Clinical Cancer Research最新文献

{"title":"Facts & Hopes: towards the next quantum leap in melanoma.","authors":"Keith T Flaherty,Andrew E Aplin,Michael A Davies,Nir Hacohen,Meenhard Herlyn,Dave Hoon,Patrick Hwu,Michal Lotem,James Mulé,Jennifer A Wargo,David E Fisher","doi":"10.1158/1078-0432.ccr-25-0278","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0278","url":null,"abstract":"Outcomes from advanced melanoma, the deadliest of the skin cancers arising from melanocytes and capable of widely metastasizing, have greatly improved with death rates decreasing for AJCC stage 4 melanoma patients by 3-5 percent annually over the past 10 years (1,2). This improvement is a result of advances in both targeted therapy and immunotherapy (Fig 1). BRAF and MEK inhibitors for advanced melanoma have led the way for targeted cancer strategies and first- in-class approvals for immune checkpoint blockers targeting CTLA4, PD1, and LAG3, T cell engager therapy targeting the antigen gp100 and tumor-infiltrating lymphocyte therapy (3). All of the preceding have contributed to enhanced outcomes including long-term durable responses in up to half of patients with advanced disease. In addition, adjuvant and neoadjuvant approaches are reducing the risk of relapse in patients with stage II and III disease. Because of its immunogenicity and defined targetable mutations, melanoma drug development has led the way for novel approaches in cancer research. Yet additional approaches are needed for patients with recurrent or non-responsive disease or rare subtypes including mucosal, acral and uveal melanomas. Progress in modified T cells, including TCR, CAR-T and CRISPR gene editing strategies holds promise for future therapeutics. Continued understanding of the molecular and immune tumor microenvironment and heterogeneity, understanding the microbiome and numerous diverse approaches to topics ranging from prevention, to mechanisms of treatment resistance and novel therapeutic approaches, will optimize opportunities to further decrease melanoma mortality.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"94 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144122221","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}

{"title":"A phase II study of neoadjuvant GVAX and cyclophosphamide combined with nivolumab and SBRT followed by surgery in borderline resectable pancreatic adenocarcinoma.","authors":"Parul Agarwal,Matthew Guo,Kabeer Munjal,Hanfei Qi,Rose Parkinson,Anna Ferguson,Christina Mitchell,Jeanne Harrison,Robert A Anders,Elizabeth D Thompson,Hao Wang,Ana De Jesus,Lei Zheng,Jin He,Richard Burkhart,Amol Narang,Ben George,Elizabeth M Jaffee,Mark Yarchoan,Daniel Laheru,Arsen Osipov","doi":"10.1158/1078-0432.ccr-24-3403","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3403","url":null,"abstract":"PURPOSEBR-PDAC is treated with perioperative chemotherapy and surgical resection +/- SBRT, but long-term survival is rare. GVAX is a GM-CSF- secreting vaccine that activates T-cell immunity against tumor-associated antigens. This multi- center phase II clinical trial evaluated the safety and immune effects of GVAX/Cy/nivolumab and SBRT on the PDAC TME.METHODSPatients received neoadjuvant mFOLFIRINOX or gemcitabine/nab-paclitaxel if intolerant to mFOLFIRINOX followed by combination immunotherapy and SBRT before surgical resection. The primary endpoint was CD8+ T-cell density in surgical specimens compared with in historical controls treated with neoadjuvant mFOLFIRINOX and SBRT. Pathologic response rate, overall survival, and exploratory immune evaluation of the TME is also reported.RESULTS31 patients were enrolled from January 2018 to July 2021. 18 patients received at least one dose of combined immunotherapy. Fourteen patients underwent definitive surgical resection and one complete pathologic complete response was observed. At a median follow-up of 19.5 months, median OS was 20.4 months (95% CI 18.2, NA). There was no difference in the mean CD8 T cell density between study patients as compared to historical control patients. Nonsignificant increases in the abundance score for specific immune cell subsets were observed in responders as compared to non-responders.CONCLUSIONSThe addition of combined immunotherapy and SBRT was safe and feasible in this patient population. No difference was observed in the mean CD8 T cell density between study patients and historical controls. These findings support the need for better characterization of how neoadjuvant immunotherapy may shift the phenotype of the PDAC TME.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"20 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144122216","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}

{"title":"Mechanism of Initial Favorable Response to Decitabine in TP53-Mutated MDS/AML and Potential Mechanisms of Subsequent Relapse","authors":"Nelson K.L. Ng, Stephen S.Y. Lam, Lichuan Zheng, Xingliang Liu, Mingxuan Liang, Lam Ng, Koon C. Chan, Chun X. Zhang, Rachel L.S. Tse, Arthur K.L. Cheung, Ho-Wan Ip, Chun H. Au, Edmond S.K. Ma, Chi T. Ng, Ying Ni, Run S. Li, Guang S. Ling, Suet Y. Leung, Asif Javed, Anskar Y.H. Leung","doi":"10.1158/1078-0432.ccr-24-3192","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3192","url":null,"abstract":"Purpose: Myelodysplastic syndrome and acute myeloid leukemia with complex and monosomy karyotypes show a high prevalence of TP53 mutations (TP53m), poor response to induction chemotherapy, and adverse outcomes. These diseases may respond to decitabine, but the mechanisms are presently unclear. Experimental Design: Patients with myelodysplastic syndrome and acute myeloid leukemia were treated with decitabine for 10 days in a phase II clinical study. In this study, we collected serial samples from patients before and at the completion of decitabine treatment, morphologic remission, and relapse. The samples were interrogated with targeted myeloid panel sequencing, nanopore DNA cytosine methylation sequencing, and single-cell transcriptomics to investigate potential interactions between leukemic and immune populations. Results: The integrative analysis allowed for the characterization of shifting dynamics within leukemic and immune cell populations in individual patients. Single-cell transcriptomic analyses confirmed immune activation in TP53m responders after decitabine treatment. At relapse, leukemic populations showed upregulation of MYC signaling and heat shock response, whereas T cells showed an exhaustion signature. Conclusions: Our work highlighted the complex interplay between leukemic and immune populations in TP53m patients upon decitabine treatment that might account for clinical responses and subsequent relapses.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"130 1","pages":"OF1-OF14"},"PeriodicalIF":11.5,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144113898","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}

{"title":"Early Postoperative Minimal Residual Disease Detection with MAESTRO Is Associated with Recurrence and Worse Survival in Patients with Head and Neck Cancer","authors":"Edward S. Sim, Justin Rhoades, Kan Xiong, Laurel Walsh, Andjela Crnjac, Timothy Blewett, Yana Al-Inaya, Julia Mendel, Daniel A. Ruiz-Torres, Vasileios Efthymiou, Gjystina Lumaj, William J. Benjamin, G. Mike Makrigiorgos, Shervin Tabrizi, Viktor A. Adalsteinsson, Daniel L. Faden","doi":"10.1158/1078-0432.ccr-25-0307","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0307","url":null,"abstract":"Purpose: Although ctDNA is a promising biomarker for minimal residual disease (MRD) detection in head and neck squamous cell carcinoma (HNSCC), more sensitive assays are needed for accurate MRD detection at clinically relevant time points. Ultrasensitive MRD detection early after surgery could guide adjuvant therapy decisions, but early ctDNA dynamics are poorly understood. Experimental Design: We applied minor allele–enriched sequencing through recognition oligonucleotides (MAESTRO), a whole-genome, tumor-informed, mutation enrichment sequencing assay, in a pooled testing format called MAESTRO-Pool, to plasma samples from patients with HNSCC collected shortly after surgery and during surveillance. We evaluated whether early MRD detection could predict outcomes. Results: Among 24 patients with predominantly human papillomavirus–independent (95.8%) HNSCC, rapid ctDNA clearance occurred by the first postoperative sample (1–3 days postoperatively) in nine patients without an event (recurrence or death). Thirteen of fifteen patients with an event were MRD-positive (positive predictive value = 92.9%; negative predictive value = 80%) with a median tumor fraction (TFx) of 54 parts per million (ppm; range 6–1,177 ppm). In the first and last samples of the early postoperative window, 8/13 and 10/13 patients, respectively, had TFx below 100 ppm, the detection limit of leading commercial assays. Early MRD detection correlated with worse overall survival (HR, 8.3; 95% confidence interval, 1.1–66.1; P = 0.02) and event-free survival (HR, 27.4; 95% confidence interval, 3.5–214.5; P < 0.0001) independent of high-risk pathology. Conclusions: Early postoperative MRD detection by MAESTRO was associated with recurrence and worse survival. Given the ultralow TFxs observed, ultrasensitive assays will be essential for reliable MRD detection during early postoperative time points to enable personalized adjuvant therapy decision-making in HNSCC. See related article by Bryan et al., p. XX .","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"131 1","pages":"OF1-OF9"},"PeriodicalIF":11.5,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144097102","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}

{"title":"Improving global access to genomic profiling in rare pediatric cancers.","authors":"Sameer Farouk Sait,Tara J O'Donohue,Tejus Bale,Anita Bowman,Katherine Hill,Emily Stockfisch,Alexandra Giantini-Larsen,Tina Alano,Marc Rosenblum,Jamal Benhamida,Ira J Dunkel,Michael Berger,Maria E Arcila,Marc Ladanyi,Michael V Ortiz,Julia Glade Bender,Alexandra Miller,Debyani Chakravarty,Kelly Cavender,Benjamin Preiser,Hongxin Zhang,Andrew L Kung,David B Solit,Matthias A Karajannis,Neerav N Shukla","doi":"10.1158/1078-0432.ccr-24-3910","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3910","url":null,"abstract":"BACKGROUNDTo address financial barriers that limit access to genomic profiling and precision medicine, philanthropy supported clinical genomic testing was offered worldwide at no cost to patients with select rare cancers via the Make-an-IMPACT program. Herein, we report our findings in pediatric patients with solid or central nervous system (CNS) tumors.METHODSTumor DNA or CSF-derived circulating tumor DNA (CSF ctDNA) was analyzed using the MSK-IMPACT assay, supplemented by targeted RNA panel sequencing in select cases. Results were returned to the patients/families and treating oncologists.RESULTS63 patients from 11 countries had successful MSK-IMPACT testing. The results provided clinically relevant new diagnostic or prognostic information in 41% and 38% of solid and CNS tumor patients, respectively. Potentially therapeutically actionable alterations were identified in 44% of pediatric solid tumor and 21% of pediatric CSF ctDNA samples, respectively. Four patients subsequently received molecularly guided therapy, resulting in partial responses in two and prolonged stable disease in one. Serial tumor and CSF sampling identified resistance mutations in two patients, informing additional molecular targeted therapy recommendations.CONCLUSIONSThe Make-an-IMPACT program provided global access to state-of-the-art tumor and CSF genomic profiling across a diverse cohort of pediatric cancer patients, providing clinically relevant and actionable diagnostic, prognostic and therapeutic information reported in real time to patients and local physicians.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"56 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144103616","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}

{"title":"Direct Comparison of Alternative Blood-Based Approaches for Early Detection and Diagnosis of HPV-Associated Head and Neck Cancers","authors":"Michael E. Bryan, Ling Aye, Dipon Das, Shun Hirayama, Yana Al-Inaya, Julia Mendel, Saskia Naegele, Vasileios Efthymiou, Bayan Alzumaili, William C. Faquin, Peter M. Sadow, Derrick Lin, Mark A. Varvares, Allen L. Feng, Daniel G. Deschler, Annie W. Chan, Jonathan Paly, Jong C. Park, Thomas Roberts, Ross Merkin, Sambit K. Mishra, Lea Kröller, Birgitta Michels, A. John Iafrate, Lori J. Wirth, Viktor A. Adalsteinsson, Mathew Crowson, Tim Waterboer, Lisa Mirabello, Michael S. Lawrence, Zoe Guan, Adam S. Fisch, Jeremy D. Richmon, Daniel L. Faden","doi":"10.1158/1078-0432.ccr-24-2525","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2525","url":null,"abstract":"Purpose: The incidence of human papillomavirus (HPV)–associated head and neck squamous cell carcinoma (HPV + HNSCC) is increasing in the United States. Currently, there are no early detection approaches for HPV + HNSCC. Two blood-based analytes for early detection and diagnosis of HPV + HNSCC, circulating tumor HPV DNA (ctHPVDNA) and HPV early protein antibodies (HPV Ab), show promise, yet current approaches lack adequate diagnostic accuracy for broad clinical utility. Further, performance metrics across various assays for detecting these analytes alone or in combination have not been compared head-to-head. To address these limitations and knowledge gaps, we developed a multifeature HPV whole-genome sequencing (WGS) liquid biopsy for improved low-level ctHPVDNA detection. We defined the performance characteristics of this WGS-based approach and compared it head-to-head with existing blood-based HPV detection approaches to determine the optimal single or combinatorial biomarker strategy for a future prospective study of HPV + HNSCC early detection. Experimental Design: We tested blood samples from 304 participants: 152 patients with untreated incident HPV + HNSCC (77% stage I) and 152 general population control patients. We compared WGS-based ctHPVDNA detection, single-plex Droplet Digital PCR (ddPCR)–based ctHPVDNA detection, multiplex ddPCR-based ctHPVDNA detection, multiplex HPV Ab detection, and clinical standard-of-care tissue biopsy, benchmarked to gold-standard HPV + HNSCC tissue diagnosis. We then modeled the operational feasibility of these approaches as screening biomarkers for HPV + HNSCC. Results: HPV WGS sensitivity and specificity were 98.7% and 98.7%, respectively. Single-plex ddPCR sensitivity and specificity were 94.2% and 98.6%, respectively. Multiplex ddPCR sensitivity and specificity were 90.6% and 96.3%, respectively. HPV Ab sensitivity and specificity were 86.4% and 96.3%, respectively. A combinatorial approach using both HPV WGS and HPV Ab yielded a sensitivity and specificity of 87.4% and 98.8%, respectively. In a head-to-head comparison, HPV WGS demonstrated significantly improved diagnostic accuracy compared with ddPCR (Youden index for HPV WGS, 0.99 vs. ddPCR, 0.90; P < 0.001), HPV Ab (HPV WGS, 0.99 vs. HPV Ab, 0.83; P < 0.001), and clinical workup (HPV WGS, 0.99 vs. clinical workup, 0.82; P < 0.001), which was maintained when evaluating only early-stage disease cases. For men ages 55 to 74, HPV WGS yielded the lowest number needed to screen (2,903 men) and the highest positive predictive value (2.6). Conclusions: HPV WGS–based ctHPVDNA detection demonstrated the highest sensitivity, specificity, and diagnostic accuracy and thus the lowest number needed to screen and highest positive predictive value compared with ddPCR-based ctHPVDNA detection, HPV Ab–based detection, and combinatorial approaches. These results highlight the promise of HPV WGS liquid biopsy for screening and early detection of HPV +","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"28 1","pages":"OF1-OF11"},"PeriodicalIF":11.5,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144097160","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}

{"title":"Integrative Immune Signature of Complementary Circulating and Tumoral Biomarkers Maximizes the Predictive Power of Adjuvant Immunotherapeutic Benefits in High-Risk Melanoma.","authors":"Ahmad A Tarhini,Alyssa Obermayer,Sandra J Lee,William A LaFramboise,F Stephen Hodi,Arivarasan D Karunamurthy,Islam Eljilany,Dung-Tsa Chen,Patrick Hwu,Issam M El Naqa,Howard Streicher,Vernon K Sondak,Walter J Storkus,Lisa H Butterfield,Timothy I Shaw,John M Kirkwood","doi":"10.1158/1078-0432.ccr-24-3980","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3980","url":null,"abstract":"PURPOSEIpilimumab (IPI) improved outcomes for high-risk melanoma patients compared to interferon-α2b (IFN) in E1609, a phase III adjuvant trial. We hypothesized that combining candidate immune biomarkers in both tumor and circulating blood could generate a superior predictive biomarker signature.PATIENTS AND METHODSWe conducted gene expression profiling on baseline tumors of patients treated with IPI and IFN. We also performed multicolor flow cytometry to compare cellular marker expressions on thawed peripheral blood mononuclear cells and multiplex Luminex to measure serum biomarkers. We tested the expression levels of 31 genes and 40 circulating biomarkers in relation to survival outcomes. We then developed two separate multivariate Lasso-Cox regression models followed by integrative modeling of risk prediction using the prioritized biomarkers.RESULTSIn blood, enriched populations of CXCR3+CD4+ T cells, CXCR3+CD8+ T cells, CTLA4+IFN-γ+CD8+ T cells, and higher levels of CCL3 and CXCL11 were associated with significantly improved overall survival (OS) and relapse-free survival (RFS), while high levels of CTLA4+Treg (CD3+CD4+CD25hi+CD152+) and monocytic (M)-MDSC (Lin-CD33+HLA-DrloCD14+CD15+) cells correlated with worse OS and RFS. In tumor, CXCL9, CD8A, CXCL10, and INPP5D were identified as Tier-1 (P<0.05) and IDO1, IGKC, IL2RB as Tier-2 (P<0.1) biomarkers of survival. Multivariate survival analysis identified that ~50% of the risk groups were defined by circulating and tumor biomarker models, indicating complementary features of defining risk groups in IPI-treated but not in IFN-treated patients.CONCLUSIONSIntegrating candidate blood and tumor immune-related biomarkers generated a baseline signature that maximizes the prediction of immunotherapeutic benefits in reference to the compartmental biomarker signatures.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"150 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144103679","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}

{"title":"Spatial transcriptomics advances the use of canine patients in cancer research: analysis of osteosarcoma-bearing pet dogs enrolled in a clinical trial.","authors":"Jessica A Beck,Anjali Garg,Sarah Church,Christina Mazcko,Amy K LeBlanc","doi":"10.1158/1078-0432.ccr-25-0687","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0687","url":null,"abstract":"PURPOSEPet dogs spontaneously develop many of the same tumor types as humans including osteosarcoma. Recent advances in spatial transcriptomics have improved our ability to utilize formalin-fixed paraffin-embedded tissues collected at canine autopsy. These techniques allow the canine model to be investigated alongside murine models to inform human cancer research. Herein we present the first application of the GeoMx Canine Cancer Atlas to outcome-linked samples from canine patients enrolled in an osteosarcoma clinical trial.EXPERIMENTAL DESIGNA tissue microarray (TMA) of primary osteosarcoma samples was assayed using the GeoMx Digital Spatial Profiler. Samples were stratified by disease-free interval (DFI). Patients within the upper and lower tertiles were assigned to the High (n = 8) and Low DFI (n = 8) groups, respectively. Analyses included the identification of differentially expressed genes, pathway enrichment, and cell deconvolution.RESULTSGenes enriched in High DFI tumors included PTEN and CDKN1B. Low DFI tumors were enriched for NCAM1. Pathways enriched in the Low DFI group included MYC, MTORC1, and oxidative phosphorylation. High DFI tumors were enriched for interferon alpha response and allograft rejection pathways among others. Macrophages and CD8+ T cells were elevated in High DFI tumors.CONCLUSIONSGene and pathway enrichment found to be associated with disease-free interval in this study overlap with that described in human osteosarcoma patients underscoring the value of the canine model in metastatic osteosarcoma research.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"138 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144103672","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}

{"title":"Nivolumab and Relatlimab for the treatment of patients with unresectable or metastatic mismatch repair proficient colorectal cancer","authors":"Eric S. Christenson, Won Jin Ho, Daniel Shu, Jennifer N. Durham, Madelena Brancati, Heather Davis Bruning, Susan Petrie, Hao Wang, Jiayun Lu, Katherine M. Bever, Daniel Laheru, Ana De Jesus-Acosta, Ilene Browner, Ross Donehower, Michael J. Pishvaian, Nilofer Azad, Qingfeng Zhu, Alens Valentin, Jayalaxmi Suresh Babu, Alexei Hernandez, George Apostol, Yiyang Gao, Nicolas Llosa, Franck Housseau, Drew Pardoll, Elizabeth M. Jaffee, Robert Anders, Dung T. Le","doi":"10.1158/1078-0432.ccr-25-0002","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-25-0002","url":null,"abstract":"Purpose: Combined inhibition of lymphocyte-activation gene 3 (LAG-3) and programmed cell death protein 1 (PD-1) improves outcomes in patients with melanoma. Increased LAG-3 expression in colorectal cancer (CRC) correlates with reduced survival. Higher mucin and PD-L1 expression in the mismatch repair proficient (pMMR) CRC tumor microenvironment (TME) was associated with increased LAG-3 and retrospectively with prolonged progression-free survival upon PD-1 blockade. This led to the hypothesis that LAG-3/PD-1 inhibition would improve clinical outcomes in this pMMR CRC subset. Patients and Methods: NCT03642067 was a phase 2 study evaluating combining relatlimab (LAG-3 inhibitor) and nivolumab (PD-1 inhibitor) in patients with previously treated metastatic pMMR CRC. Patients were enrolled onto one of three cohorts, A: mucin/PD-L1 high, B: mucin/PD-L1 low, or C: mucin/PD-L1 unselected. The primary endpoint for each cohort was overall response rate. Results: We enrolled 59 evaluable patients; best treatment responses were partial response: 3, stable disease: 6, progressive disease: 50. Response rates did not differ significantly between cohorts. Subgroup analyses demonstrated 2 of 5 patients with lung-only metastases had a partial response. Comparison of liver and lung metastases identified higher baseline dendritic cell densities in lung lesions. Nivolumab/relatlimab resulted in increased intratumoral cytotoxic T cells. Lower baseline intratumoral Tregs and ADAM10+ cancer cells correlated with clinical response. Conclusions: This investigation did not reach its primary endpoint for any of the three treatment cohorts, but does provide critical insight into the effects of combining nivolumab/relatlimab on the CRC TME and identifies subgroups that may derive greater benefit from this combination.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"132 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144097163","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}

{"title":"The CD70-CD27 axis in cancer immunotherapy: Predictive biomarker and therapeutic target.","authors":"Ikuan Sam,Nadine Ben Hamouda,Marina Alkatrib,Cecile Gonnin,Peter J Siska,Stephane Oudard,Céleste Lebbé,Eric Tartour","doi":"10.1158/1078-0432.ccr-24-2668","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2668","url":null,"abstract":"The CD27-CD70 interaction is recognized as a positive costimulatory pathway for T cell priming and expansion. However, recent studies showed that chronic CD27-CD70 interaction in cancer can lead to apoptosis of T cells, rendering them dysfunctional. CD70 is expressed not only by hematological tumors but also by solid tumor cells. This expression is regulated by hypoxia-induced factor (HIF), Epstein-Barr virus (EBV) infection, and epithelial-mesenchymal transition. CD27 expression on intratumoral T cells identifies exhausted and dysfunctional T cells, as well as regulatory T cells with enhanced immunosuppressive activity. Given the preferential expression of CD70 on certain tumor cells, several therapeutic approaches including antibody-drug conjugate, anti-CD70 CAR T cells, and anti-CD70 monoclonal antibodies (mAb), have been investigated in various preclinical models and clinical trials. To date, the most significant clinical results are observed in hematological malignancies. However, no therapeutic tools specifically targeting the deleterious CD27-CD70 interaction have been developed. Most CD70-targeting mAb also deplete other CD70-expressing cells, such as activated T cells. Interestingly, chronic CD27-CD70 interaction results in the release of detectable soluble CD27 in patient plasma. The presence of high levels of soluble CD27 in plasma correlates with resistance to anti-PD-(L)1 in renal cancer, melanoma, and non-small cell lung cancer. Conversely, the absence of a predictive impact soluble CD27 in melanoma patients treated with the more toxic combination of anti-PD-1 and anti-CTLA-4 may justify therapeutic escalation with this regimen. Thus, the CD27-CD70 axis may serve as both a potential biomarker to guide the choice of immunotherapy and a novel clinical target.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"18 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144087742","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}