Clinical Cancer Research最新文献

{"title":"Phase I Study of ROR1-Specific CAR-T Cells in Advanced Hematopoietic and Epithelial Malignancies.","authors":"Carla A Jaeger-Ruckstuhl, Jennifer M Specht, Jenna M Voutsinas, Hugh R MacMillan, Qian Vicky Wu, Vishaka Muhunthan, Carolina Berger, Shalini Pullarkat, Jocelyn H Wright, Cecilia C S Yeung, Teresa S Hyun, Brandon Seaton, Lauri D Aicher, Xiaoling Song, Robert H Pierce, Yun Lo, Gabriel O Cole, Sylvia M Lee, Evan W Newell, David G Maloney, Stanley R Riddell","doi":"10.1158/1078-0432.CCR-24-2172","DOIUrl":"10.1158/1078-0432.CCR-24-2172","url":null,"abstract":"<p><strong>Purpose: </strong>The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is expressed in hematopoietic and epithelial cancers but has limited expression on normal adult tissues. This phase I study evaluated the safety of targeting ROR1 with autologous T lymphocytes engineered to express a ROR1 chimeric antigen receptor (CAR). Secondary objectives evaluated the persistence, trafficking, and antitumor activity of CAR-T cells.</p><p><strong>Patients and methods: </strong>Twenty-one patients with ROR1+ tumors received CAR-T cells at one of four dose levels: 3.3 × 105, 1 × 106, 3.3 × 106, and 1 × 107 cells/kg body weight, administered after lymphodepletion with cyclophosphamide/fludarabine or oxaliplatin/cyclophosphamide. Cohort A included patients with chronic lymphocytic leukemia (CLL, n = 3); cohort B included patients with triple-negative breast cancer (TNBC, n = 10) or non-small cell lung cancer (NSCLC, n = 8). A second infusion was administered to one patient in cohort A with residual CLL in the marrow and three patients in cohort B with stable disease after first infusion.</p><p><strong>Results: </strong>Treatment was well tolerated, apart from one dose-limiting toxicity at dose level 4 in a patient with advanced NSCLC. Two of the three (67%) patients with CLL showed robust CAR-T-cell expansion and a rapid antitumor response. In patients with NSCLC and TNBC, CAR-T cells expanded to variable levels and infiltrated tumors poorly and 1 of 18 patients (5.5%) achieved partial response by RECIST 1.1.</p><p><strong>Conclusions: </strong>ROR1 CAR-T cells were well tolerated in most patients. Antitumor activity was observed in CLL but was limited in TNBC and NSCLC. Immunogenicity of the CAR and lack of sustained tumor infiltration were identified as limitations. See related commentary by Kobold, p. 437.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"503-514"},"PeriodicalIF":10.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11788652/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496191","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":"Framework for the Pathology Workup of Metastatic Castration-Resistant Prostate Cancer Biopsies.","authors":"Michael C Haffner, Michael J Morris, Chien-Kuang C Ding, Erolcan Sayar, Rohit Mehra, Brian Robinson, Lawrence D True, Martin Gleave, Tamara L Lotan, Rahul Aggarwal, Jiaoti Huang, Massimo Loda, Peter S Nelson, Mark A Rubin, Himisha Beltran","doi":"10.1158/1078-0432.CCR-24-2061","DOIUrl":"10.1158/1078-0432.CCR-24-2061","url":null,"abstract":"<p><p>Lineage plasticity and histologic transformation from prostate adenocarcinoma to neuroendocrine (NE) prostate cancer (NEPC) occur in up to 15% to 20% of patients with castration-resistant prostate cancer (CRPC) as a mechanism of treatment resistance and are associated with aggressive disease and poor prognosis. NEPC tumors typically display small cell carcinoma morphology with loss of androgen receptor (AR) expression and gain of NE lineage markers. However, there is a spectrum of phenotypes that are observed during the lineage plasticity process, and the clinical significance of mixed histologies or those that co-express AR and NE markers or lack all markers is not well defined. Translational research studies investigating NEPC have used variable definitions, making clinical trial design challenging. In this manuscript, we discuss the diagnostic workup of metastatic biopsies to help guide the reproducible classification of phenotypic CRPC subtypes. We recommend classifying CRPC tumors based on histomorphology (adenocarcinoma, small cell carcinoma, poorly differentiated carcinoma, other morphologic variant, or mixed morphology) and IHC markers with a priority for AR, NK3 homeobox 1, insulinoma-associated protein 1, synaptophysin, and cell proliferation based on Ki-67 positivity, with additional markers to be considered based on the clinical context. Ultimately, a unified workup of metastatic CRPC biopsies can improve clinical trial design and eventually practice.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"466-478"},"PeriodicalIF":10.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11790385/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715500","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":"Safety and Tolerability of Letetresgene Autoleucel (GSK3377794): Pilot Studies in Patients with Advanced Non-Small Cell Lung Cancer.","authors":"Mehmet Altan, Gilberto Lopes, T Jeroen N Hiltermann, Ramaswamy Govindan, Liza C Villaruz, Emiliano Calvo, Martin J Edelman, Muhammad Furqan, Joel Neal, Enriqueta Felip, Jennifer W Carlisle, John V Heymach, Róisín Eilish O'Cearbhaill, Marjorie Zauderer, Michael Chisamore, Ellie Corigliano, Ioanna Eleftheriadou, Stefan Zajic, Ben Jenkins, Sophia Goodison, Sunil Suchindran, Natalia Ramos-Hernandez, Nidale Tarek, Adam J Schoenfeld","doi":"10.1158/1078-0432.CCR-24-1591","DOIUrl":"10.1158/1078-0432.CCR-24-1591","url":null,"abstract":"<p><strong>Purpose: </strong>The study aims to evaluate the safety, tolerability, and antitumor response of letetresgene autoleucel (lete-cel), genetically modified autologous T cells expressing a T-cell receptor specific for New York esophageal squamous cell carcinoma 1 (NY-ESO-1)/LAGE-1a shared epitope, alone or in combination with pembrolizumab, in HLA-A*02-positive (HLA-A*02:01, HLA-A*02:05, and/or HLA-A*02:06) patients with NY-ESO-1- and/or LAGE-1a-positive non-small cell lung cancer.</p><p><strong>Patients and methods: </strong>Study 208749 was a single-arm study of lete-cel alone. Study 208471 was a multiarm study of lete-cel alone or in combination with pembrolizumab in patients with advanced or recurrent non-small cell lung cancer.</p><p><strong>Results: </strong>More than 2,500 patients were screened for target expression. In the multiarm study, 738 (45%) of 1,638 tested patients were HLA-A*02-positive. NY-ESO-1 and LAGE-1a testing was positive in 12% (62/525) and 4% (15/348) of tested patients, respectively. Forty-one patients positive for HLA-A*02 and antigen expression were screened in the single-arm study. Overall, 43 patients underwent leukapheresis and 18 received lete-cel across studies. Lete-cel demonstrated a manageable safety profile. No fatal treatment-related serious adverse events (AE) were reported in either study. Cytopenias and cytokine release syndrome were the most common treatment-emergent AEs. Combining pembrolizumab with lete-cel did not seem to increase toxicity over lete-cel alone. Limited antitumor activity was observed; one of 18 patients had a durable response persisting for 18 months. Pharmacokinetic data showed similar T-cell expansion in all patients.</p><p><strong>Conclusions: </strong>Extensive HLA-A*02 and antigen expression testing was performed to identify potential participants. Lete-cel was generally well tolerated and had no unexpected AEs. Antitumor activity was observed in a limited number of patients.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"529-542"},"PeriodicalIF":10.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11788651/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142686254","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":"Antitumor Activity and Biomarker Analysis for TROP2 Antibody-Drug Conjugate Datopotamab Deruxtecan in Patient-Derived Breast Cancer Xenograft Models.","authors":"Funda Meric-Bernstam, Erkan Yuca, Kurt W Evans, Ming Zhao, Takanori Maejima, Tsuyoshi Karibe, Maria Gabriela Raso, Ximing Tang, Xiaofeng Zheng, Yasmeen Qamar Rizvi, Argun Akcakanat, Stephen M Scott, Bailiang Wang, Lauren A Byers, Debu Tripathy, Daisuke Okajima, Senthil Damodaran","doi":"10.1158/1078-0432.CCR-24-1948","DOIUrl":"10.1158/1078-0432.CCR-24-1948","url":null,"abstract":"<p><strong>Purpose: </strong>Datopotamab deruxtecan (Dato-DXd) is a humanized anti-trophoblast cell-surface antigen-2 (TROP2) IgG1 mAb linked to a potent topoisomerase I inhibitor payload (DXd). Dato-DXd has already shown antitumor activity in breast cancer; however, the determinants of response, including the importance of TROP2 expression, remain unclear. We tested the activity of Dato-DXd in a panel of breast cancer patient-derived xenografts (BCX) varying in TROP2 expression.</p><p><strong>Experimental design: </strong>The antitumor activity of Dato-DXd and isotype-control-DXd (IgG-DXd) was assessed against 11 BCXs varying in TROP2 expression, 10 representing tumors postneoadjuvant chemotherapy. Pharmacodynamic effects were assessed at 24 and 72 hours. The effects of TROP2 expression on Dato-DXd activity was assessed in vitro and in vivo using viral overexpression in BCX-derived cell lines.</p><p><strong>Results: </strong>Models differed in their sensitivity to both Dato-DXd and IgG-DXd. Dato-DXd (10 mg/kg) led to objective response in 4 (36%) models and statistically significant prolongation of event-free survival in 8 (73%) models, whereas IgG-DXd (10 mg/kg) led to response in 1 (9%) and prolonged event-free survival in 3 (27%) models. TROP2 RNA and protein were significantly higher in Dato-DXd-sensitive models. In isogenic cell lines derived from Dato-DXd-resistant BCXs, overexpression of TROP2 conferred Dato-DXd antitumor activity in vitro and in vivo. Dato-DXd increased γH2AX and phospho-KAP1 in the two Dato-DXd-sensitive BCXs but not in a Dato-DXd-resistant BCX. In Dato-DXd-sensitive models, antitumor activity was enhanced in combination with a PARP inhibitor, olaparib.</p><p><strong>Conclusions: </strong>Dato-DXd is active in breast cancer models. Dato-DXd has TROP2-dependent and -independent mediators of activity; however, high TROP2 expression enhances Dato-DXd antitumor activity.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"573-587"},"PeriodicalIF":10.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11788653/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142709620","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":"Early Hepatic Decompensation Identifies Patients with Hepatocellular Carcinoma Treated with Atezolizumab plus Bevacizumab or Sorafenib at Highest Risk of Death.","authors":"Giuseppe Cabibbo, Ciro Celsa, Salvatore Battaglia, Marco Enea, Gabriele Di Maria, Alessandro Grova, Roberta Ciccia, Giulia F Manfredi, Massimo Iavarone, Arndt Vogel, Amit G Singal, Maria Reig, David J Pinato, Calogero Cammà","doi":"10.1158/1078-0432.CCR-24-2582","DOIUrl":"10.1158/1078-0432.CCR-24-2582","url":null,"abstract":"<p><strong>Purpose: </strong>The prognosis of patients with unresectable hepatocellular carcinoma (HCC) and compensated cirrhosis is influenced by cancer progression. Data on the incidence and the prognostic role of clinical hepatic decompensation (CHD) following immune checkpoint inhibitor therapy are lacking. We aimed to assess whether early CHD within 3 months from commencement of systemic therapy affects overall survival (OS) of patients treated with atezolizumab plus bevacizumab or sorafenib.</p><p><strong>Patients and methods: </strong>Individual patient data from the IMbrave150 trial were analyzed. Cumulative incidence of CHD was assessed by competing risk analysis against HCC radiologic progression. Early CHD and HCC radiologic progression were assessed as predictors of OS by the time-dependent Cox model.</p><p><strong>Results: </strong>The 3- and 12-month rates of CHD were 7% and 12%, respectively, whereas the 3- and 12-month rates of HCC radiologic progression were 23% and 52%, respectively. Albumin-bilirubin grade 2 [subdistribution HR (sHR) = 1.79, 95% confidence interval (CI), 1.01-3.19; P = 0.049], INR (sHR = 1.97, 95% CI, 1.64-2.37; P < 0.001), and presence of neoplastic macrovascular invasion (sHR = 2.01, 95% CI, 1.14-3.54; P = 0.020) were independently associated with higher risk of CHD. Early CHD (HR = 7.56, 95% CI, 4.47-12.8) and early HCC radiologic progression (HR = 5.92, 95% CI, 4.03-8.69), as first events, were independently associated with higher mortality.</p><p><strong>Conclusions: </strong>This study provides robust evidence that early CHD is associated with the highest risk of death in patients with unresectable HCC undergoing systemic treatment. Within well-compensated participants, albumin-bilirubin, INR, and macrovascular invasion identify a population at higher risk of decompensation. Inclusion of clinical decompensation events in future prospective clinical trials may improve characterization of OS from systemic therapy of HCC.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"543-550"},"PeriodicalIF":10.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142686252","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 I/II Study of the Aurora Kinase A Inhibitor Alisertib and Pembrolizumab in Refractory, Rb-Deficient Head and Neck Squamous Cell Carcinomas.","authors":"Faye M Johnson, Madison P O'Hara, Lacin Yapindi, Peixin Jiang, Hai T Tran, Alexandre Reuben, Weihong Xiao, Maura L Gillison, Xiaowen Sun, Alexander Khalaf, J Jack Lee, Jagannadha K Sastry, Soma Ghosh","doi":"10.1158/1078-0432.CCR-24-2290","DOIUrl":"10.1158/1078-0432.CCR-24-2290","url":null,"abstract":"<p><strong>Purpose: </strong>Effective therapy for recurrent head and neck squamous cell carcinoma (HNSCC) that is refractory to chemotherapy and immunotherapy is a considerable need. Aurora kinase A inhibition leads to apoptosis and immunogenic cell death in preclinical models of human papilloma virus (HPV)-driven cancers.</p><p><strong>Patients and methods: </strong>Alisertib was administered orally twice daily on days 1-7 and pembrolizumab on day 1 of a 21-day cycle to adults with advanced solid tumors (phase I) or with immunotherapy- and platinum-resistant, HPV-positive HNSCC (phase II).</p><p><strong>Results: </strong>The recommended phase II alisertib dose was 40 mg, which had only the expected toxicity including cytopenia that led to dose reductions in two phase II patients at cycles 13 and 16. We saw no objective responses, but the combination led to prolonged stable disease (SD) in several patients, including two of 10 phase I patients (8 and 27 months). Eight of the 15 HPV-positive patients had SD, of which four (heavily pretreated) had ≥6 months, with median overall and progression-free survival durations of 16.8 and 1.4 months, respectively. In circulating immune cells and plasma, patients with SD had markedly higher levels of HLA de novo resistance-expressing NK cells than did progressive disease patients who demonstrated a more immunosuppressive and inflammatory profile. Pharmacokinetics did not indicate any significant drug-drug interactions between pembrolizumab and alisertib.</p><p><strong>Conclusions: </strong>The combination of alisertib and pembrolizumab was well tolerated and led to prolonged SD in some immunotherapy-resistant patients, supporting our hypothesis that Aurora kinase A inhibition can reverse immunotherapy resistance of retinoblastoma protein-deficient HNSCC.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"479-490"},"PeriodicalIF":10.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11790391/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715503","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":"Update on Cancer Screening in Children with Syndromes of Bone Lesions, Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome, and Other Rare Syndromes.","authors":"Orli Michaeli, Sun Young Kim, Sarah G Mitchell, Marjolijn C J Jongmans, Jonathan D Wasserman, Melissa R Perrino, Anirban Das, Suzanne P MacFarland, Sarah R Scollon, Mary-Louise C Greer, Nara Sobreira, Bailey Gallinger, Philip J Lupo, David Malkin, Kami Wolfe Schneider, Kris Ann P Schultz, William D Foulkes, Emma R Woodward, Douglas R Stewart","doi":"10.1158/1078-0432.CCR-24-2171","DOIUrl":"10.1158/1078-0432.CCR-24-2171","url":null,"abstract":"<p><p>The management of children with syndromes associated with an increased risk of benign and malignant neoplasms is a complex challenge for health care professionals. The 2023 American Association for Cancer Research Childhood Cancer Predisposition Workshop provided updated consensus guidelines on cancer surveillance in these syndromes, aiming to improve early detection and intervention and reduce morbidity associated with such neoplasms. In this article, we review several of the rare conditions discussed in this workshop. Ollier disease and Maffucci syndrome are enchondromatoses (disorders featuring benign bone lesions) with up to 50% risk of malignancy, including chondrosarcoma. These patients require surveillance with baseline whole-body MRI and routine monitoring of potential malignant transformation of bony lesions. Hereditary multiple osteochondromas carry a lower risk of chondrosarcoma (<6%) but still require lifelong surveillance and baseline imaging. Related syndromes of benign bone lesions are also described. Hereditary leiomyomatosis and renal cell carcinoma syndrome, associated with fumarate hydratase pathogenic variants, is discussed in detail. Surveillance for renal cell carcinoma in pediatric age is recommended, as well as prompt intervention when a lesion is detected. Schinzel-Giedion syndrome and Rubinstein-Taybi syndrome are described for their associated malignancies and other complications, as well as expert consensus on the need for childhood cancer surveillance. Clinical recommendations, including imaging modalities and frequency of screenings, are proposed and are tailored to each syndrome's age-specific tumor risk profile. In all syndromes, patients and their families should be educated about the potential malignancy risk and advised to seek medical care for rapid growth of a mass, persistent pain, or other unexplained symptoms.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"457-465"},"PeriodicalIF":10.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11790369/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142726504","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":"Mitochondria-targeting of oxidative phosphorylation inhibitors to alleviate hypoxia and enhance anticancer treatment efficacy.","authors":"Anne P M Beerkens, Sandra Heskamp, Flavia V Reinema, Gosse J Adema, Paul N Span, Johan Bussink","doi":"10.1158/1078-0432.CCR-24-3296","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-3296","url":null,"abstract":"<p><p>Hypoxia is a common feature of solid tumors and is associated with a poor response to anticancer therapies. Hypoxia also induces metabolic changes, such as a switch to glycolysis. This glycolytic switch causes acidification of the tumor microenvironment (TME), thereby attenuating the anticancer immune response. A promising therapeutic strategy to reduce hypoxia and thereby sensitize tumors to irradiation and/or antitumor immune responses is pharmacological inhibition of oxidative phosphorylation (OXPHOS). Several OXPHOS inhibitors (OXPHOSi) have been tested in clinical trials. However, moderate responses and/or substantial toxicity has hampered clinical implementation. OXPHOSi tested in clinical trials inhibit the oxidative metabolism in tumor cells as well as healthy cells. Therefore, new strategies are needed to improve the efficacy of OXPHOSi while minimizing side effects. To enhance the therapeutic window, available OXPHOSi have, for instance, been conjugated to triphenylphosphonium (TPP+) to preferentially target the mitochondria of cancer cells, resulting in increased tumor uptake compared to healthy cells, as cancer cells have a higher mitochondrial membrane potential. However, OXPHOS inhibition also induces reactive oxygen species (ROS), and subsequent antioxidant responses, which may influence the efficacy of therapies, such as platinum-based chemotherapy and radiotherapy. Here, we review the limitations of the clinically tested OXPHOSi metformin, atovaquone, tamoxifen, BAY 87-2243 and IACS-010759 and the potential of mito-targeted OXPHOSi and their influence on ROS production. Furthermore, the effect of the mitochondria-targeting moiety TPP+ on mitochondria is discussed as this affects mitochondrial bioenergetics.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143078587","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 Ib Pharmacodynamic Study of the MNK Inhibitor Tomivosertib (eFT508) Combined With Paclitaxel in Patients With Refractory Metastatic Breast Cancer.","authors":"Cristiano Ferrario, John Mackey, Karen A Gelmon, Nathalie Levasseur, Poul H Sorensen, Htoo Zarni Oo, Gian L Negri, Veronica W L Tse, Sandra E Spencer, Grace Cheng, Gregg B Morin, Sonia Del Rincon, Tiziana Cotechini, Christophe Gonçalves, Charles C T Hindmarch, Wilson H Miller, Mehdi Amiri, Tayebeh Basiri, Victor Villareal-Corpuz, Sam Sperry, Kevin Gregorczyk, Gonzalo Spera, Nahum Sonenberg, Michael Pollak","doi":"10.1158/1078-0432.CCR-24-0841","DOIUrl":"10.1158/1078-0432.CCR-24-0841","url":null,"abstract":"<p><strong>Purpose: </strong>Preclinical data motivate clinical evaluation of inhibitors of MAPK-interacting kinases 1 and 2 (MNK1/2). We conducted a phase 1b clinical trial to study target engagement and safety of tomivosertib, a MNK1/2 inhibitor, alone and in combination with paclitaxel.</p><p><strong>Patients and methods: </strong>Eligible patients had metastatic breast cancer resistant to standard-of-care treatments. Biopsies were obtained at baseline and during treatment with tomivosertib, and then tomivosertib was continued with the addition of paclitaxel until disease progression or toxicity. Serum drug levels were measured, and pharmacodynamic endpoints included IHC, proteomics, translatomics, and imaging mass cytometry.</p><p><strong>Results: </strong>Tomivosertib alone and in combination with paclitaxel was well tolerated. There was no pharmacokinetic interaction between the drugs. We observed a clear reduction in phosphorylation of eIF4E at S209, a major substrate of MNK1/2, and identified tomivosertib-induced perturbations in the proteome, translatome, and cellular populations of biopsied metastatic breast cancer tissue.</p><p><strong>Conclusions: </strong>We conclude that tomivosertib effectively inhibits MNK1/2 activity in metastatic breast cancer tissue and that it can safely be combined with paclitaxel in future phase II studies. We demonstrate feasibility of using proteomic profiles, translatomic profiles, and spatial distribution of immune cell infiltrates for clinical pharmacodynamic studies.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"491-502"},"PeriodicalIF":10.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142686253","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":"Response-Adaptive Surgical Timing in Neoadjuvant Immunotherapy Demonstrates Enhanced Pathologic Treatment Response in Head and Neck Squamous Cell Carcinoma.","authors":"Eric V Mastrolonardo, Kathryn L Nunes, Pablo Llerena, Anastasia Nikitina, Anastasia Sobol, E Reilly Scott, Madalina Tuluc, Christopher J H Davitt, Jessica Scher, Sruti Tekumalla, Derek Mann, Camilo Henao, Victor Jegede, Stacey Gargano, Larry A Harshyne, Angela Alnemri, Andrey Tyshevich, Vladimir Kushnarev, Madison Chasse, Danielle Sookiasian, Rita Axelrod, Tingting Zhan, Benjamin E Leiby, Matthew Old, Nolan Seim, My G Mahoney, Ubaldo Martinez-Outschoorn, David M Cognetti, Joseph M Curry, George Prendergast, Athanassios Argiris, Andrew P South, Alban J Linnenbach, Jennifer M Johnson, Adam J Luginbuhl","doi":"10.1158/1078-0432.CCR-24-0037","DOIUrl":"10.1158/1078-0432.CCR-24-0037","url":null,"abstract":"<p><strong>Purpose: </strong>We evaluated whether indoleamine 2,3-dioxygenase (IDO1) inhibitor (IDOi) BMS986205 + PD-1 inhibitor nivolumab enhanced T-cell activity and augmented immune-mediated antitumor responses in untreated, resectable head and neck squamous cell carcinoma (HNSCC). We employed response-adaptive surgical timing to identify responders to immunotherapy and enhance their response.</p><p><strong>Patients and methods: </strong>Patients with HNSCC were 3:1 randomized to receive nivolumab with or without BMS986205 orally daily (NCT03854032). In the combination arm, BMS986205 was initiated 7 days prior to nivolumab. Patients were stratified by human papillomavirus (HPV) status. Response-adaptive surgical timing involved response assessment by radiographic criteria 4 weeks after treatment with nivolumab in both arms. Nonresponders underwent surgical resection, whereas responders received 4 more weeks of randomized therapy before surgery. Biomarker analysis utilized pathologic treatment response (pTR) and RNA sequencing.</p><p><strong>Results: </strong>Forty-two patients were enrolled, and the addition of IDOi to nivolumab did not result in greater rate of radiographic response (P = 0.909). Treatment was well tolerated, with only 2 (5%) patients experiencing grade 3 immune-related adverse events. The addition of IDOi augmented rates of pTR in patients with high baseline IDO1 RNA expression (P < 0.05). Response-adaptive surgical timing demonstrated reliability in differentiating pathologic responders versus nonresponders (P = 0.009). A pretreatment NK cell signature, PD-L1 status, and IFN-γ expression in the HPV- cohort correlated with response. The HPV+ cohort found B-cell and cancer-associated fibroblast signatures predictive of response/nonresponse.</p><p><strong>Conclusions: </strong>Response-adaptive surgical timing enhanced treatment response. IDOi BMS986205 augmented pTR in patients with high IDO1 expression in baseline samples, indicating a need for identifying and targeting resistant nodes to immunotherapy. HPV status-dependent signatures predicting response to immunotherapy in HNSCC warrant further study.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"515-528"},"PeriodicalIF":10.0,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142709626","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}