Purpose: Preclinical model found that elective nodal irradiation (ENI) attenuated the efficacy of radiotherapy and radio-immunotherapy. However, limited clinical studies have explored the correlation between radiation dose-volume parameters of negative tumor draining lymph nodes (TDLNs) and T-cell activation/prognosis for cancer patients treated with definitive radio(chemo)therapy. Experimental Design: Patients with locally advanced esophageal cancer undergoing definitive chemoradiotherapy (CRT) were selected from two prospective trials. Dose-volume parameters of TDLN as well as other lymphocyte-related organs at risk (LOARs) and lymphocyte subsets such as CD3-CD19+ B cells, CD8+CD28+ T cells, and activated T cells (CD3+CD8+HLA-DR+) before and at the end of radiotherapy (RT) were collected. Logistic analysis was utilized to correlate dose-volume parameters with reductions in lymphocyte subsets. Prognosis of TDLN irradiation was investigated through Kaplan-Meier analysis and Cox hazards models. Results: Among 512 patients, the median mean dose of TDLN and negative non-TDLN was 25.6 Gy and 15.1 Gy, respectively. Multivariable analyses indicated TDLN V15 >50% was an independent predictor of poorer local-recurrence free survival (HR, 1.31; p=0.029) and distant-metastasis free survival (HR, 1.39; p<0.001), as well as greater reductions in CD3-CD19+ B cells (OR, 1.98; p=0.002), CD8+CD28+ T cells (OR, 3.42; p<0.001) and CD3+CD8+HLA-DR+ T cells (OR, 4.67; p=0.002) post-RT. Conclusions: A higher radiation dose-volume parameter of TDLNs in esophageal cancer patients undergoing CRT was significantly associated with suppression of T-cell activation and a worse prognosis. Limiting the percentage of TDLN V15 may be beneficial for improving the prognosis of CRT with or without PD-1 inhibitors.
{"title":"Radiation Dose-Volume Effects on Negative Tumor-Draining Lymph Nodes Impacted T-Cell Activation and Prognosis in Esophageal Cancer with Chemoradiotherapy","authors":"Ihsuan Tseng, Yun Chen, Dashan Ai, Zhengfei Zhu, Weixin Zhao, Min Fan, Ling Li, Hongcheng Zhu, Fangfang Li, Yang Xu, Lu Yu, Zezhou Wang, Junqi Wang, Qi Liu, Jiaying Deng, Shengnan Hao, Qingsong Fan, Jinjun Ye, Jialiang Zhou, Chaoyang Wu, Huarong Tang, Qin Lin, Jiancheng Li, Yunhai Li, Shihong Wei, Hui Luo, Jianzhong Cao, Xiangpeng Zheng, Guang Huang, Yuwei Zheng, Bo Ping, Kuaile Zhao","doi":"10.1158/1078-0432.ccr-24-4123","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-4123","url":null,"abstract":"Purpose: Preclinical model found that elective nodal irradiation (ENI) attenuated the efficacy of radiotherapy and radio-immunotherapy. However, limited clinical studies have explored the correlation between radiation dose-volume parameters of negative tumor draining lymph nodes (TDLNs) and T-cell activation/prognosis for cancer patients treated with definitive radio(chemo)therapy. Experimental Design: Patients with locally advanced esophageal cancer undergoing definitive chemoradiotherapy (CRT) were selected from two prospective trials. Dose-volume parameters of TDLN as well as other lymphocyte-related organs at risk (LOARs) and lymphocyte subsets such as CD3-CD19+ B cells, CD8+CD28+ T cells, and activated T cells (CD3+CD8+HLA-DR+) before and at the end of radiotherapy (RT) were collected. Logistic analysis was utilized to correlate dose-volume parameters with reductions in lymphocyte subsets. Prognosis of TDLN irradiation was investigated through Kaplan-Meier analysis and Cox hazards models. Results: Among 512 patients, the median mean dose of TDLN and negative non-TDLN was 25.6 Gy and 15.1 Gy, respectively. Multivariable analyses indicated TDLN V15 &gt;50% was an independent predictor of poorer local-recurrence free survival (HR, 1.31; p=0.029) and distant-metastasis free survival (HR, 1.39; p&lt;0.001), as well as greater reductions in CD3-CD19+ B cells (OR, 1.98; p=0.002), CD8+CD28+ T cells (OR, 3.42; p&lt;0.001) and CD3+CD8+HLA-DR+ T cells (OR, 4.67; p=0.002) post-RT. Conclusions: A higher radiation dose-volume parameter of TDLNs in esophageal cancer patients undergoing CRT was significantly associated with suppression of T-cell activation and a worse prognosis. Limiting the percentage of TDLN V15 may be beneficial for improving the prognosis of CRT with or without PD-1 inhibitors.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"18 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143575251","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 : 2025-03-07DOI: 10.1158/1078-0432.ccr-24-2000
Eugenio Morelli, Caroline Fidalgo. Ribeiro, Silvia D. Rodrigues, Claire Gao, Fabio Socciarelli, Domenico Maisano, Vanessa Favasuli, Na Liu, Katia Todoerti, Chandraditya Chakraborty, Yao Yao, Mariateresa Fulciniti, Mehmet Samur, Anil Aktas-Samur, Nicola Amodio, Marcello Turi, Francesca Barello, Johany Penailillo, Cesarina Giallongo, Alessandra Romano, Annamaria Gulla, Kenneth C. Anderson, Giorgio Inghirami, Nikhil C. Munshi, Massimo Loda
Purpose: In multiple myeloma (MM), tumor cells reprogram metabolic pathways to sustain growth and monoclonal immunoglobulin production. This study examines acetyl-CoA carboxylase 1 (ACC1), the enzyme driving the rate-limiting step in de novo lipogenesis (DNL), in MM metabolic reprogramming, particularly in c-MYC (MYC)-driven subtypes. Experimental design: ACC1 expression was evaluated across MM genetic subgroups, focusing on MYC translocations. Functional studies using ACC1 inhibitors and genetic knockdown assessed MM cell growth, lipid synthesis, and metabolic homeostasis in vitro and in vivo. The role of MYC overexpression in ACC1 sensitivity was examined, with palmitate rescue experiments. Lipidomic analysis and assessments of ER stress, protein translation, and oxidative damage elucidated underlying mechanisms. Results: ACC1 was overexpressed in MYC-translocated MM. Its inhibition or knockdown reduced MM cell growth in vitro and in vivo, particularly in MYC-overexpressing cells. ACC1 knockdown suppressed de novo lipid synthesis, partially rescued by palmitate. Lipidomic disruptions increased cholesterol ester desaturation and altered phospholipid ratios, inducing ER stress, impaired translation, protein carbonylation, oxidative damage, and apoptosis. Conclusions: ACC1 is a metabolic vulnerability in MYC-driven MM. Inhibiting ACC1 disrupts lipid homeostasis, induces ER stress, and causes oxidative damage, impairing cell survival. Targeting lipid synthesis pathways, especially in MYC-dependent subtypes, offers a promising therapeutic strategy for MM.
{"title":"Targeting Acetyl-CoA Carboxylase Suppresses De Novo Lipogenesis and Tumor Cell Growth in Multiple Myeloma","authors":"Eugenio Morelli, Caroline Fidalgo. Ribeiro, Silvia D. Rodrigues, Claire Gao, Fabio Socciarelli, Domenico Maisano, Vanessa Favasuli, Na Liu, Katia Todoerti, Chandraditya Chakraborty, Yao Yao, Mariateresa Fulciniti, Mehmet Samur, Anil Aktas-Samur, Nicola Amodio, Marcello Turi, Francesca Barello, Johany Penailillo, Cesarina Giallongo, Alessandra Romano, Annamaria Gulla, Kenneth C. Anderson, Giorgio Inghirami, Nikhil C. Munshi, Massimo Loda","doi":"10.1158/1078-0432.ccr-24-2000","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2000","url":null,"abstract":"Purpose: In multiple myeloma (MM), tumor cells reprogram metabolic pathways to sustain growth and monoclonal immunoglobulin production. This study examines acetyl-CoA carboxylase 1 (ACC1), the enzyme driving the rate-limiting step in de novo lipogenesis (DNL), in MM metabolic reprogramming, particularly in c-MYC (MYC)-driven subtypes. Experimental design: ACC1 expression was evaluated across MM genetic subgroups, focusing on MYC translocations. Functional studies using ACC1 inhibitors and genetic knockdown assessed MM cell growth, lipid synthesis, and metabolic homeostasis in vitro and in vivo. The role of MYC overexpression in ACC1 sensitivity was examined, with palmitate rescue experiments. Lipidomic analysis and assessments of ER stress, protein translation, and oxidative damage elucidated underlying mechanisms. Results: ACC1 was overexpressed in MYC-translocated MM. Its inhibition or knockdown reduced MM cell growth in vitro and in vivo, particularly in MYC-overexpressing cells. ACC1 knockdown suppressed de novo lipid synthesis, partially rescued by palmitate. Lipidomic disruptions increased cholesterol ester desaturation and altered phospholipid ratios, inducing ER stress, impaired translation, protein carbonylation, oxidative damage, and apoptosis. Conclusions: ACC1 is a metabolic vulnerability in MYC-driven MM. Inhibiting ACC1 disrupts lipid homeostasis, induces ER stress, and causes oxidative damage, impairing cell survival. Targeting lipid synthesis pathways, especially in MYC-dependent subtypes, offers a promising therapeutic strategy for MM.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"87 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143575432","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 : 2025-03-07DOI: 10.1158/1078-0432.ccr-24-3001
Saranya Chumsri, Joseph J. Larson, Emily Liu, Kathleen S. Tenner, Daniel Adams, Morgan T. Weidner, Amanda N. Arnold, Dana L. Haley, Pooja Advani, Kostandinos Sideras, Alvaro Moreno-Aspitia, E. Aubrey Thompson, Edith A. Perez, Keith L. Knutson
Purpose: Activation of the RAS/MAPK pathway is associated with reduced tumor-infiltrating lymphocytes and poor outcomes in triple-negative breast cancer (TNBC). Previous studies demonstrated that inhibition of the MAPK pathway with a MEK inhibitor is synergistic with immune checkpoint inhibitors. Experimental Design: We conducted a phase I/II trial of pembrolizumab and binimetinib in patients with metastatic TNBC with ≤ 3 prior lines of therapy. There were two dose levels (DL) with binimetinib at 45 mg at DL 0 and 30 mg at DL -1. Results: The recommended phase II dose was the standard dose of pembrolizumab with binimetinib 30 mg twice daily. The objective response rate (ORR) was 30.4%, with a numerically higher ORR in patients without liver metastasis at 45.5%. Among patients who achieved objective responses, 80% had a duration of response > 12 months and ongoing even after stopping treatment (5.4 - 69.0 months). Patients with PD-L1-positive tumors (CPS ≥ 10) were more likely to respond with an ORR of 66.7%. However, clinical benefit was observed in 25% of patients with PD-L1-negative tumors. Consistent with preclinical studies, 4 out of 6 patients with clinical benefit had either increased PD-L1 or decreased p-ERK expressions in serial circulating cancer-associated macrophage-like cells (CAMLs) after starting binimetinib. Conclusions: Pembrolizumab and binimetinib at 30 mg are safe with manageable toxicities. Promising activity was observed in patients without liver metastases. Future larger clinical trials are warranted to further evaluate the efficacy of this chemotherapy-free combination.
{"title":"Pembrolizumab in combination with binimetinib in patients with unresectable locally advanced or metastatic triple-negative breast cancer","authors":"Saranya Chumsri, Joseph J. Larson, Emily Liu, Kathleen S. Tenner, Daniel Adams, Morgan T. Weidner, Amanda N. Arnold, Dana L. Haley, Pooja Advani, Kostandinos Sideras, Alvaro Moreno-Aspitia, E. Aubrey Thompson, Edith A. Perez, Keith L. Knutson","doi":"10.1158/1078-0432.ccr-24-3001","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3001","url":null,"abstract":"Purpose: Activation of the RAS/MAPK pathway is associated with reduced tumor-infiltrating lymphocytes and poor outcomes in triple-negative breast cancer (TNBC). Previous studies demonstrated that inhibition of the MAPK pathway with a MEK inhibitor is synergistic with immune checkpoint inhibitors. Experimental Design: We conducted a phase I/II trial of pembrolizumab and binimetinib in patients with metastatic TNBC with ≤ 3 prior lines of therapy. There were two dose levels (DL) with binimetinib at 45 mg at DL 0 and 30 mg at DL -1. Results: The recommended phase II dose was the standard dose of pembrolizumab with binimetinib 30 mg twice daily. The objective response rate (ORR) was 30.4%, with a numerically higher ORR in patients without liver metastasis at 45.5%. Among patients who achieved objective responses, 80% had a duration of response &gt; 12 months and ongoing even after stopping treatment (5.4 - 69.0 months). Patients with PD-L1-positive tumors (CPS ≥ 10) were more likely to respond with an ORR of 66.7%. However, clinical benefit was observed in 25% of patients with PD-L1-negative tumors. Consistent with preclinical studies, 4 out of 6 patients with clinical benefit had either increased PD-L1 or decreased p-ERK expressions in serial circulating cancer-associated macrophage-like cells (CAMLs) after starting binimetinib. Conclusions: Pembrolizumab and binimetinib at 30 mg are safe with manageable toxicities. Promising activity was observed in patients without liver metastases. Future larger clinical trials are warranted to further evaluate the efficacy of this chemotherapy-free combination.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"3 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143575433","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 : 2025-03-07DOI: 10.1158/1078-0432.ccr-24-3490
Wenjie Xiong, Yuting Yan, Tingyu Wang, Weiwei Sui, Ying Yu, Tengteng Yu, Rui Lyu, Yi Wang, Wei Liu, Huimin Liu, Gang An, Yan Xu, Wenyang Huang, Dehui Zou, Lugui Qiu, Shuhua Yi
Purpose: Waldenström macroglobulinemia (WM) is a rare type of lymphoma, with no optimal treatment. BTK inhibitor have shown promising outcomes, yet achieving deep remission (VGPR or CR) remains challenging and time-limited therapy with proteasome-inhibition has not been reported. We conducted a phase 2 clinical trial (NCT04463953) to evaluate the efficacy and safety of combining zanubrutinib, ixazomib and dexamethasone (ZID) in newly diagnosed WM patients. Patients and Methods: 27 patients were enrolled in the study. Patients received ZID induction therapy for up to six 28-days’ cycles, followed by consolidation therapy up to total 24 cycles. The primary endpoint was the deep remission rate. Results: Overall, 24 of 27 enrolled patients completed induction treatment. One patient (4.2%) achieved CR. 10 patients (41.6%) achieved VGPR. The overall, major and deep remission rates were 100%, 95.8% and 45.8%, respectively. The median time to response was 2 months (range, 1-5). Five of 22 patients had CXCR4 mutation, with no disparity in the deep remission between the patients with/without CXCR4 mutation (40% vs 50%, P=0.594). The median abnormal lymphocyte (7.6% vs 1.6%, P =0.0019) and plasma cells (0.28% to 0.02%, P =0.0306) in bone marrow were significantly reduced after treatment. With a median follow-up of 30.9 months (range, 15-42). The estimated median PFS and OS were 40 months (95% CI:35.5-44.5) and not reached, respectively, with no difference in patients with/without CXCR4mutations. The most common AE was hematological toxicity. Conclusion: ZID regimen might offer deep remission and provided a time-limited BTKi therarpy in WM patients<SPAN style="font-weight: 400;">. </SPAN>
{"title":"Zanubrutinib plus Ixazomib and Dexamethasone in newly diagnosed symptomatic Waldenström macroglobulinemia:a phase II study","authors":"Wenjie Xiong, Yuting Yan, Tingyu Wang, Weiwei Sui, Ying Yu, Tengteng Yu, Rui Lyu, Yi Wang, Wei Liu, Huimin Liu, Gang An, Yan Xu, Wenyang Huang, Dehui Zou, Lugui Qiu, Shuhua Yi","doi":"10.1158/1078-0432.ccr-24-3490","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3490","url":null,"abstract":"Purpose: Waldenström macroglobulinemia (WM) is a rare type of lymphoma, with no optimal treatment. BTK inhibitor have shown promising outcomes, yet achieving deep remission (VGPR or CR) remains challenging and time-limited therapy with proteasome-inhibition has not been reported. We conducted a phase 2 clinical trial (NCT04463953) to evaluate the efficacy and safety of combining zanubrutinib, ixazomib and dexamethasone (ZID) in newly diagnosed WM patients. Patients and Methods: 27 patients were enrolled in the study. Patients received ZID induction therapy for up to six 28-days’ cycles, followed by consolidation therapy up to total 24 cycles. The primary endpoint was the deep remission rate. Results: Overall, 24 of 27 enrolled patients completed induction treatment. One patient (4.2%) achieved CR. 10 patients (41.6%) achieved VGPR. The overall, major and deep remission rates were 100%, 95.8% and 45.8%, respectively. The median time to response was 2 months (range, 1-5). Five of 22 patients had CXCR4 mutation, with no disparity in the deep remission between the patients with/without CXCR4 mutation (40% vs 50%, P=0.594). The median abnormal lymphocyte (7.6% vs 1.6%, P =0.0019) and plasma cells (0.28% to 0.02%, P =0.0306) in bone marrow were significantly reduced after treatment. With a median follow-up of 30.9 months (range, 15-42). The estimated median PFS and OS were 40 months (95% CI:35.5-44.5) and not reached, respectively, with no difference in patients with/without CXCR4mutations. The most common AE was hematological toxicity. Conclusion: ZID regimen might offer deep remission and provided a time-limited BTKi therarpy in WM patients&lt;SPAN style=\"font-weight: 400;\"&gt;. &lt;/SPAN&gt;","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"27 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143575434","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 : 2025-03-06DOI: 10.1158/1078-0432.CCR-24-3347
Ioannis P Trontzas, Mengni He, Anna Wurtz, Charles J Robbins, Nathaniel Robinson, Katherine Bates, Matthew Liu, Thazin N Aung, Liam Scott, Nay Chan, Sneha Burela, Jacob Schillo, Daniel C Liebler, Salisha Hill, Ryan D Morrison, Ioannis Vathiotis, Konstantinos N Syrigos, Sarah B Goldberg, Katerina Politi, David L Rimm
Background: Antibody-drug conjugates (ADCs) are a promising approach for the management of patients with non-small cell lung cancer (NSCLC). However, only a small subset of patients derive benefit from these therapies.
Patients and methods: We employed quantitative immunofluorescence (QIF) assays to measure the levels of four ADC target proteins (HER2, TROP2, HER3, EGFR) in three NSCLC tissue microarray cohorts stratified according to EGFR mutation (EGFRmut (n=83), EGFRwt (n=128), and EGFR unknown (n=232)). Assay limits were established by mass spectrometry on standard cell lines.
Results: All four targets demonstrated a broad and comparable dynamic range of expression in all three cohorts. High proportions of cases were above assay limits for all targets. Comparison of target expression showed a significant association of HER2 with EGFR expression and a non-significant association with EGFR mutation (p=0.0005 and 0.14, respectively). TROP2 expression was not associated with EGFR expression or mutation. HER3 demonstrated a significant negative correlation with EGFR mutation, but no significant association with EGFR expression (p<0.0001 and 0.9869, respectively). EGFR expression was significantly associated with EGFR mutation (p=0.047).
Conclusions: ADC targets are highly expressed in NSCLC, implying that the benefit from these agents may be broad. Benefit from these therapies may go beyond mutation status and fully quantitative approaches may help to select patients for ADC targeting. Inter-target correlation may provide insight on the underlying signaling pathways and/or treatment-related resistant mechanisms. In the future, QIF may be a valuable tool to select ADC treatment sequence.
{"title":"Quantitative Protein Expression of Antibody-Drug Conjugate Targets in EGFR Mutated and Wild-Type Non-Small Cell Lung Cancer.","authors":"Ioannis P Trontzas, Mengni He, Anna Wurtz, Charles J Robbins, Nathaniel Robinson, Katherine Bates, Matthew Liu, Thazin N Aung, Liam Scott, Nay Chan, Sneha Burela, Jacob Schillo, Daniel C Liebler, Salisha Hill, Ryan D Morrison, Ioannis Vathiotis, Konstantinos N Syrigos, Sarah B Goldberg, Katerina Politi, David L Rimm","doi":"10.1158/1078-0432.CCR-24-3347","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-3347","url":null,"abstract":"<p><strong>Background: </strong>Antibody-drug conjugates (ADCs) are a promising approach for the management of patients with non-small cell lung cancer (NSCLC). However, only a small subset of patients derive benefit from these therapies.</p><p><strong>Patients and methods: </strong>We employed quantitative immunofluorescence (QIF) assays to measure the levels of four ADC target proteins (HER2, TROP2, HER3, EGFR) in three NSCLC tissue microarray cohorts stratified according to EGFR mutation (EGFRmut (n=83), EGFRwt (n=128), and EGFR unknown (n=232)). Assay limits were established by mass spectrometry on standard cell lines.</p><p><strong>Results: </strong>All four targets demonstrated a broad and comparable dynamic range of expression in all three cohorts. High proportions of cases were above assay limits for all targets. Comparison of target expression showed a significant association of HER2 with EGFR expression and a non-significant association with EGFR mutation (p=0.0005 and 0.14, respectively). TROP2 expression was not associated with EGFR expression or mutation. HER3 demonstrated a significant negative correlation with EGFR mutation, but no significant association with EGFR expression (p<0.0001 and 0.9869, respectively). EGFR expression was significantly associated with EGFR mutation (p=0.047).</p><p><strong>Conclusions: </strong>ADC targets are highly expressed in NSCLC, implying that the benefit from these agents may be broad. Benefit from these therapies may go beyond mutation status and fully quantitative approaches may help to select patients for ADC targeting. Inter-target correlation may provide insight on the underlying signaling pathways and/or treatment-related resistant mechanisms. In the future, QIF may be a valuable tool to select ADC treatment sequence.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566198","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 : 2025-03-05DOI: 10.1158/1078-0432.ccr-24-2618
Sumanta K. Pal, Alice Bernard-Tessier, Peter Grell, Xin Gao, Ritesh R. Kotecha, Joel Picus, Filippo de Braud, Shunji Takahashi, Alvin Wong, Cristina Suárez, Javier A. Otero, Nicole Kundamal, Xin Yang, Sherif Sharaby, Mike Roy, Patrizia Barzaghi-Rinaudo, Nizar M. Tannir
Background: Mutations or silencing of the von Hippel Lindau (VHL) tumor suppressor gene accumulates hypoxia-inducible factors (HIFs). HIF-2α is implicated in the oncogenesis of ~50% of patients with clear cell renal cell carcinoma (ccRCC) but, has been considered “undruggable”. DFF332, an orally administered novel allosteric inhibitor of HIF-2α showed dose-dependent antitumor efficacy in preclinical models of ccRCC. Methods: This first-in-human study evaluated the safety, tolerability, antitumor activity, pharmacokinetics, and pharmacodynamics of DFF332 in patients with heavily pretreated advanced ccRCC. Preliminary data from the dose escalation of DFF332 monotherapy, administered orally at 50 or 100 mg weekly or 25, 50, 100, or 150 mg once daily in 28-day treatment cycles is reported. Results: As of January 15, 2024, 40 patients (median age, 62.5 years) received DFF332 for a median duration of 12.1 weeks. Overall, 2 patients (5%) achieved a partial response and 19 (48%) achieved stable disease as the best overall response. DFF332 showed a favorable safety profile, with treatment-related adverse events (TRAEs) occurring in 25 patients (63%). Only 5 patients (13%) experienced treatment-related anemia, and no hypoxia was observed. The only serious TRAE, hypertension, was reported in 1 patient. The maximum tolerated dose wasn’t reached. Conclusions: While clinical responses were limited in the doses evaluated, dose exploration halted prematurely, making it difficult to draw definitive conclusions about the efficacy of DFF332. Further investigation is required to establish a recommended dose regimen, assess its efficacy and safety, and evaluate its full potential as a partner in combination studies.
{"title":"A phase I dose escalation study of the HIF-2 alpha inhibitor DFF332 in patients with advanced clear cell renal cell carcinoma","authors":"Sumanta K. Pal, Alice Bernard-Tessier, Peter Grell, Xin Gao, Ritesh R. Kotecha, Joel Picus, Filippo de Braud, Shunji Takahashi, Alvin Wong, Cristina Suárez, Javier A. Otero, Nicole Kundamal, Xin Yang, Sherif Sharaby, Mike Roy, Patrizia Barzaghi-Rinaudo, Nizar M. Tannir","doi":"10.1158/1078-0432.ccr-24-2618","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2618","url":null,"abstract":"Background: Mutations or silencing of the von Hippel Lindau (VHL) tumor suppressor gene accumulates hypoxia-inducible factors (HIFs). HIF-2α is implicated in the oncogenesis of ~50% of patients with clear cell renal cell carcinoma (ccRCC) but, has been considered “undruggable”. DFF332, an orally administered novel allosteric inhibitor of HIF-2α showed dose-dependent antitumor efficacy in preclinical models of ccRCC. Methods: This first-in-human study evaluated the safety, tolerability, antitumor activity, pharmacokinetics, and pharmacodynamics of DFF332 in patients with heavily pretreated advanced ccRCC. Preliminary data from the dose escalation of DFF332 monotherapy, administered orally at 50 or 100 mg weekly or 25, 50, 100, or 150 mg once daily in 28-day treatment cycles is reported. Results: As of January 15, 2024, 40 patients (median age, 62.5 years) received DFF332 for a median duration of 12.1 weeks. Overall, 2 patients (5%) achieved a partial response and 19 (48%) achieved stable disease as the best overall response. DFF332 showed a favorable safety profile, with treatment-related adverse events (TRAEs) occurring in 25 patients (63%). Only 5 patients (13%) experienced treatment-related anemia, and no hypoxia was observed. The only serious TRAE, hypertension, was reported in 1 patient. The maximum tolerated dose wasn’t reached. Conclusions: While clinical responses were limited in the doses evaluated, dose exploration halted prematurely, making it difficult to draw definitive conclusions about the efficacy of DFF332. Further investigation is required to establish a recommended dose regimen, assess its efficacy and safety, and evaluate its full potential as a partner in combination studies.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"15 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143560642","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 : 2025-03-05DOI: 10.1158/1078-0432.ccr-24-3753
Junsik Park, Je-Gun Joung, Myong Cheol Lim, Jungbok Lee, Byoung-Gie Kim, Jae-Weon Kim, So Jin Shin, Sunghoon Kim, Eunhyang Park, Chel Hun Choi, Hee Seung Kim, Sang Yoon Park, Jung-Yun Lee
Purpose: This open-label, investigator-initiated, phase II study was conducted to evaluate the safety, survival and neoadjuvant outcomes of NAC combined with dual immune checkpoint inhibitors in advanced-stage EOC. Patients and Methods: Between June 2019 and July 2021, 45 patients with unresectable stage III–IV EOC were enrolled. The patients received three cycles of NAC combined with durvalumab and tremelimumab. All patients underwent interval debulking surgery and received three cycles of durvalumab and adjuvant chemotherapy, followed by 12 cycles of durvalumab as maintenance therapy. The primary endpoint was the 12-month progression-free survival (PFS) rate; the secondary endpoints were the objective response rate (ORR) after NAC, a chemotherapy response score (CRS), pathologic complete response (pCR), overall survival (OS), and safety. The pre-planned exploratory analyses assessed the lymphocyte infiltration, PD-L1 expression, and genomic profiles of pre-treatment tumors. Results: The 12-month PFS rate was 65.9% (95% CI, 52.8–NE), while the 24- and 30-month PFS rates were 38.6% (95% CI, 26.7–NE) and 36.4% (95% CI, 24.7–NE), respectively. After NAC, the ORR was 86.7%, while 14 patients (31.1%) had a CRS 3, and five (11.1%) achieved pCR. The 30-month OS rate was 87.7%. The most common grade ≥ 3 adverse events was neutropenia (26.7%). In an exploratory analysis, patients with pre-NAC tumors showing PD-L1 (CPS) ≥1, high Mutation Signature 3, and a high extracellular matrix signature demonstrated improved PFS outcomes. Conclusions: NAC combined with dual immune checkpoint inhibitors is feasible for advanced-stage EOC and shows promising activity with a durable clinical response.
{"title":"Neoadjuvant Chemotherapy with Dual Immune Checkpoint Inhibitors for Advanced-Stage Ovarian Cancer: Final Analysis of TRU-D Phase II Nonrandomized Clinical Trial","authors":"Junsik Park, Je-Gun Joung, Myong Cheol Lim, Jungbok Lee, Byoung-Gie Kim, Jae-Weon Kim, So Jin Shin, Sunghoon Kim, Eunhyang Park, Chel Hun Choi, Hee Seung Kim, Sang Yoon Park, Jung-Yun Lee","doi":"10.1158/1078-0432.ccr-24-3753","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3753","url":null,"abstract":"Purpose: This open-label, investigator-initiated, phase II study was conducted to evaluate the safety, survival and neoadjuvant outcomes of NAC combined with dual immune checkpoint inhibitors in advanced-stage EOC. Patients and Methods: Between June 2019 and July 2021, 45 patients with unresectable stage III–IV EOC were enrolled. The patients received three cycles of NAC combined with durvalumab and tremelimumab. All patients underwent interval debulking surgery and received three cycles of durvalumab and adjuvant chemotherapy, followed by 12 cycles of durvalumab as maintenance therapy. The primary endpoint was the 12-month progression-free survival (PFS) rate; the secondary endpoints were the objective response rate (ORR) after NAC, a chemotherapy response score (CRS), pathologic complete response (pCR), overall survival (OS), and safety. The pre-planned exploratory analyses assessed the lymphocyte infiltration, PD-L1 expression, and genomic profiles of pre-treatment tumors. Results: The 12-month PFS rate was 65.9% (95% CI, 52.8–NE), while the 24- and 30-month PFS rates were 38.6% (95% CI, 26.7–NE) and 36.4% (95% CI, 24.7–NE), respectively. After NAC, the ORR was 86.7%, while 14 patients (31.1%) had a CRS 3, and five (11.1%) achieved pCR. The 30-month OS rate was 87.7%. The most common grade ≥ 3 adverse events was neutropenia (26.7%). In an exploratory analysis, patients with pre-NAC tumors showing PD-L1 (CPS) ≥1, high Mutation Signature 3, and a high extracellular matrix signature demonstrated improved PFS outcomes. Conclusions: NAC combined with dual immune checkpoint inhibitors is feasible for advanced-stage EOC and shows promising activity with a durable clinical response.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"303 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143560643","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 : 2025-03-04DOI: 10.1158/1078-0432.CCR-24-4368
Hao Yuan, Qun Chen, Kuirong Jiang, Courtney W Houchen, Yuqing Zhang, Min Li
The shared HLA-bound neoepitopes in pancreatic ductal adenocarcinoma (PDAC) represent a novel class of non-canonical antigens with single amino acid substitutions, resulting from translational errors. These peptides, shared across PDAC patients, showed higher immunogenicity than wild-type counterparts, offering potential candidates for specific immunotherapy development in PDAC.
{"title":"Shared HLA-Bound Neoepitopes Are New Targets for Pancreatic Cancer Immunotherapy.","authors":"Hao Yuan, Qun Chen, Kuirong Jiang, Courtney W Houchen, Yuqing Zhang, Min Li","doi":"10.1158/1078-0432.CCR-24-4368","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-4368","url":null,"abstract":"<p><p>The shared HLA-bound neoepitopes in pancreatic ductal adenocarcinoma (PDAC) represent a novel class of non-canonical antigens with single amino acid substitutions, resulting from translational errors. These peptides, shared across PDAC patients, showed higher immunogenicity than wild-type counterparts, offering potential candidates for specific immunotherapy development in PDAC.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143540408","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}
Purpose: Neoadjuvant anti-PD-1 immunotherapy combined with chemotherapy has shown promising pathological responses in various cancers, including oral squamous cell carcinoma (OSCC). However, the pathological response of lymph node (LN) metastases remains poorly understood. This study aims to systematically evaluate the pathological response rates (pRRs) of LN metastases in OSCC patients and identify potential targets to improve therapeutic outcomes. Experimental design: We assessed the pRRs of LN metastases and matched primary tumors (PTs) in OSCC patients enrolled in a randomized, two-arm, phase II clinical trial (NCT04649476). Single-cell and spatial transcriptomics and multiplex immunohistochemistry were performed to analyze the tumor microenvironment and identify potential therapeutic targets in LN metastases. A neoadjuvant orthotopic OSCC mouse model was established to evaluate the therapeutic potential of these targets. Results: We observed significant heterogeneity in pathological regression of LN metastases, with lower pRRs compared to PTs. pRRs in LN metastases were correlated with overall and disease-free survival in OSCC patients. We identified an abundance of macrophages in LN metastases exhibiting an unfolded protein response and activated PERK signaling. These macrophages contributed to an extracellular matrix-enriched microenvironment through interactions with fibroblasts, which hindered T cell-mediated cytotoxicity. Pharmacological inhibition of the PERK pathway significantly enhanced anti-PD-1 therapy in LN metastases and PTs in the mouse model. Conclusions: Our study confirms that the pathological response of LN metastases in OSCC patients undergoing neoadjuvant immunotherapy or immunochemotherapy is inferior to that of PTs. It suggests targeting the PERK pathway in macrophages could be a potential strategy to enhance treatment outcomes.
{"title":"PERK+ macrophages drive immunotherapy resistance in lymph node metastases of oral squamous cell carcinoma","authors":"Wei Zhang, Jin-Bang Li, Hai-Ming Liu, Kui-Ming Wang, Bo-Lin Xiao, Yi-Man Wang, Jia-Jie Liang, Jun Zeng, Lin-Zhou Zhang, Yang-Ying-Fan Feng, Qiu-Yun Fu, Xin-Xin Wang, Yu-Tong Liu, Xiao-Xia Cheng, Jing Li, Yu-Ying Zhang, Gao Zhang, Jia-Li Zhang, Zi-Li Yu, Zhe Shao, Xue-Peng Xiong, Jun Jia, Bing Liu, Gang Chen","doi":"10.1158/1078-0432.ccr-24-3135","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3135","url":null,"abstract":"Purpose: Neoadjuvant anti-PD-1 immunotherapy combined with chemotherapy has shown promising pathological responses in various cancers, including oral squamous cell carcinoma (OSCC). However, the pathological response of lymph node (LN) metastases remains poorly understood. This study aims to systematically evaluate the pathological response rates (pRRs) of LN metastases in OSCC patients and identify potential targets to improve therapeutic outcomes. Experimental design: We assessed the pRRs of LN metastases and matched primary tumors (PTs) in OSCC patients enrolled in a randomized, two-arm, phase II clinical trial (NCT04649476). Single-cell and spatial transcriptomics and multiplex immunohistochemistry were performed to analyze the tumor microenvironment and identify potential therapeutic targets in LN metastases. A neoadjuvant orthotopic OSCC mouse model was established to evaluate the therapeutic potential of these targets. Results: We observed significant heterogeneity in pathological regression of LN metastases, with lower pRRs compared to PTs. pRRs in LN metastases were correlated with overall and disease-free survival in OSCC patients. We identified an abundance of macrophages in LN metastases exhibiting an unfolded protein response and activated PERK signaling. These macrophages contributed to an extracellular matrix-enriched microenvironment through interactions with fibroblasts, which hindered T cell-mediated cytotoxicity. Pharmacological inhibition of the PERK pathway significantly enhanced anti-PD-1 therapy in LN metastases and PTs in the mouse model. Conclusions: Our study confirms that the pathological response of LN metastases in OSCC patients undergoing neoadjuvant immunotherapy or immunochemotherapy is inferior to that of PTs. It suggests targeting the PERK pathway in macrophages could be a potential strategy to enhance treatment outcomes.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"35 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143546207","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 : 2025-03-04DOI: 10.1158/1078-0432.ccr-24-3357
Timil H. Patel, Amy Corneli, Pamela Balcazar, Craig Lipset, Sara B. Calvert, Sabrena Mervin-Blake, Vinit Nalawade, Paul G. Kluetz
The COVID-19 pandemic disrupted cancer clinical trials, prompting sponsors to adopt decentralized clinical trial (DCT) elements to ensure patient safety and trial continuity. Supported by FDA emergency guidance, the FDA Oncology Center of Excellence, in collaboration with the Clinical Trials Transformation Initiative (CTTI), conducted an assessment of DCT elements in cancer trials leading to FDA approval during the pandemic. Between December 6, 2022, and January 17, 2023, CTTI collected survey data from trial sponsors about DCT elements used in response to the pandemic, implementation challenges, and anticipated future use. Out of 52 eligible trials, 19 responses were received from 13 sponsors, predominantly large pharmaceutical companies. The majority of trials (89%) included both U.S. and international sites, and nearly all sponsors (95%) adopted at least one DCT element during the pandemic. Key DCT elements included remote site monitoring (89%), telemedicine (68%), remote laboratory assessments (63%), and remote distribution of investigational products (58%). Main challenges encountered included institutional policies (83%), technology adoption (61%), and regulatory restrictions (56%). Despite challenges, sponsors showed strong intent to continue DCT use, especially for remote monitoring, patient-reported outcomes collection, and telemedicine. This study demonstrates the viability of DCT elements for generating FDA-approvable data, suggesting potential for expanded trial access and reduced patient burden. Continued attention to site-level challenges is needed to sustain DCT adoption in cancer clinical trials.
{"title":"Adoption of Decentralized Trial Elements in Cancer Clinical Trials Supporting FDA Approvals During COVID-19","authors":"Timil H. Patel, Amy Corneli, Pamela Balcazar, Craig Lipset, Sara B. Calvert, Sabrena Mervin-Blake, Vinit Nalawade, Paul G. Kluetz","doi":"10.1158/1078-0432.ccr-24-3357","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3357","url":null,"abstract":"The COVID-19 pandemic disrupted cancer clinical trials, prompting sponsors to adopt decentralized clinical trial (DCT) elements to ensure patient safety and trial continuity. Supported by FDA emergency guidance, the FDA Oncology Center of Excellence, in collaboration with the Clinical Trials Transformation Initiative (CTTI), conducted an assessment of DCT elements in cancer trials leading to FDA approval during the pandemic. Between December 6, 2022, and January 17, 2023, CTTI collected survey data from trial sponsors about DCT elements used in response to the pandemic, implementation challenges, and anticipated future use. Out of 52 eligible trials, 19 responses were received from 13 sponsors, predominantly large pharmaceutical companies. The majority of trials (89%) included both U.S. and international sites, and nearly all sponsors (95%) adopted at least one DCT element during the pandemic. Key DCT elements included remote site monitoring (89%), telemedicine (68%), remote laboratory assessments (63%), and remote distribution of investigational products (58%). Main challenges encountered included institutional policies (83%), technology adoption (61%), and regulatory restrictions (56%). Despite challenges, sponsors showed strong intent to continue DCT use, especially for remote monitoring, patient-reported outcomes collection, and telemedicine. This study demonstrates the viability of DCT elements for generating FDA-approvable data, suggesting potential for expanded trial access and reduced patient burden. Continued attention to site-level challenges is needed to sustain DCT adoption in cancer clinical trials.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"16 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143546206","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}
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