":null,"abstract":"<p><strong>Purpose: </strong>This single-arm, phase Ib trial aimed to evaluate the safety and preliminary efficacy of epirubicin, ifosfamide, and nivolumab as first-line treatment for advanced UPS.</p><p><strong>Experimental design: </strong>Adult patients with a centrally confirmed diagnosis of advanced undifferentiated pleomorphic sarcoma were eligible. Patients received epirubicin 60 mg/m² (days 1-2), ifosfamide 3 g/m² (days 1-3) every 21 days for up to six cycles, and nivolumab 360 mg flat dose IV (day 3/ each cycle), followed by maintenance nivolumab for one year. The primary endpoint was the determination of the recommended phase II dose (RP2D).</p><p><strong>Results: </strong>Sixteen patients were enrolled with no dose-limiting toxicities observed; the RP2D was established at full-dose epirubicin, ifosfamide, and nivolumab 360 mg. Grade 3-4 treatment-related adverse events included neutropenia (62.5%) and anemia (43.8%). The ORR was 68.8%, with 94% of patients experiencing tumor shrinkage. Median PFS was 9.9 months (95% CI, 7.0-12.7), and median OS was not reached.</p><p><strong>Conclusion: </strong>The combination of epirubicin, ifosfamide, and nivolumab is a safe, feasible, and highly active treatment for advanced UPS.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147431271","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}
Pub Date : 2026-03-10DOI: 10.1158/1078-0432.ccr-25-3315
Belén Sierra-Rodero, Ángeles Gil-González, Marta Molina-Alejandre, Ernest Nadal, Virginia Calvo, Martín Lázaro, Amelia Insa, Bartomeu Massuti, Alex Martinez Marti, Javier de Castro, Rosario García Campelo, Jose Luis González Larriba, Reyes Bernabé, Manuel Dómine, Santiago Ponce Aix, Manuel Cobo, Carlos Camps, Noemi Reguart, Joaquím Bosch-Barrera, Margarita Majem, Andres Aguilar, Ramón Palmero, Mariola Blanco Clemente, Javier Martín-López, Rafael Muñoz-Viana, Diego Megías, Juan Manuel Gutiérrez-Escobedo, Cristina Martínez-Toledo, Alberto Cruz-Bermúdez, Mariano Provencio Pulla
Purpose: Complete pathological response (CPR) correlates with long-term survival after perioperative chemoimmunotherapy (ChIO) in resectable non–small cell lung cancer (NSCLC). We provide a multiomic characterization of B cells and tertiary lymphoid structures (TLS) to dissect the immune landscape associated with CPR. Experimental Design: We integrated B cell receptor (BCR) repertoire profiling (n=87 tissue, n=25 blood), multiplex immunofluorescence (n=67), and bulk (n=15), spatial (n=12), and single-cell transcriptomics (n=15) from tumor tissue and blood (baseline, surgery, and six-months adjuvant therapy) in 123 patients (NADIM/NADIM II trials, NCT03081689/NCT03838159). Results: CPR tumors exhibited a more clonal baseline BCR repertoire (AUC 0.775; p=0.030) that was better conserved and reinvigorated during neoadjuvant ChIO. In blood, patients with CPR tumors displayed a repertoire enriched in class-switched clones (AUC 0.833; p=0.008) characterized by higher diversity, lower clonality, and upregulation of activation-related transcriptional programs. Neoadjuvant ChIO was associated with the induction of B cell–related genes within TLS regions and with higher TLS density at surgery compared to Ch (p=0.034). TLS density was not associated with CPR (p=0.129), however, mature-TLSs in CPR tumors were enriched in immune-activation and antigen presenting pathways, estimated Tfh cells, pDCs, and plasma cells, while low-B cell regions from CPR tumors displayed higher inferred infiltration of CD8⁺ T cells, NK cells, and macrophages with reduced neutrophils and Tregs. Conclusions: Patients with CPR tumors exhibit a pre-existing and more mature B cell response that develops further during neoadjuvant ChIO. Our findings link B cell–related features to CPR and highlight BCR metrics as promising predictive biomarkers in NSCLC.
{"title":"Decoding B Cell Signatures of Complete Pathological Response to Perioperative Chemoimmunotherapy in Non-Small Cell Lung Cancer.","authors":"Belén Sierra-Rodero, Ángeles Gil-González, Marta Molina-Alejandre, Ernest Nadal, Virginia Calvo, Martín Lázaro, Amelia Insa, Bartomeu Massuti, Alex Martinez Marti, Javier de Castro, Rosario García Campelo, Jose Luis González Larriba, Reyes Bernabé, Manuel Dómine, Santiago Ponce Aix, Manuel Cobo, Carlos Camps, Noemi Reguart, Joaquím Bosch-Barrera, Margarita Majem, Andres Aguilar, Ramón Palmero, Mariola Blanco Clemente, Javier Martín-López, Rafael Muñoz-Viana, Diego Megías, Juan Manuel Gutiérrez-Escobedo, Cristina Martínez-Toledo, Alberto Cruz-Bermúdez, Mariano Provencio Pulla","doi":"10.1158/1078-0432.ccr-25-3315","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-3315","url":null,"abstract":"Purpose: Complete pathological response (CPR) correlates with long-term survival after perioperative chemoimmunotherapy (ChIO) in resectable non–small cell lung cancer (NSCLC). We provide a multiomic characterization of B cells and tertiary lymphoid structures (TLS) to dissect the immune landscape associated with CPR. Experimental Design: We integrated B cell receptor (BCR) repertoire profiling (n=87 tissue, n=25 blood), multiplex immunofluorescence (n=67), and bulk (n=15), spatial (n=12), and single-cell transcriptomics (n=15) from tumor tissue and blood (baseline, surgery, and six-months adjuvant therapy) in 123 patients (NADIM/NADIM II trials, NCT03081689/NCT03838159). Results: CPR tumors exhibited a more clonal baseline BCR repertoire (AUC 0.775; p=0.030) that was better conserved and reinvigorated during neoadjuvant ChIO. In blood, patients with CPR tumors displayed a repertoire enriched in class-switched clones (AUC 0.833; p=0.008) characterized by higher diversity, lower clonality, and upregulation of activation-related transcriptional programs. Neoadjuvant ChIO was associated with the induction of B cell–related genes within TLS regions and with higher TLS density at surgery compared to Ch (p=0.034). TLS density was not associated with CPR (p=0.129), however, mature-TLSs in CPR tumors were enriched in immune-activation and antigen presenting pathways, estimated Tfh cells, pDCs, and plasma cells, while low-B cell regions from CPR tumors displayed higher inferred infiltration of CD8⁺ T cells, NK cells, and macrophages with reduced neutrophils and Tregs. Conclusions: Patients with CPR tumors exhibit a pre-existing and more mature B cell response that develops further during neoadjuvant ChIO. Our findings link B cell–related features to CPR and highlight BCR metrics as promising predictive biomarkers in NSCLC.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"53 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147383208","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}
Pub Date : 2026-03-09DOI: 10.1158/1078-0432.ccr-25-3431
Jhanelle E Gray,Konstantin Laktionov,Sang-We Kim,Terufumi Kato,Jialei Wang,Zhigang Han,Paul Mitchell,Shoichi Kuyama,Jerry Tan Chun Bing,Juan Cundom,Gustavo Pinto,Frances A Shepherd,Lynne Poole,Rachel Lai,Muna Albayaty,Neha P Amin,Kunihiko Kobayashi,Chee Khoon Lee
PURPOSEIn FLAURA2, first-line osimertinib plus platinum-pemetrexed induction, with osimertinib plus pemetrexed maintenance improved progression-free survival versus osimertinib alone in EGFR-mutated, advanced non-small cell lung cancer (NSCLC) (HR, 0.62; P < 0.001). Combining osimertinib with chemotherapy increased induction grade ≥3 adverse event rates, which reduced during maintenance. We report FLAURA2 patient-reported outcomes (PROs).PATIENTS AND METHODSHealth-related quality of life (HRQoL) was measured using EORTC QLQ-C30 (baseline, Week [W] 4, W7, W10, then 6-weekly until progression) and QLQ-LC13 (baseline, weekly until W10, then 3-weekly until progression). Score changes (baseline to progression/19 months) were analyzed by mixed models for repeated measures. Within-patient ≥10-point changes from baseline were considered clinically meaningful. Tolerability was assessed by PRO-CTCAE.RESULTSPatients had intermediate-to-high baseline functioning and global health status (GHS)/QoL (mean scores ≥63), with mild symptomology (≤35). Most key scales showed non-clinically meaningful improvements; average least-squares mean [LSM] changes (95% CI) for GHS/QoL and physical function, respectively, were 3.32 (1.67-4.98) and 2.37 (0.70-4.04) with combination and 7.38 (5.70-9.07) and 6.74 (5.04-8.43) with monotherapy. Improvements in cough were clinically meaningful with combination and monotherapy from W5 (except monotherapy at W73); average LSM change (95% CI) -13.23 (-14.85 - -11.62) and -11.19 (-12.83 - -9.55), respectively. Non-clinically meaningful deteriorations in fatigue and appetite loss were seen with the combination during induction. Both treatments were similarly well tolerated (PRO-CTCAE).CONCLUSIONSIn FLAURA2, osimertinib monotherapy and combination with platinum-pemetrexed as first-line treatment for EGFR-mutated advanced NSCLC had non-clinically meaningful impacts on HRQoL in mildly symptomatic patients.
{"title":"Patient-Reported Outcomes in FLAURA2: Osimertinib with or without Chemotherapy in Patients with Previously Untreated EGFR-Mutated Advanced Non-Small Cell Lung Cancer.","authors":"Jhanelle E Gray,Konstantin Laktionov,Sang-We Kim,Terufumi Kato,Jialei Wang,Zhigang Han,Paul Mitchell,Shoichi Kuyama,Jerry Tan Chun Bing,Juan Cundom,Gustavo Pinto,Frances A Shepherd,Lynne Poole,Rachel Lai,Muna Albayaty,Neha P Amin,Kunihiko Kobayashi,Chee Khoon Lee","doi":"10.1158/1078-0432.ccr-25-3431","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-3431","url":null,"abstract":"PURPOSEIn FLAURA2, first-line osimertinib plus platinum-pemetrexed induction, with osimertinib plus pemetrexed maintenance improved progression-free survival versus osimertinib alone in EGFR-mutated, advanced non-small cell lung cancer (NSCLC) (HR, 0.62; P < 0.001). Combining osimertinib with chemotherapy increased induction grade ≥3 adverse event rates, which reduced during maintenance. We report FLAURA2 patient-reported outcomes (PROs).PATIENTS AND METHODSHealth-related quality of life (HRQoL) was measured using EORTC QLQ-C30 (baseline, Week [W] 4, W7, W10, then 6-weekly until progression) and QLQ-LC13 (baseline, weekly until W10, then 3-weekly until progression). Score changes (baseline to progression/19 months) were analyzed by mixed models for repeated measures. Within-patient ≥10-point changes from baseline were considered clinically meaningful. Tolerability was assessed by PRO-CTCAE.RESULTSPatients had intermediate-to-high baseline functioning and global health status (GHS)/QoL (mean scores ≥63), with mild symptomology (≤35). Most key scales showed non-clinically meaningful improvements; average least-squares mean [LSM] changes (95% CI) for GHS/QoL and physical function, respectively, were 3.32 (1.67-4.98) and 2.37 (0.70-4.04) with combination and 7.38 (5.70-9.07) and 6.74 (5.04-8.43) with monotherapy. Improvements in cough were clinically meaningful with combination and monotherapy from W5 (except monotherapy at W73); average LSM change (95% CI) -13.23 (-14.85 - -11.62) and -11.19 (-12.83 - -9.55), respectively. Non-clinically meaningful deteriorations in fatigue and appetite loss were seen with the combination during induction. Both treatments were similarly well tolerated (PRO-CTCAE).CONCLUSIONSIn FLAURA2, osimertinib monotherapy and combination with platinum-pemetrexed as first-line treatment for EGFR-mutated advanced NSCLC had non-clinically meaningful impacts on HRQoL in mildly symptomatic patients.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"15 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147373835","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}
Pub Date : 2026-03-09DOI: 10.1158/1078-0432.ccr-25-3764
Cameron Crowell,Nikhil P Mankuzhy,Julie Bennett,Pratiti Bandopadhayay,Dominik Sturm,Adam L Green,Tejpal Gupta,Abhishek Chatterjee,Sridhar Epari,Girish Chinnaswamy,Maya Prasad,Sohil H Patel,Mary MacNeil,Magimairajan Issai Vanan,Valérie Larouche,Samuele Renzi,Jacquelyn Jones,Sébastien Perreault,Daddy Mata-Mbemba,Yuhei Sangatsuda,Koji Yoshimoto,Emily Lin,Charlotte Feddersen,Ofelia Cruz,Miriam Pavon-Mengual,Olivia Vizzini,Michal Zápotocký,Aimee Popovacki,Darren Klawinski,Jordan R Hansford,Mary-Pat Schlosser,Egiroh Omene,Kimberley L Alexander,Laveniya Satgunaseelan,Andrew Williams,Kristin Yao,Rebecca Ronsley,Sylvia Cheng,Louise Ludlow,David Eisenstat,Dong-Anh Khuong-Quang,Emeline Tabouret,Nicolas André,Kara Matheson,Aimee Chan,Mary Jane Lim-Fat,Sarah Lapointe,Romain Cayrol,Christina Coleman,Nikoleta Juretic,Sheila McThenia,Sara Khan,Mariah Wright-Nadkarni,Ralph Salloum,Robert T Galvin,Ugur Sener,Cynthia Hawkins,Brandon S Imber,Matthias A Karajannis,David T W Jones,Keith L Ligon,Nada Jabado,Craig Erker
PURPOSEKnowledge regarding prognostic factors and long-term survival for patients with diffuse hemispheric glioma, H3 G34-mutant (DHG, H3 G34) is limited in this poor-outcome tumor.EXPERIMENTAL DESIGNThis retrospective, multi-institutional study investigated prognostic variables for patients with DHG, H3 G34 and their association with progression-free survival (PFS) and overall survival (OS). Univariable and multivariable Cox proportional hazard models were applied with multiple imputed data sets.RESULTSOne hundred fifty-three patients (142 G34R, 9 G34V, 2 via DNA methylation) were included. Median age at diagnosis was 17 years (range, 2-45). Initial gross/near total resection (GTR/NTR) was achieved in 43% of patients. Radiation was given in 91% (85% focal irradiation) and initial chemotherapy in 87% (70% temozolomide-based (TMZ), 25% TMZ/CCNU, 5% non-TMZ). Median OS was 24 months (interquartile range [IQR], 22-28) with a median PFS of 14.0 months (IQR 12.0-19.0). Twelve patients (8%) were found to be long-term survivors ≥ 5 years. Exploratory multivariable analysis showed adjuvant radiation therapy (HR 0.076, 95% CI 0.033, 0.17) and achieving GTR/NTR compared to < NTR (HR 0.51, 95% CI 0.33, 0.78) were associated with improved PFS. Multivariable analysis showed improved OS with increasing age at diagnosis (HR 0.70, 95% CI 0.57, 0.87), initial radiation therapy (HR 0.38, 95% CI 0.15, 0.96), and initial GTR/NTR compared to < NTR (HR 0.60, 95% CI 0.37, 0.97).CONCLUSIONThis cohort highlights prognostic factors for patients with DHG, H3 G34, describes relapse patterns, and therapy approaches. Clinical trials and prospective registries are needed to improve outcomes.
目的：关于弥漫性半球胶质瘤H3 G34突变体（DHG, H3 G34）患者预后因素和长期生存的知识在这种预后差的肿瘤中是有限的。实验设计：这项回顾性、多机构研究探讨了DHG、H3 G34患者的预后变量及其与无进展生存期（PFS）和总生存期（OS）的关系。单变量和多变量Cox比例风险模型应用于多个输入数据集。结果共纳入153例患者（G34R 142例，G34V 9例，DNA甲基化2例）。诊断时的中位年龄为17岁（范围2-45岁）。43%的患者实现了初始全切除/近全切除（GTR/NTR）。放疗占91%（85%为局部放疗），初始化疗占87%（70%为替莫唑胺基（TMZ）， 25%为TMZ/CCNU， 5%为非TMZ）。中位OS为24个月（四分位间距[IQR]， 22-28），中位PFS为14.0个月（IQR为12.0-19.0）。12例患者（8%）长期存活≥5年。探索性多变量分析显示，辅助放疗（HR 0.076, 95% CI 0.033, 0.17）和实现GTR/NTR （HR 0.51, 95% CI 0.33, 0.78）与改善PFS相关。多变量分析显示，随着诊断年龄的增加（HR 0.70, 95% CI 0.57, 0.87）、初始放射治疗（HR 0.38, 95% CI 0.15, 0.96）和初始GTR/NTR (HR 0.60, 95% CI 0.37, 0.97)， OS得到改善。结论：该队列突出了DHG、h3g34患者的预后因素，描述了复发模式和治疗方法。需要临床试验和前瞻性登记来改善结果。
{"title":"Clinical Outcomes and Prognostic Features of Diffuse Hemispheric Glioma, H3 G34-mutant: An International Multi-Institutional Study.","authors":"Cameron Crowell,Nikhil P Mankuzhy,Julie Bennett,Pratiti Bandopadhayay,Dominik Sturm,Adam L Green,Tejpal Gupta,Abhishek Chatterjee,Sridhar Epari,Girish Chinnaswamy,Maya Prasad,Sohil H Patel,Mary MacNeil,Magimairajan Issai Vanan,Valérie Larouche,Samuele Renzi,Jacquelyn Jones,Sébastien Perreault,Daddy Mata-Mbemba,Yuhei Sangatsuda,Koji Yoshimoto,Emily Lin,Charlotte Feddersen,Ofelia Cruz,Miriam Pavon-Mengual,Olivia Vizzini,Michal Zápotocký,Aimee Popovacki,Darren Klawinski,Jordan R Hansford,Mary-Pat Schlosser,Egiroh Omene,Kimberley L Alexander,Laveniya Satgunaseelan,Andrew Williams,Kristin Yao,Rebecca Ronsley,Sylvia Cheng,Louise Ludlow,David Eisenstat,Dong-Anh Khuong-Quang,Emeline Tabouret,Nicolas André,Kara Matheson,Aimee Chan,Mary Jane Lim-Fat,Sarah Lapointe,Romain Cayrol,Christina Coleman,Nikoleta Juretic,Sheila McThenia,Sara Khan,Mariah Wright-Nadkarni,Ralph Salloum,Robert T Galvin,Ugur Sener,Cynthia Hawkins,Brandon S Imber,Matthias A Karajannis,David T W Jones,Keith L Ligon,Nada Jabado,Craig Erker","doi":"10.1158/1078-0432.ccr-25-3764","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-3764","url":null,"abstract":"PURPOSEKnowledge regarding prognostic factors and long-term survival for patients with diffuse hemispheric glioma, H3 G34-mutant (DHG, H3 G34) is limited in this poor-outcome tumor.EXPERIMENTAL DESIGNThis retrospective, multi-institutional study investigated prognostic variables for patients with DHG, H3 G34 and their association with progression-free survival (PFS) and overall survival (OS). Univariable and multivariable Cox proportional hazard models were applied with multiple imputed data sets.RESULTSOne hundred fifty-three patients (142 G34R, 9 G34V, 2 via DNA methylation) were included. Median age at diagnosis was 17 years (range, 2-45). Initial gross/near total resection (GTR/NTR) was achieved in 43% of patients. Radiation was given in 91% (85% focal irradiation) and initial chemotherapy in 87% (70% temozolomide-based (TMZ), 25% TMZ/CCNU, 5% non-TMZ). Median OS was 24 months (interquartile range [IQR], 22-28) with a median PFS of 14.0 months (IQR 12.0-19.0). Twelve patients (8%) were found to be long-term survivors ≥ 5 years. Exploratory multivariable analysis showed adjuvant radiation therapy (HR 0.076, 95% CI 0.033, 0.17) and achieving GTR/NTR compared to < NTR (HR 0.51, 95% CI 0.33, 0.78) were associated with improved PFS. Multivariable analysis showed improved OS with increasing age at diagnosis (HR 0.70, 95% CI 0.57, 0.87), initial radiation therapy (HR 0.38, 95% CI 0.15, 0.96), and initial GTR/NTR compared to < NTR (HR 0.60, 95% CI 0.37, 0.97).CONCLUSIONThis cohort highlights prognostic factors for patients with DHG, H3 G34, describes relapse patterns, and therapy approaches. Clinical trials and prospective registries are needed to improve outcomes.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"16 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147373829","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}
Pub Date : 2026-03-09DOI: 10.1158/1078-0432.ccr-25-4816
Angela Dalia Ricci,Alessandro Rizzo
The results of a recent trial undoubtedly contribute a vital element to the overarching management of rare tumors and offer new treatment hopes for patients with brain metastases, thereby paving the way for future research in immunotherapy.
{"title":"Unlocking New Possibilities: Dual Immune Blockade in Brain Metastases from Rare Tumors.","authors":"Angela Dalia Ricci,Alessandro Rizzo","doi":"10.1158/1078-0432.ccr-25-4816","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-4816","url":null,"abstract":"The results of a recent trial undoubtedly contribute a vital element to the overarching management of rare tumors and offer new treatment hopes for patients with brain metastases, thereby paving the way for future research in immunotherapy.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"15 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147374112","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}
Pub Date : 2026-03-09DOI: 10.1158/1078-0432.ccr-25-1788
Qingxiang Lin,Alvin A Morales-Giron,Conrad Sander,Jacquelyn M Curtis,Haley Barnes,Parasvi S Patel,Ferran Fece de la Cruz,Jakob M Riedl,Hiroyuki Matsubara,Hajime Nakamura,Andrew S Liss,Ryan B Corcoran
PURPOSEOncogenic KRAS mutations are present in >90% of pancreatic ductal adenocarcinoma (PDAC) with KRASG12D being the most common. Mutant-selective KRASG12D inhibitors (KRASiG12D) have demonstrated promising initial clinical activity in KRASG12D-mutant PDAC. However, adaptive resistance to KRASi constrains efficacy in some tumor types, such as colorectal cancer, where EGFR-mediated RAS-MAPK pathway reactivation can be targeted toimprove response. Some studies have suggested a similar role for EGFR in PDAC, but the mechanisms of adaptive resistance to KRAS inhibition are unclear.EXPERIMENTAL DESIGNMechanisms of adaptive resistance to KRASiG12D were investigated in a panel of KRASG12D-mutant PDAC models.RESULTSWe observed RTK-driven adaptive reactivation of RAS pathway signaling following KRASiG12D in PDAC models. EGFR was a primary driver of adaptive RAS-MAPK reactivation in some models, but limited to those with epithelial differentiation. Conversely, adaptive RAS MAPK reactivation in models with mesenchymal differentiation was primarily driven by FGFR signaling. In clinical PDAC specimens from TCGA, EGFR and ERBB3 expression was highly correlated with expression of epithelial markers, while expression of FGFR1 and mesenchymal markers were correlated. Notably, a RAS(ON) multi-selective inhibitor, which inhibits both wild-type and mutant RAS, abrogated RAS-MAPK reactivation in combination with KRASi in both epithelial and mesenchymal models and led to more consistent antitumor activity compared to combinations of KRASi and EGFR blockade.CONCLUSIONSIn PDAC, adaptive RAS-MAPK reactivation following KRASG12D inhibition can be mediated by different RTKs and influenced by cell state. Combinations of mutant-selective KRASi and RAS(ON) multi-selective inhibitors may represent a promising universal strategy to surmount adaptive resistance in PDAC patients.
{"title":"Overcoming adaptive resistance to KRASG12D blockade in pancreatic cancer through vertical pathway inhibition.","authors":"Qingxiang Lin,Alvin A Morales-Giron,Conrad Sander,Jacquelyn M Curtis,Haley Barnes,Parasvi S Patel,Ferran Fece de la Cruz,Jakob M Riedl,Hiroyuki Matsubara,Hajime Nakamura,Andrew S Liss,Ryan B Corcoran","doi":"10.1158/1078-0432.ccr-25-1788","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-1788","url":null,"abstract":"PURPOSEOncogenic KRAS mutations are present in >90% of pancreatic ductal adenocarcinoma (PDAC) with KRASG12D being the most common. Mutant-selective KRASG12D inhibitors (KRASiG12D) have demonstrated promising initial clinical activity in KRASG12D-mutant PDAC. However, adaptive resistance to KRASi constrains efficacy in some tumor types, such as colorectal cancer, where EGFR-mediated RAS-MAPK pathway reactivation can be targeted toimprove response. Some studies have suggested a similar role for EGFR in PDAC, but the mechanisms of adaptive resistance to KRAS inhibition are unclear.EXPERIMENTAL DESIGNMechanisms of adaptive resistance to KRASiG12D were investigated in a panel of KRASG12D-mutant PDAC models.RESULTSWe observed RTK-driven adaptive reactivation of RAS pathway signaling following KRASiG12D in PDAC models. EGFR was a primary driver of adaptive RAS-MAPK reactivation in some models, but limited to those with epithelial differentiation. Conversely, adaptive RAS MAPK reactivation in models with mesenchymal differentiation was primarily driven by FGFR signaling. In clinical PDAC specimens from TCGA, EGFR and ERBB3 expression was highly correlated with expression of epithelial markers, while expression of FGFR1 and mesenchymal markers were correlated. Notably, a RAS(ON) multi-selective inhibitor, which inhibits both wild-type and mutant RAS, abrogated RAS-MAPK reactivation in combination with KRASi in both epithelial and mesenchymal models and led to more consistent antitumor activity compared to combinations of KRASi and EGFR blockade.CONCLUSIONSIn PDAC, adaptive RAS-MAPK reactivation following KRASG12D inhibition can be mediated by different RTKs and influenced by cell state. Combinations of mutant-selective KRASi and RAS(ON) multi-selective inhibitors may represent a promising universal strategy to surmount adaptive resistance in PDAC patients.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"47 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147374107","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}
Pub Date : 2026-03-06DOI: 10.1158/1078-0432.ccr-25-3726
Sandra J Casak,Yiming Zhang,Chi Song,Pallavi S Mishra-Kalyani,Shenghui Tang,Doris Auth,R Angelo de Claro,Richard Pazdur,Steven J Lemery
On May 5, 2021 and March 19, 2025, the Food and Drug Administration (FDA) granted accelerated and regular approval for pembrolizumab plus trastuzumab and platinum-based chemotherapy for unresectable or metastatic human epidermal growth factor receptor-2 (HER2) gastric or gastroesophageal junction carcinoma. Both approvals were based on KEYNOTE-811, a randomized, multiregional trial, comparing pembrolizumab plus trastuzumab and chemotherapy versus placebo plus trastuzumab and chemotherapy. Accelerated approval was granted based on overall response rate (ORR) in the first 264 patients randomized, showing a statistically significant improvement with pembrolizumab (74.4% vs. 51.9%, p= 0.00006). The final overall survival (OS) analysis demonstrated a clinically meaningful improvement, with a median OS of 20.0 months (95% CI 17.8, 22.1) and 16.8 months (95% CI 14.9, 18.7) in the pembrolizumab and placebo arms respectively (HR 0.80 [95% CI 0.67, 0.94]; p= 0.004). However, in exploratory subgroup analyses treatment benefit appeared to be driven by the PD-L1 CPS ≥1 population (85% of patients, with an OS HR of 0.79 [95% CI 0.66, 0.95]), whereas in the CPS <1 subgroup (15% of patients) treatment with pembrolizumab did not show improvement (HR 1.10, [95% CI 0.72-1.68]). These results are consistent with analysis of pembrolizumab and other immune checkpoint inhibitors across multiple clinical trials in patients with gastric cancer. KEYNOTE-811 utilized a "one-trial" approach allowing accelerated approval based on response rate with subsequent conversion to regular approval based on survival outcomes. KEYNOTE-811 also provided data for earlier access to therapies in a frontline metastatic setting, following FDA's Project Frontrunner approach.
在2021年5月5日和2025年3月19日，美国食品和药物管理局（FDA）批准了派姆单抗联合曲妥珠单抗和铂基化疗治疗不可切除或转移性人表皮生长因子受体-2 （HER2）胃癌或胃食管结癌的加速和常规批准。这两项批准均基于KEYNOTE-811，这是一项随机的多区域试验，比较了派姆单抗加曲妥珠单抗和化疗与安慰剂加曲妥珠单抗和化疗。基于首批264名随机患者的总缓解率（ORR）， pembrolizumab获得了加速批准，显示统计学上显着改善（74.4% vs. 51.9%, p= 0.00006）。最终总生存期（OS）分析显示有临床意义的改善，派姆单抗组和安慰剂组的中位生存期分别为20.0个月（95% CI 17.8, 22.1）和16.8个月（95% CI 14.9, 18.7） （HR 0.80 [95% CI 0.67, 0.94]; p= 0.004）。然而，在探索性亚组分析中，治疗获益似乎是由PD-L1 CPS≥1的人群（85%的患者，OS HR为0.79 [95% CI 0.66, 0.95]）驱动的，而在CPS <1的亚组（15%的患者）中，使用派姆单抗治疗没有显示出改善（HR 1.10, [95% CI 0.72-1.68]）。这些结果与pembrolizumab和其他免疫检查点抑制剂在胃癌患者的多个临床试验中的分析一致。KEYNOTE-811采用了“一次试验”方法，允许根据反应率加速批准，随后根据生存结果转换为定期批准。KEYNOTE-811还根据FDA的项目领跑者方法，为一线转移性疾病的早期治疗提供了数据。
{"title":"FDA Approval Summary: Pembrolizumab for the Treatment of HER2-Positive Gastric Cancer.","authors":"Sandra J Casak,Yiming Zhang,Chi Song,Pallavi S Mishra-Kalyani,Shenghui Tang,Doris Auth,R Angelo de Claro,Richard Pazdur,Steven J Lemery","doi":"10.1158/1078-0432.ccr-25-3726","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-3726","url":null,"abstract":"On May 5, 2021 and March 19, 2025, the Food and Drug Administration (FDA) granted accelerated and regular approval for pembrolizumab plus trastuzumab and platinum-based chemotherapy for unresectable or metastatic human epidermal growth factor receptor-2 (HER2) gastric or gastroesophageal junction carcinoma. Both approvals were based on KEYNOTE-811, a randomized, multiregional trial, comparing pembrolizumab plus trastuzumab and chemotherapy versus placebo plus trastuzumab and chemotherapy. Accelerated approval was granted based on overall response rate (ORR) in the first 264 patients randomized, showing a statistically significant improvement with pembrolizumab (74.4% vs. 51.9%, p= 0.00006). The final overall survival (OS) analysis demonstrated a clinically meaningful improvement, with a median OS of 20.0 months (95% CI 17.8, 22.1) and 16.8 months (95% CI 14.9, 18.7) in the pembrolizumab and placebo arms respectively (HR 0.80 [95% CI 0.67, 0.94]; p= 0.004). However, in exploratory subgroup analyses treatment benefit appeared to be driven by the PD-L1 CPS ≥1 population (85% of patients, with an OS HR of 0.79 [95% CI 0.66, 0.95]), whereas in the CPS <1 subgroup (15% of patients) treatment with pembrolizumab did not show improvement (HR 1.10, [95% CI 0.72-1.68]). These results are consistent with analysis of pembrolizumab and other immune checkpoint inhibitors across multiple clinical trials in patients with gastric cancer. KEYNOTE-811 utilized a \"one-trial\" approach allowing accelerated approval based on response rate with subsequent conversion to regular approval based on survival outcomes. KEYNOTE-811 also provided data for earlier access to therapies in a frontline metastatic setting, following FDA's Project Frontrunner approach.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"1 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147359318","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}
Pub Date : 2026-03-06DOI: 10.1158/1078-0432.ccr-25-4540
Helena A Yu,Kwan Ho Tang,Aleksandra A Markovets,Ryan Hartmaier,Paul E Smith,Byoung Chul Cho,Adrianus Johannes De Langen,Sarah B Goldberg,Jonathan W Goldman,Xiuning Le,Eiji Iwama,Jan Cosaert,Jonathan W Riess,Zofia Piotrowska
PURPOSEOsimertinib is standard-of-care for first-line treatment for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). Understanding the tumor molecular profile of patients following progression on osimertinib could help inform optimal second-line treatment.PATIENTS AND METHODSORCHARD (NCT03944772), a phase II biomarker-directed study, enrolled patients with EGFR-mutated NSCLC who progressed on first-line osimertinib to receive treatment based on their tumor molecular profile post-progression. The study comprised three groups into which patients were allocated based on the molecular profile of their tumor, determined via next-generation sequencing (NGS) of a tumor biopsy. We report results from a pre-specified, exploratory analysis of baseline tumor tissue and plasma samples to evaluate mechanisms of resistance to first-line osimertinib identified by tissue and plasma NGS. Agreement between tissue and plasma NGS was also assessed.RESULTSThe study provided a comprehensive dataset exploring tissue (n = 400) and plasma (n = 191) genomics, enabling characterization of the histo-genomic landscape post-first-line osimertinib treatment. TP53 and MDM2/4 alterations were mutually exclusive and occurred in 85% of tumors. When combining tissue and plasma genomics, resistance alterations were detected in 87% of samples, with multiple resistance alterations in 46%. Alterations in the PI3K pathway, SOX2, and MYC were frequently detected in histologically transformed tumors. Additionally, differential patterns of co-occurring EGFR mutations in tumors with L858R versus exon 19 deletion were observed.CONCLUSIONSThis comprehensive analysis highlights potential heterogeneous resistance to first-line osimertinib treatment, providing a rationale for combining treatments with broad activity to improve patient outcomes.
{"title":"Genomic Profiling of Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer Post-Progression on First-Line Osimertinib: Phase II ORCHARD Study.","authors":"Helena A Yu,Kwan Ho Tang,Aleksandra A Markovets,Ryan Hartmaier,Paul E Smith,Byoung Chul Cho,Adrianus Johannes De Langen,Sarah B Goldberg,Jonathan W Goldman,Xiuning Le,Eiji Iwama,Jan Cosaert,Jonathan W Riess,Zofia Piotrowska","doi":"10.1158/1078-0432.ccr-25-4540","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-4540","url":null,"abstract":"PURPOSEOsimertinib is standard-of-care for first-line treatment for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). Understanding the tumor molecular profile of patients following progression on osimertinib could help inform optimal second-line treatment.PATIENTS AND METHODSORCHARD (NCT03944772), a phase II biomarker-directed study, enrolled patients with EGFR-mutated NSCLC who progressed on first-line osimertinib to receive treatment based on their tumor molecular profile post-progression. The study comprised three groups into which patients were allocated based on the molecular profile of their tumor, determined via next-generation sequencing (NGS) of a tumor biopsy. We report results from a pre-specified, exploratory analysis of baseline tumor tissue and plasma samples to evaluate mechanisms of resistance to first-line osimertinib identified by tissue and plasma NGS. Agreement between tissue and plasma NGS was also assessed.RESULTSThe study provided a comprehensive dataset exploring tissue (n = 400) and plasma (n = 191) genomics, enabling characterization of the histo-genomic landscape post-first-line osimertinib treatment. TP53 and MDM2/4 alterations were mutually exclusive and occurred in 85% of tumors. When combining tissue and plasma genomics, resistance alterations were detected in 87% of samples, with multiple resistance alterations in 46%. Alterations in the PI3K pathway, SOX2, and MYC were frequently detected in histologically transformed tumors. Additionally, differential patterns of co-occurring EGFR mutations in tumors with L858R versus exon 19 deletion were observed.CONCLUSIONSThis comprehensive analysis highlights potential heterogeneous resistance to first-line osimertinib treatment, providing a rationale for combining treatments with broad activity to improve patient outcomes.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"1 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147359319","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}
Pub Date : 2026-03-05DOI: 10.1158/1078-0432.ccr-25-3749
Huaibin Ge,Housaiyin Li,Aditi Kulkarni,Zhangguo Chen,Pragati Upadhyay,Robert L Ferris,Jing H Wang
PURPOSEImmune checkpoint inhibitors (ICI) elicit variable responses in head and neck squamous cell carcinoma (HNSCC), yet mechanisms driving major pathological responses (MPR) remain poorly defined. We sought to evaluate longitudinal CD8 T-cell repertoire evolution to identify determinants of MPR.EXPERIMENTAL DESIGNWe analyzed high-resolution single-cell TCR sequencing data from paired pre- and post-treatment CD8 tumor-infiltrating lymphocytes (TILs) obtained from HNSCC patients treated with neoadjuvant anti-PD-1 combined with either anti-CTLA-4 or anti-LAG-3.RESULTSContrary to "clonal replacement" hypothesis, post-treatment CD8 T-cell pools were dominated by pre-existing TCR clones regardless of clinical outcome. MPR was uniquely characterized by higher abundance and greater expansion magnitude of "super-expanded" clones. We developed the TCR Adaptivity Index (TAI) to quantify coordinate flux (expansion and contraction) of all TCR clones detected across pre- and post-treatment timepoints; this index emerged as the most significant parameter associated with MPR. Importantly, clonal expansion in non-MPR was "uncoupled" from the productive, therapy-induced transcriptional reprogramming-characterized by markers of effector vigor and cellular fitness-that was observed in MPR. Furthermore, expansion dynamics positively correlated with predicted tumor reactivity as calculated by the Tumor Reactive Signature (TRS) score. Finally, a TRS-integrated TAI remained significantly correlated with MPR.CONCLUSIONSDual ICI drives MPR predominantly through the adaptivity and functional reprogramming of pre-existing immunity. Successful therapy relies on a coordinate repertoire response that promotes transition of putative tumor-reactive super-expanders into productive functional states. TRS-integrated TAI provides a high-throughput framework incorporating clonal dynamics and functional reprogramming to predict therapeutic efficacy.
{"title":"Pre-existing TCR clones drive major pathological responses in HNSCC patients treated with dual immune checkpoint inhibitors.","authors":"Huaibin Ge,Housaiyin Li,Aditi Kulkarni,Zhangguo Chen,Pragati Upadhyay,Robert L Ferris,Jing H Wang","doi":"10.1158/1078-0432.ccr-25-3749","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-3749","url":null,"abstract":"PURPOSEImmune checkpoint inhibitors (ICI) elicit variable responses in head and neck squamous cell carcinoma (HNSCC), yet mechanisms driving major pathological responses (MPR) remain poorly defined. We sought to evaluate longitudinal CD8 T-cell repertoire evolution to identify determinants of MPR.EXPERIMENTAL DESIGNWe analyzed high-resolution single-cell TCR sequencing data from paired pre- and post-treatment CD8 tumor-infiltrating lymphocytes (TILs) obtained from HNSCC patients treated with neoadjuvant anti-PD-1 combined with either anti-CTLA-4 or anti-LAG-3.RESULTSContrary to \"clonal replacement\" hypothesis, post-treatment CD8 T-cell pools were dominated by pre-existing TCR clones regardless of clinical outcome. MPR was uniquely characterized by higher abundance and greater expansion magnitude of \"super-expanded\" clones. We developed the TCR Adaptivity Index (TAI) to quantify coordinate flux (expansion and contraction) of all TCR clones detected across pre- and post-treatment timepoints; this index emerged as the most significant parameter associated with MPR. Importantly, clonal expansion in non-MPR was \"uncoupled\" from the productive, therapy-induced transcriptional reprogramming-characterized by markers of effector vigor and cellular fitness-that was observed in MPR. Furthermore, expansion dynamics positively correlated with predicted tumor reactivity as calculated by the Tumor Reactive Signature (TRS) score. Finally, a TRS-integrated TAI remained significantly correlated with MPR.CONCLUSIONSDual ICI drives MPR predominantly through the adaptivity and functional reprogramming of pre-existing immunity. Successful therapy relies on a coordinate repertoire response that promotes transition of putative tumor-reactive super-expanders into productive functional states. TRS-integrated TAI provides a high-throughput framework incorporating clonal dynamics and functional reprogramming to predict therapeutic efficacy.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"32 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350345","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号