Clinical Cancer Research最新文献

{"title":"Phenotype/Immunologic Profiling in ircAEs-Letter.","authors":"Sindhuja Sominidi Damodaran, Julia S Lehman","doi":"10.1158/1078-0432.CCR-24-2702","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-2702","url":null,"abstract":"","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"30 24","pages":"5693"},"PeriodicalIF":10.0,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827361","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":"Oxygen-Enhanced MRI Detects Incidence, Onset, and Heterogeneity of Radiation-Induced Hypoxia Modification in HPV-Associated Oropharyngeal Cancer.","authors":"Michael J Dubec, James Price, Michael Berks, John Gaffney, Ross A Little, Nuria Porta, Nivetha Sridharan, Anubhav Datta, Damien J McHugh, Christina J Hague, Susan Cheung, Prakash Manoharan, Marcel van Herk, Ananya Choudhury, Julian C Matthews, Geoff J M Parker, David L Buckley, Kevin J Harrington, Andrew McPartlin, James P B O'Connor","doi":"10.1158/1078-0432.CCR-24-1170","DOIUrl":"10.1158/1078-0432.CCR-24-1170","url":null,"abstract":"<p><strong>Purpose: </strong>Hypoxia mediates treatment resistance in solid tumors. We evaluated if oxygen-enhanced MRI-derived hypoxic volume (HVMRI) is repeatable and can detect radiotherapy-induced hypoxia modification in human papillomavirus-associated oropharyngeal head and neck squamous cell cancer.</p><p><strong>Experimental design: </strong>A total of 27 patients were recruited prospectively between March 2021 and January 2024. HVMRI was measured in primary and nodal tumors prior to standard-of-care (chemo)radiotherapy and then at weeks 2 and 4 (W2 and W4) into therapy. Two pretreatment scans assessed biomarker within-subject coefficient of variation and repeatability coefficient (RC). Cohort treatment response was measured using mixed-effects modeling. Responding lesions were identified by comparing HVMRI change with RC limits of agreement.</p><p><strong>Results: </strong>Oxygen-enhanced MRI identified hypoxia in all lesions. The HVMRI within-subject coefficient of variation was 24.6%, and RC limits of agreement were -45.7% to 84.1%. A cohort median pretreatment HVMRI of 11.3 cm3 reduced to 6.9 cm3 at W2 and 5.9 cm3 at W4 (both P < 0.001). HVMRI was reduced in 54.5% of individual lesions by W2 and in 88.2% by W4. All lesions with W2 hypoxia reduction showed persistent modification at W4. HVMRI reduced in some lesions that showed no overall volume change. Hypoxia modification was discordant between primary and nodal tumors in 50.0% of patients.</p><p><strong>Conclusions: </strong>Radiation-induced hypoxia modification can occur as early as W2, but onset varies between patients and was not necessarily associated with overall size change. Half of all patients had discordant changes in primary and nodal tumors. These findings have implications for patient selection and timing of dose de-escalation strategies in human papillomavirus-associated oropharyngeal carcinoma. See related commentary by Mason, p. 5503.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"5620-5629"},"PeriodicalIF":10.0,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11654720/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phenotype/Immunologic Profiling in ircAEs-Response.","authors":"Elena Goleva, Mario E Lacouture, Andrea P Moy, Jeffrey A Kern, Donald Y M Leung","doi":"10.1158/1078-0432.CCR-24-2949","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-2949","url":null,"abstract":"","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"30 24","pages":"5694"},"PeriodicalIF":10.0,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827365","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":"HMGA2 Expression Predicts Subtype, Survival, and Treatment Outcome in Pancreatic Ductal Adenocarcinoma.","authors":"Naomi Yamamoto, Stephanie Dobersch, Ian Loveless, Annie N Samraj, Gun Ho Jang, Miki Haraguchi, Liang-I Kang, Marianna B Ruzinova, Kiran R Vij, Jacqueline L Mudd, Thomas Walsh, Rachael A Safyan, E Gabriela Chiorean, Sunil R Hingorani, Nathan M Bolton, Li Li, Ryan C Fields, David G DeNardo, Faiyaz Notta, Howard C Crawford, Nina G Steele, Sita Kugel","doi":"10.1158/1078-0432.CCR-24-2200","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-2200","url":null,"abstract":"<p><strong>Purpose: </strong>To establish HMGA2 as a marker of basal-like disease in pancreatic ductal adenocarcinoma (PDAC) and explore its use as a biomarker for prognosis and treatment resistance.</p><p><strong>Experimental design: </strong>We identified high expression of HMGA2 in basal PDAC cells in a scRNAseq Atlas of 172 patient samples. We then analyzed HMGA2 expression, along with expression of the classical marker GATA6, in a cohort of 580 PDAC samples with multiplex immunohistochemistry. We further supplemented these data with an additional 30 diverse patient samples and multiple independent single-cell RNAseq databases.</p><p><strong>Results: </strong>We found that expression of HMGA2, but not previously described basal markers CK5 or CK17, predicted overall survival in our cohort. Combining HMGA2 and GATA6 status allowed for identification of two key study groups: an HMGA2+/GATA6- cohort with worse survival, low tumor-infiltrating CD8+ T cells, increased FAP+ fibroblasts, and poorer response to gemcitabine-based chemotherapies (n=94, median survival=11.2 months post-surgery); and an HMGA2-/GATA6+ cohort with improved survival, increased CD8+ T-cell infiltrate, decreased FAP+ fibroblasts, and improved survival with gemcitabine-based chemotherapy (n=198, median survival=21.7 months post-surgery). HMGA2 was also prognostic for overall survival in RNA sequencing from an independent cohort.</p><p><strong>Conclusions: </strong>IHC stratification of primary tumors by HMGA2 and GATA6 status in pancreatic cancer is associated with differential outcomes, survival following chemotherapy, and tumor microenvironments. As a nuclear marker for basal disease, HMGA2 complements GATA6 to identify disease subtypes in PDAC.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827349","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 Landscape of Circulating Tumor DNA (ctDNA) in Appendiceal Adenocarcinoma","authors":"Michael G. White, Mohammad A. Zeineddine, Eleanor A. Fallon, Fadl A. Zeineddine, Julia Dansby, Saikat Chowdhury, Nicholas Hornstein, Abdelrahman Yousef, Mahmoud Yousef, Neal Bhutiani, Yue Gu, Bryan Kee, Arvind Dasari, Michael J. Overman, Kanwal Raghav, Scott Kopetz, Abhineet Uppal, Melissa Taggart, Timothy Newhook, Keith Fournier, Beth Helmink, Leylah M. Drusbosky, John Paul Shen","doi":"10.1158/1078-0432.ccr-24-2474","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2474","url":null,"abstract":"Purpose: Appendiceal adenocarcinoma (AA) is a rare malignancy with distinct histopathologic subtypes and a natural history with metastasis primarily limited to the peritoneum. Little is known about the molecular pathogenesis of AA relative to common tumors. Experimental Design: We analyzed molecular data for patients within the Guardant Health database with appendix cancer (n = 718). We then identified patients with AA at our institution (from 10/2004-9/2022) for whom circulating tumor DNA (ctDNA) mutation profiling (liquid biopsy) was performed (n=168) and extracted clinicopathologic and outcomes data. Of these 168 patients 57 also had tissue-based tumor mutational profiling allowing for evaluation of concordance between liquid and tissue assays. Results: The mutational landscape of ctDNA in AA is distinct from tissue-based sequencing, with TP53 being the most frequently mutated (46%). Relative to other tumors, AA appears less likely to shed ctDNA, with only 38% of metastatic AA patients having detectable ctDNA (OR 0.26, p &amp;lt; 0.0001 relative to CRC). When detectable the median VAF was significantly lower in AA (0.4% vs. 1.3% for CRC, p≤0.001). High grade, signet-ring or colonic-type histology, metastatic spread beyond the peritoneum, and TP53 mutation were associated with detectable ctDNA. With respect to clinical translation, patients with detectable ctDNA had worse overall survival (HR = 2.32, p = 0.048). In the Guardant Health cohort actionable mutations were found in 93 patients (13.0%). Conclusions: Although metastatic AA tumors are less likely to shed tumor DNA into the blood relative to CRC, ctDNA profiling in AA has clinical utility.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"47 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142825125","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":"Human Papilloma Virus Circulating Cell-Free DNA Kinetics in Cervical Cancer Patients Undergoing Definitive Chemoradiation.","authors":"Aaron Seo, Weihong Xiao, Olsi Gjyshi, Kyoko Yoshida-Court, Peng Wei, David Swanson, Tatiana Cisneros Napravnik, Adam Grippin, Aradhana M Venkatesan, Megan C Jacobsen, David T Fuentes, Erica Lynn, Julie Sammouri, Anuja Jhingran, Melissa Joyner, Lilie L Lin, Lauren E Colbert, Maura L Gillison, Ann H Klopp","doi":"10.1158/1078-0432.CCR-24-2343","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-2343","url":null,"abstract":"<p><strong>Purpose: </strong>The human papillomavirus (HPV) is a significant cause of cervical cancer. We hypothesized that detecting viral cell-free HPV DNA (cfDNA) before, during, and after chemoradiation (chemoRT) could provide insights into disease extent, clinical staging, and treatment response.</p><p><strong>Experimental design: </strong>Sixty-six patients with locally advanced cervical cancer were enrolled between 2017 and 2023. 49 received standard-of-care (SOC) treatment and 17 participated in a clinical trial combining a therapeutic HPV vaccine (PDS0101; IMMUNOCERV). Plasma was collected at baseline, weeks 1, 3, and 5 of chemoRT, and 3-4 months after chemoRT. HPV cfDNA was quantified using droplet digital PCR targeting the HPV E6/E7 oncogenes of 13 high-risk types. MRI was performed at baseline and before brachytherapy.</p><p><strong>Results: </strong>The median follow-up was 23 months, with recurrence-free survival (RFS) of 78.4% at 2 years. Baseline nodal disease extent correlated with HPV cfDNA levels. HPV cfDNA levels peaked in week 1 of radiation and decreased through treatment. Patients receiving the PDS0101 vaccine had a higher rate of undetectable HPV type 16 cfDNA compared to SOC. HPV cfDNA clearance correlated with better 2-yr RFS (92.9% vs. 30%, log-rank p=0.0067). The strongest predictor of RFS was HPV cfDNA clearance in follow-up achieving a concordance index (CI) 0.83, which improved when combined with MRI response (CI 0.88).</p><p><strong>Conclusions: </strong>HPV cfDNA levels change dynamically during chemoRT. HPV cfDNA at follow-up predicts RFS. Delivery of therapeutic HPV vaccine with chemoRT was linked to rapid HPV cfDNA decline. Monitoring HPV cfDNA during and after chemoRT may guide tailoring of personalized treatment.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827354","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":"Next generation sequencing-based MSI scoring predict benefit in mismatch repair deficient tumors treated with nivolumab: follow-up on NCI-MATCH arm Z1D.","authors":"Jonathan D Schoenfeld, Nilofer S Azad, Jacob Gross, Li Chen, Michael J Overman, Katrina Kao, Latifa F Jackson, Donna Brunnquell, Xiangning Bu, Christina Coppola, Ping Guan, Jennifer Lee, David Sims, Rebecca Fuchs, Jason L Weirather, Kathleen L Pfaff, Lauren Gunasti, Srin Ranasinghe, Stanley R Hamilton, Victoria Wang, Peter J O'Dwyer, Catherine J Wu, Scott J Rodig, David R Patton, Lyndsay Harris","doi":"10.1158/1078-0432.CCR-24-0427","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-0427","url":null,"abstract":"<p><strong>Purpose: </strong>Mismatch repair deficient (dMMR) tumors have demonstrated favorable responses to immune checkpoint inhibition targeting PD-1. However, more in-depth identification of predictors of response could further refine patient selection for immunotherapy treatment.</p><p><strong>Experimental design: </strong>We undertook integrated evaluation performed on samples collected from 28 of 42 patients enrolled on the NCI-MATCH arm Z1D trial that evaluated PD-1 inhibition treatment with nivolumab in patients with non-colorectal dMMR tumors. Genomic analyses were performed using next-generation sequencing (NGS), whole exome sequencing, and RNA sequencing and supplemented by multiplex immunofluorescence performed on tissue samples.</p><p><strong>Results: </strong>In this dMMR population, more extensive alterations of microsatellites as assessed by measures of NGS was associated with clinical benefit and tumor mutational burden. RNA sequencing further revealed associations between clinical benefit and immune infiltration index. Gene sets enriched in patients with clinical benefit included interferon signaling, antigen processing and PI3K-AKT-mTOR signaling, while hedgehog signaling was found to be enriched in subjects lacking clinical benefit.</p><p><strong>Conclusions: </strong>These genomic data highlight the importance of immune infiltration and antigen presentation in dMMR tumors that respond to immune checkpoint blockade. In addition, they suggest that, even within a dMMR population, NGS based measures of MSI could serve as biomarkers of immunotherapy response.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142817441","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":"Phase 1/2 Study of the Indoleamine 2,3-Dioxygenase 1 Inhibitor Linrodostat Mesylate Combined With Nivolumab or Nivolumab and Ipilimumab in Advanced Solid Tumors or Hematologic Malignancies.","authors":"Jason J Luke, Karen Gelmon, Lillian L Siu, Victor Moreno, Jayesh Desai, Carlos A Gomez-Roca, Matteo S Carlino, Russell K Pachynski, Rasha Cosman, Quincy Siu-Chung Chu, Silvia Damian, Giuseppe Curigliano, Rachel Tam, Xianling Wang, Chandrika Jeyamohan, Lily Wang, Li Zhu, Julia Santucci-Pereira, Danielle M Greenawalt, Josep Tabernero","doi":"10.1158/1078-0432.CCR-24-0439","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-0439","url":null,"abstract":"<p><strong>Purpose: </strong>To evaluate linrodostat mesylate, a selective, oral indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, combined with nivolumab ± ipilimumab in advanced solid tumors and hematologic malignancies.</p><p><strong>Patients and methods: </strong>In this phase 1/2 study, patients received once-daily (QD) linrodostat (part 1 [escalation], 25-400 mg; part 2 [expansion], 100 or 200 mg) plus nivolumab (480 mg every [Q] 4 weeks [W] or 240 mg Q2W) or triplet therapy (part 3, linrodostat 20-100 mg QD; nivolumab 360 mg Q3W or 480 mg Q4W; ipilimumab 1 mg/kg Q6W or Q8W). Endpoints included safety and efficacy (co-primary; parts 2, 3), pharmacokinetics, pharmacodynamics, biomarkers, and efficacy (part 1).</p><p><strong>Results: </strong>Fifty-five, 494, and 41 patients were enrolled in parts 1, 2, and 3, respectively. Linrodostat exposures exceeded predicted therapeutic target concentrations starting at 50 mg. Rates of grade 3/4 adverse events were 50.1%-63.4%. The maximum tolerated linrodostat dose was 200 mg; dose-limiting toxicities were primarily immune related. Responses were observed across different cohorts, study parts, and tumor types, particularly in immunotherapy-naive patients. Kynurenine decreased with linrodostat + nivolumab, regardless of response. In contrast, interferon gamma (IFN-γ) gene expression signature was associated with response; in nonmelanoma patients, a composite of low tryptophan 2,3-dioxygenase (TDO2) gene expression plus high IFN-γ signature was associated with response.</p><p><strong>Conclusions: </strong>Linrodostat + nivolumab ± ipilimumab demonstrated a manageable safety profile. Kynurenine changes supported IDO1 pathway inhibition but did not correlate with response. A composite biomarker of low TDO2 expression plus high IFN-γ gene expression may predict response to linrodostat + nivolumab.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142817442","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":"Complete remissions of HER2-positive trastuzumab-resistant xenografts using a potent [225Ac]Ac-labeled anti-HER2 antibody-drug radioconjugate.","authors":"Jessica Pougoue Ketchemen, Fabrice Ngoh Njotu, Hanan Babeker, Alissar Monzer, Emmanuel Nwangele, Anjong Florence Tikum, Nikita Henning, Nava Hassani, Sarah Frye, Randy Perron, Chris Byrne, Candice Didychuk, Qi Qi, Laura Bannister, Alireza Doroudi, Humphrey Fonge","doi":"10.1158/1078-0432.CCR-24-1779","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-1779","url":null,"abstract":"<p><strong>Purpose: </strong>There is overwhelming interest to use actinium-225 ([225Ac]Ac) to develop targeted alpha therapies. Antibody-drug conjugates (ADCs) are highly cytotoxic. Combining [225Ac]Ac with ADC to develop an antibody-drug radioconjugate (ADR) [225Ac]Ac-Macropa-trastuzumab-PEG6-DM1, is expected to be more effective than its ADC (trastuzumab-PEG6-DM1) against breast cancer (BC).</p><p><strong>Experimental design: </strong>[89Zr]Zr-DFO-trastuzumab-PEG6-DM1 (imaging) and [225Ac]Ac-Macropa-trastuzumab-PEG6-DM1 (radiotherapy) were developed. Biodistribution and safety evaluation of [225Ac]Ac-Macropa-trastuzumab-PEG6-DM1 were carried out in non-tumor bearing Balb/C mice. MicroPET imaging and biodistribution were done using [89Zr]Zr-DFO-trastuzumab-PEG6-DM1, and radiotherapy using [225Ac]Ac-Macropa-trastuzumab-PEG6-DM1 was carried-out in athymic Balb/C nude mice bearing trastuzumab-resistant HCC1954 and T-DM1/trastuzumab resistant JIMT-1 tumor bearing mice.</p><p><strong>Results: </strong>After 7-days (d) of incubation at 37ºC, [225Ac]Ac-Macropa-trastuzumab-PEG6-DM1 was stable in both human serum (89.2 ± 0.9%) and phosphate buffered saline (82.8 ± 0.4%). Trastuzumab-PEG6-DM1 (8 mg/kg) and [225Ac]Ac-Macropa-trastuzumab-PEG6-DM1 (3 x 18 kBq) administered separately in non-tumor bearing mice, 10-d apart was well tolerated biochemically and haematologically. Imaging and biodistribution showed high tumor uptake of [89Zr]Zr-DFO-trastuzumab-PEG6-DM1 in tumor-bearing mice at 120 h post injection: 38.1 ± 2.8% IA/g (HCC1954) and 14.6 ± 1% IA/g (JIMT-1). In HCC1954-tumor bearing mice, all treatment groups had complete remission (8/8 CR) indicative of the responsiveness of the xenograft to T-DM1-based treatments, while for JIMT-1 xenograft (having 1/8 CR) at 23-d post treatment, tumor volumes were 332.1 ± 77.5 vs 244.6 ± 63 vs 417.9 ± 62.1 vs 102.4 ± 18.5 for the saline (negative control), T-DM1 (positive control), trastuzumab-PEG6-DM1 and [225Ac]Ac-Macropa-trastuzumab-PEG6-DM1, respectively.</p><p><strong>Conclusion: </strong>[225Ac]Ac-Macropa-trastuzumab-PEG6-DM1 is more potent than ADC against trastuzumab-resistant BC and necessitates clinical translation.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142817509","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":"Longitudinal blood immune-inflammatory and radiomic profiling to decode different patterns of acquired resistance to immunotherapy in patients with NSCLC.","authors":"Giulia Mazzaschi, Cristina Marrocchio, Lucas Moron Dalla Tor, Ludovica Leo, Maurizio Balbi, Gianluca Milanese, Ganiyat A R Adebanjo, Bruno Lorusso, Gregorio Monica, Monica Pluchino, Roberta Minari, Simona D'Agnelli, Elisa Cardinale, Fabiana Perrone, Paola Bordi, Alessandro Leonetti, Roberta E Ledda, Mario Silva, Sebastiano Buti, Giovanni Roti, Stefano Bettati, Federico Quaini, Marcello Tiseo, Nicola Sverzellati","doi":"10.1158/1078-0432.CCR-24-1926","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-1926","url":null,"abstract":"<p><strong>Purpose: </strong>To uncover the underpinnings of acquired resistance (AR) to immunotherapy (IO), we determined whether distinctive clinico-pathological, radiomic and peripheral blood (PB) immune-inflammatory features reflect oligo- and systemic (sys)-AR in advanced NSCLC patients undergoing immune checkpoints inhibitors.</p><p><strong>Experimental design: </strong>On 105 consecutive IO-treated advanced NSCLC, PB immunophenotypes, cytokines and CT-derived radiomic features (RFs), extracted from primary and merged metastatic lesions, were prospectively collected at baseline (T0) and first disease assessment (T1, 9-12 weeks), and their delta (Δ) variation [(T1-T0)/T0] computed. AR, defined as progression after initial response (complete/partial) or stable disease ≥ 6 months, was subdivided according to the number of new and/or progressive lesions in oligoAR (≤3) and sysAR (>3). Clinico-pathological, PB and radiomic parameters and survival outcome were statistically correlated to AR patterns.</p><p><strong>Results: </strong>OligoAR and sysAR involved 24% and 12.4% of cases, respectively. While baseline PB immune profiles were comparable, a Δpos cytotoxic (NK, CD8+GnzB+) and Δneg immunosuppressive (CD14+ monocytes) dynamic coupled with different modulation of IL-6, TGF-β1, TNFα and sPD-L1 represented distinctive features of oligoAR vs sysAR (P<0.05). Significantly longer post-progression survival characterized oligoAR vs sysAR (median 20.3 vs 5.6 months;HR:0.22,P<0.001). The number and sites of oligoAR involvement appeared to condition blood immune background (P<0.05) and survival. Delta radiomic outperformed baseline RFs, with 15 ΔRFs sharply discriminating oligoAR from sysAR (P range:<0.001-0.04). ROC analysis confirmed the optimal performance of top-ranked ΔRFs (AUC range:0.88-0.99).</p><p><strong>Conclusions: </strong>Longitudinal analysis of blood immune hallmarks and radiomic descriptors may decipher distinct patterns of AR to IO in advanced NSCLC patients.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142817510","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}