Clinical Cancer Research最新文献

{"title":"Pretargeted Trop-2 immunoPET for rapid, selective detection of pancreatic tumors","authors":"Edwin C. Pratt, Komal Mandleywala, David Bauer, Alexander Bolaender, Grace Chao, Mark A. Castanares, Emily C. Collins, Jason S. Lewis","doi":"10.1158/1078-0432.ccr-24-3098","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3098","url":null,"abstract":"Purpose: Recent clinical advances with the approval of antibody-drug conjugates targeting Trop-2 such as sacituzumab-govitecan and datopotomab-deruxtecan have garnered tremendous interest for their therapeutic efficacy in numerous tumor types including breast and lung cancers. ImmunoPET can stratify tumor avidity, clarifying patient eligibility for ADC therapy as well as a diagnostic companion during therapy. Slow antibody circulation requires days to reach optimal imaging timepoints. To overcome this shortfall, bioorthogonal click chemistry for pretargeting can be employed, decoupling antibody circulation time and the delivery of the radionuclide. Experimental Design: Here we report the characterization of a new full-length Trop-2.2 antibody showing high affinity for Trop-2 positive cancers and leverage different site selective labeling and pretargeting radionuclide combinations to yield rapid imaging with minimal radionuclide footprint after imaging. Three pretargeting strategies for Fluorine-18, Copper-64, and Zirconium-89 were explored in addition to site specific bioconjugation. Results: We found pretargeting with [64Cu]Cu-Sar-Tz to yield the best images identifying Trop-2 positive tumors with optimal tumor-to-background ratios. Intriguingly we found the full-length antibody when directly conjugated, yielded rapid accumulation starting at 3 hours post injection and leading to over 50% injected activity per gram in the tumor before 24 hours. Conclusions: [89Zr]Zr-DFO-Trop-2 as well as pretargeting with [64Cu]Cu-Sar-Tz are viable imaging strategies to quickly identify Trop-2 positive tumors for subsequent Trop-2 therapies.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"8 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143020744","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":"In situ RAS:RAF binding correlates with response to KRASG12C inhibitors in KRASG12C--mutant non-small cell lung cancer.","authors":"Ryoji Kato,Hitendra S Solanki,Hilal Ozakinci,Bina Desai,Harika Gundlapalli,Yu Chi Yang,Ida Aronchik,Mallika Singh,Joseph Johnson,Andriy Marusyk,Theresa A Boyle,Eric B Haura","doi":"10.1158/1078-0432.ccr-24-3714","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3714","url":null,"abstract":"PURPOSETherapeutic efficacy of KRASG12C(OFF) inhibitors (KRASG12Ci) in KRASG12C-mutant non-small cell lung cancer (NSCLC) varies widely. The activation status of RAS signaling in tumors with KRASG12C mutation remains unclear, as its ability to cycle between the active GTP-bound and inactive GDP-bound states may influence downstream pathway activation and therapeutic responses. We hypothesized that the interaction between RAS and its downstream effector RAF in tumors may serve as indicators of RAS activity, rendering NSCLC tumors with a high degree of RAS engagement and downstream effects more responsive to KRASG12Ci compared to tumors with lower RAS---RAF interaction.EXPERIMENTAL DESIGNWe developed a method for measuring in situ RAS binding to RAF in cancer samples using proximity ligation assays (PLAs) designed to detect panRAS-CRAF interactions.RESULTSThe panRAS-CRAF PLA signal correlated with levels of both RAS-GTP and phosphorylated ERK protein, suggesting that this assay can effectively assess active RAS signaling. We found that elevated panRAS-CRAF PLA signals were associated with increased sensitivity to KRASG12Ci in KRASG12C-mutant NSCLC cell lines, xenograft models, and patient samples. Applying a similar PLA approach to measure the interactions between EGFR and its adaptor protein GRB2 as a surrogate for EGFR activity, we found no relationship between EGFR activity and response to KRASG12Ci in the same samples.CONCLUSIONSOur study highlights the importance of evaluating in situ RAS-RAF interactions as a potential predictive biomarker for identifying NSCLC patients most likely to benefit from KRASG12Ci. The PLA developed for quantifying these interactions represents a valuable tool for guiding treatment strategies.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"9 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142991797","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":"MAPK pathway activating alteration and immunotherapy efficacy in squamous cell lung carcinoma: results from the randomized, prospective SQUINT trial.","authors":"Federico Cappuzzo,Biagio Ricciuti,Angelo Delmonte,Laura Bonanno,Xiaoyue Wang,Weng Kit Lye,Andreas Görtz,Kalliopi Andrikou,Alessandro Dal Maso,Gabriele Minuti,Maximilian Papi,Joao Victor Alessi,Alessandro Di Federico,Scott Rodig,Mark Magdi Awad,Giulio Metro,Ilaria Attili,Fabiana Vitiello,Sara Pilotto,Stefania Gori,Giulio Rossi,Simonetta Buglioni,Diana Giannarelli,Lorenza Landi","doi":"10.1158/1078-0432.ccr-24-2077","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2077","url":null,"abstract":"BACKGROUNDThe role of activating alterations in the MAPK pathway in predicting immunotherapy efficacy in lung squamous cell carcinoma (LSCC) patients is largely unknown. The aims of the randomized, phase II SQUINT trial were to assess the efficacy of nivolumab plus ipilimumab (NI) versus platinum-based chemotherapy plus nivolumab (N-CT) and to identify clinically available biomarkers of response to immunotherapy in patients with advanced or metastatic LSCC.METHODSSQUINT was an open-label, randomized, parallel, non-comparative, phase II trial of NI versus N-CT in chemo-naïve, metastatic or recurrent LSCC adult patients. The study was conducted across 15 Italian centers from September 2017 to February 2022 (ClinicalTrials.gov ID: NCT03823625).RESULTS45 patients were included in the NI arm and 46 in the N-CT arm. At 12 months, the overall survival (OS) rate was 62% in the NI arm and 50% in the N-CT arm. 74 patients were included in the analyses for individual biomarkers. In patients with mutations or copy number variations of genes involved in the MAPK pathway, we observed higher response to immunotherapy (43% vs 15%), longer progression-free survival (PFS) (p=0.03) and OS (p<0.001). A higher density of CD8+PD1+ T cells (p=0.04) among MAPK-altered tumors versus wild-type, together with an increased CD8+PD1+/FOXP3 ratio (p=0.047) were observed. In the validation cohort of patients not exposed to immunotherapy, OS was similar between MAPK13 mutant and wild-type LSCC.CONCLUSIONWe showed for the first time that MAPK pathway activating alteration influences the outcome of LSCC treated with immunotherapy, highlighting the relevance of gene profiling.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"107 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142991803","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":"Randomized phase II study of bevacizumab with weekly anetumab ravtansine or weekly paclitaxel in platinum-resistant/refractory high grade ovarian cancer (NCI trial).","authors":"Husam A Alqaisi,David E Cohn,Jing-Yi Chern,Linda R Duska,Andrea Jewell,Bradley R Corr,Ira Seth Winer,Eugenia Girda,Marta A Crispens,Neesha C Dhani,Ainhoa Madariaga,Robert C Grant,Matthew Malaguti,Crystal Lee,Valerie Bowering,Horace Wong,Andrew Poothullil,Vanessa Speers,Lisa Wang,Philippe L Bedard,John C Brady,Andrew B Nixon,Li Chen,Claire O'Connor,William Zamboni,Tawyna McKee,Jeffrey A Moscow,Amit M Oza,Stephanie Lheureux","doi":"10.1158/1078-0432.ccr-24-3128","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3128","url":null,"abstract":"PURPOSEMesothelin (MSLN) is highly expressed in high grade serous/ endometrioid ovarian cancers (HGOC). Anetumab ravtansine (AR) is an antibody drug conjugate directed at MSLN antigen with a tubulin polymerization inhibitor. We assessed safety, activity and pharmacokinetics of the combination AR/bevacizumab (Bev) (ARB) versus weekly paclitaxel (wP)/Bev (PB) in patients with platinum resistant/refractory HGOC (prrHGOC). Expiremental design: Following a run-in phase I study to assess ARB safety, prrHGOC patients with centrally confirmed MSLN positive expression were randomized to ARB or PB (wP 80mg/m2 with Bev 10mg/kg biweekly). Patients were stratified by platinum resistance/refractory and prior Bev. The primary endpoint was progression-free survival (PFS), secondary endpoints were overall response rate (ORR), safety, and blood-based angiome biomarker assessment. A futility analysis was planned after 35 PFS events.RESULTSThe combination of Bev (10mg/kg) biweekly with AR (2.2mg/kg) weekly was well tolerated. Regarding phase II results, mesothelin positivity was 88% and 57 pts were randomized (28 ARB, 29 PB). 42% pts received prior Bev and 23% were platinum refractory. At futility analysis, the median PFS was 5.3 and 12.7 months for ARB and PB respectively (p=0.03, HR= 2.02 [1.06-3.86]). ORR was 21% with ARB and 65% with PB. The most common treatment-related grade ≥ 3 adverse events were anemia (18%) with ARB, and neutropenia (24%) with PB. Higher baseline levels of circulating IL-6 were associated with worse PFS, and its levels decreased with PB treatment.CONCLUSIONOur study stopped at interim analysis highlighting the benefit of PB in prrHGOC as standard of care.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"205 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142991796","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":"CA-125 as a Biomarker in Renal Medullary Carcinoma: Integrated Molecular Profiling, Functional Characterization, and Prospective Clinical Validation.","authors":"Sandra L Grimm,Menuka Karki,Kyle A Blum,Jean-Philippe Bertocchio,Rong He,Durga N Tripathi,Niki M Zacharias,Justin M Lebenthal,Rahul A Sheth,Priya Rao,Giannicola Genovese,Zhen Lu,Robert C Bast,Davis R Ingram,Rossana Lazcano,Khalida M Wani,Wei-Lien Wang,Alexander J Lazar,Nizar M Tannir,Cheryl L Walker,Cristian Coarfa,Pavlos Msaouel","doi":"10.1158/1078-0432.ccr-24-3324","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3324","url":null,"abstract":"PURPOSERenal medullary carcinoma (RMC) is a highly aggressive malignancy defined by the loss of the SMARCB1 tumor suppressor. It mainly affects young individuals of African descent with sickle cell trait, and it is resistant to conventional therapies used for other renal cell carcinomas. This study aimed to identify potential biomarkers for early detection and disease monitoring of RMC.EXPERIMENTAL DESIGNIntegrated profiling of primary untreated RMC tumor tissues and paired adjacent kidney controls was performed using RNA-sequencing (RNA-seq) and histone Chromatin Immunoprecipitation Sequencing (ChIP-seq). The expression of serum cancer antigen 125 (CA-125), was prospectively evaluated in 47 patients with RMC. Functional studies were conducted in RMC cell lines to assess the effects of SMARCB1 re-expression.RESULTSMUC16, encoding for CA-125, was identified as one of the top upregulated genes in RMC tissues, with concomitant enrichment of active histone marks H3K4me3 and H3K27ac at its promoter. Elevated serum CA-125 levels were found in 31 of 47 (66%) RMC patients and correlated significantly with metastatic tumor burden (p = 0.03). Functional studies in RMC cell lines demonstrated that SMARCB1 re-expression significantly reduced MUC16 expression.CONCLUSIONSThe correlation between serum CA-125 levels and metastatic burden suggests that CA-125 is a clinically relevant biomarker for RMC. These findings support further exploration of CA-125 for disease monitoring and targeted therapeutics in RMC.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"37 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142991798","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":"Population Pharmacokinetics of Orvacabtagene Autoleucel, an Autologous BCMA-Directed Chimeric Antigen Receptor T-Cell Product, in Patients with Relapsed/Refractory Multiple Myeloma.","authors":"Hongxiang Hu,Yan Li,Julia Piasecki,Daniela Hosseyni,Zhicheng Yan,Xianghong Liu,Ken Ogasawara,Simon Zhou,Yiming Cheng","doi":"10.1158/1078-0432.ccr-24-2753","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2753","url":null,"abstract":"PURPOSEOrvacabtagene autoleucel (orva-cel; JCARH125), a CAR T-cell therapy targeting B-cell maturation antigen (BCMA), was evaluated in relapsed/refractory multiple myeloma (RRMM) patients in the EVOLVE phase 1/2 study (NCT03430011). We applied a modified piecewise model to characterize orva-cel transgene kinetics and assessed the impact of various covariates on its pharmacokinetics (PK).EXPERIMENTAL DESIGNThe population PK analysis included 159 patients from the EVOLVE study. Traditional piecewise models, employing a first-order expansion rate with or without lag time followed by a bi-exponential contraction phase, were compared with a modified model incorporating a cell number-dependent expansion phase aligned with cellular physiology. Covariates assessed encompassed baseline demographics, dose levels (50 to 600 × 106 CD3+ CAR+ T cells), prior/concomitant medications, baseline disease burden, and anti-therapeutic antibody (ATA) status.RESULTSTraditional piecewise models failed to accurately describe maximum orva-cel transgene level (Cmax) and underestimated the time to Cmax (Tmax). Our modified model incorporating a cell number-dependent expansion rate outperformed traditional models by 1) more accurately capturing the cellular expansion phase, and 2) yielding a Tmax that closely matches observed values. Additionally, dose level, percentage of plasma cells in bone marrow, and treatment-induced ATA were identified as statistically significant covariates and associated with orva-cel expansion and/or persistence.CONCLUSIONSOrva-cel PK were adequately described by the modified piecewise model incorporating a cell number-dependent expansion phase, which aligns closely with T cell biology.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"9 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142991795","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":"First-in-Human clinical trial of a small molecule EBNA1 inhibitor, VK-2019, in patients with Epstein-Barr positive nasopharyngeal cancer, with pharmacokinetic and pharmacodynamic studies.","authors":"A. Dimitrios Colevas, Zahra Talebi, Elizabeth Winters, Caroline Even, Victor Ho-Fun. Lee, Maura L. Gillison, Saad A. Khan, Rong Lu, Benjamin A. Pinsky, Samantha S. Soldan, Olga Vladmirova, Paul M. Lieberman, Troy E. Messick","doi":"10.1158/1078-0432.ccr-24-2814","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2814","url":null,"abstract":"Purpose: A first-in-human phase one study was conducted in nasopharyngeal carcinoma (NPC) patients to assess the safety and tolerability of VK-2019, a small molecule selective inhibitor of Epstein-Barr virus Nuclear Antigen 1 (EBNA1). Patients and Methods: Pharmacokinetic and pharmacodynamic studies, including circulating tumor EBV DNA plasma levels, were performed. Twenty-three patients received VK-2019 orally once daily at doses ranging from 60 to 1800 mg using an accelerated titration design, with cohort expansion at 1800 mg. EBV genome copy number and spatial transcriptomic analyses were conducted on biopsies collected from three patients at baseline and after treatment. Results: VK-2019 was well tolerated. One patient achieved a partial response. Pharmacokinetic results demonstrated good systemic exposure, with high intersubject variability. Decreases in circulating tumor EBV DNA plasma levels were observed in some patients. VK-2019 reduced EBV genome copy number and viral gene expression in patient tumor samples and induced changes in immune cell markers. Conclusions: VK-2019 at doses up to 1800 mg daily demonstrated an acceptable safety profile, achieved micromolar plasma concentrations, and showed on-target biological activity in tumors from patients with advanced EBV-positive nasopharyngeal carcinoma.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"138 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142990849","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 First-in-Human Study of Cinrebafusp Alfa, a HER2/4-1BB Bispecific Molecule, in Patients with HER2-Positive Advanced Solid Malignancies.","authors":"Sarina Piha-Paul, Shane A Olwill, Erika Hamilton, Anthony Tolcher, Paula Pohlmann, Stephen V Liu, Cornelia Wurzenberger, Laura-Carolin Hasenkamp, Eva-Maria Hansbauer, Rachna Shroff, Sara Hurvitz, Anuradha Krishnamurthy, Amita Patnaik, Noah Hahn, Raman Kumar, Manuela Duerr, Markus Zettl, Kayti Aviano, Louis Matis, Ingmar Bruns, Geoffrey Ku","doi":"10.1158/1078-0432.CCR-24-1552","DOIUrl":"10.1158/1078-0432.CCR-24-1552","url":null,"abstract":"<p><strong>Purpose: </strong>4-1BB (CD137) is a costimulatory immune receptor expressed on activated T cells, activated B cells, NK cells, and tumor-infiltrating lymphocytes, making it a promising target for cancer immunotherapy. Cinrebafusp alfa, a monoclonal antibody-like bispecific protein targeting HER2 and 4-1BB, aims to localize 4-1BB activation to HER2-positive tumors. This study evaluated the safety, tolerability, and preliminary efficacy of cinrebafusp alfa in patients with previously treated HER2-positive malignancies.</p><p><strong>Patients and methods: </strong>This was a multicenter dose-escalation study involving patients with HER2-positive malignancies who received prior treatment. The study assessed the safety and efficacy of cinrebafusp alfa across various dose levels. Patients were assigned to different cohorts, and antitumor responses were evaluated. The study aimed to determine the MTD and to observe any clinical activity at different dose levels.</p><p><strong>Results: </strong>Of 40 evaluable patients in the \"active dose\" efficacy cohorts, five showed an antitumor response, resulting in an overall response rate of 12.5% and a disease-control rate of 52.5%. Clinical activity was observed at the 8 and 18 mg/kg dose levels, with confirmed objective response rates of 28.6% and 25.0%, respectively. Cinrebafusp alfa was safe and tolerable, with grade ≤2 infusion-related reactions being the most frequent treatment-related adverse event. MTD was not reached during the study.</p><p><strong>Conclusions: </strong>Cinrebafusp alfa demonstrates promising activity in patients with HER2-positive malignancies who have progressed on prior HER2-targeting regimens. Its acceptable safety profile suggests it could be a treatment option for patients not responding to existing HER2-directed therapies. See related commentary by Eguren-Santamaría et al., p. 231.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"288-298"},"PeriodicalIF":10.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739778/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139437","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":"Divergent Clinical and Immunologic Outcomes Based on STK11 Co-mutation Status in Resectable KRAS-Mutant Lung Cancers Following Neoadjuvant Immune Checkpoint Blockade.","authors":"Samuel Rosner, Sydney Connor, Khaled Sanber, Marianna Zahurak, Tianbei Zhang, Isha Gurumurthy, Zhen Zeng, Brad Presson, Dipika Singh, Roni Rayes, Lavanya Sivapalan, Gavin Pereira, Zhicheng Ji, Rohit Thummalapalli, Joshua E Reuss, Stephen R Broderick, David R Jones, Julie S Deutsch, Tricia R Cottrell, Jamie E Chaft, Jonathan Spicer, Janis Taube, Valsamo Anagnostou, Julie R Brahmer, Drew M Pardoll, Hongkai Ji, Patrick M Forde, Kristen A Marrone, Kellie N Smith","doi":"10.1158/1078-0432.CCR-24-2983","DOIUrl":"10.1158/1078-0432.CCR-24-2983","url":null,"abstract":"<p><strong>Purpose: </strong>Co-mutations of the Kirsten rat sarcoma virus (KRAS) and serine/threonine kinase 11 (STK11) genes in advanced non-small cell lung cancer (NSCLC) are associated with immune checkpoint blockade (ICB) resistance. Although neoadjuvant chemoimmunotherapy is now a standard-of-care treatment for resectable NSCLC, the clinical and immunologic impacts of KRAS and STK11 co-mutations in this setting are unknown.</p><p><strong>Experimental design: </strong>We evaluated and compared recurrence-free survival of resectable KRAS-mutated NSCLC tumors, with or without co-occurring STK11 mutations, treated with neoadjuvant ICB. Single-cell transcriptomics was performed on tumor-infiltrating T cells from seven KRASmut/STK11wt tumors and six KRAS and STK11 co-mutated (KRASmut/STK11mut) tumors.</p><p><strong>Results: </strong>Relative to KRASmut/STK11wt tumors, KRASmut/STK11mut exhibited significantly higher recurrence risk. Single-cell transcriptomics showed enhanced oxidative phosphorylation with evidence of decreased prostaglandin E2 signaling and increased IL-2 signaling in CD8+ tumor-infiltrating lymphocytes (TIL) from KRASmut/STK11mut tumors, a finding that was mirrored in KRASwt tumors that relapsed. TILs from KRASmut/STK11mut tumors expressed high levels of molecules associated with tumor residence, including CD39 and ZNF683 (HOBIT).</p><p><strong>Conclusions: </strong>These divergent T-cell transcriptional fates suggest that T-cell maintenance and residence may be detrimental to antitumor immunity in the context of neoadjuvant ICB for resectable NSCLC, regardless of KRAS mutation status. Our work provides a basis for future investigations into the mechanisms underpinning prostaglandin E2 signaling and IL-2 signaling as they relate to T-cell immunity to cancer and to divergent clinical outcomes in KRASmut/STK11mut NSCLC treated with neoadjuvant ICB.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"339-351"},"PeriodicalIF":10.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739779/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638585","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":"Phase I study of adavosertib with radiation therapy and temozolomide in newly diagnosed glioblastoma and intratumoral drug levels in recurrent glioblastoma","authors":"Eudocia Q. Lee, Brian M. Alexander, Carlos G. Romo, Jeffrey G. Supko, Nathalie Y.R. Agar, Zahra Talebi, Manmeet S. Ahluwalia, Arati S. Desai, Jorg Dietrich, Thomas J. Kaley, David M. Peereboom, Jennifer Gantchev, Gerard Baquer, Sandro Santagata, Naoko Takebe, Serena Desideri, Joy D. Fisher, Megan Sims, Xiaobu Ye, Keith L. Ligon, Louis B. Nabors, Stuart A. Grossman, Patrick Y. Wen","doi":"10.1158/1078-0432.ccr-24-2311","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2311","url":null,"abstract":"PURPOSE: Adavosertib is an oral small molecular inhibitor of Wee1. The Adult Brain Tumor Consortium performed a phase I study of adavosertib, radiation (RT) and temozolomide (TMZ) in newly diagnosed glioblastoma (GBM) as well as a surgical window of opportunity study in recurrent GBM. PATIENTS AND METHODS: The maximum tolerated dose (MTD) of adavosertib was determined in adult patients with newly diagnosed GBM using a standard 3+3 design in 2 separate cohorts: with concurrent RT/TMZ or with adjuvant TMZ. A combination cohort with both concurrent and adjuvant adavosertib at MTD followed. We also performed intratumoral drug distribution studies in recurrent GBM patients undergoing surgery. RESULTS: As separate cohorts, MTD for concurrent adavosertib with RT/TMZ was 200 mg daily M-F x 6 weeks during RT and for adjuvant adavosertib with TMZ was 425 mg daily for 5 days of each 28-day cycle. However, 6/12 patients experienced DLTs in the combination cohort. The mean ratio of the intratumoral-to-plasma concentration of adavosertib was 4.18 ± 3.36 for contrast-enhancing tissue and 0.74 ± 0.63 in non-enhancing tissue. CONCLUSIONS: Adavosertib 200 mg daily M-F x 6 weeks with RT/TMZ and 425 mg daily on a 5d/28d cycle with TMZ had an unacceptable DLT rate. Additional dose levels in combination cohorts resulted in DLTs and we deemed concurrent adavosertib too toxic for further examination. Adavosertib 425 mg daily on a 5d/28d cycle with adjuvant TMZ is the recommended phase II dose. Tissue PK in tissue homogenates and by microdialysis provided complementary information about drug penetration.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"98 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142988519","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}