Clinical Cancer Research最新文献

{"title":"Clonal Evolution of PPM1D Mutations in the Spectrum of Myeloid Disorders.","authors":"David Fandrei, Jean Pegliasco, Florence Pasquier, Nathalie Ibrahim, Maria Kfoury, Céline Berthon, Mael Heiblig, Delphine Lebon, Ambroise Marçais, Mathieu Meunier, Ahmad Al Jijakli, Emilie Lemasle, Sylvain Chantepie, Cecile Pautas, Pierre-Yves Dumas, Celia Salanoubat, Diana Carp, Romain Loyaux, Cyril Quivoron, Arnaud Pages, Bastien Job, Remy Jelin, Gerome Jules-Clement, Iléana Antony-Debré, Aline Renneville, Sophie Cotteret, Raphael Itzykson, Herve Dombret, Nicolas Duployez, Nathalie Droin, Alexandra Leary, Christophe Marzac, Elsa Bernard, Jean-Baptiste Micol","doi":"10.1158/1078-0432.CCR-24-3683","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-3683","url":null,"abstract":"<p><strong>Purpose: </strong>PPM1D, a central regulator of the DNA damage response, is commonly mutated in therapy-related clonal hematopoiesis (CH), acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). PPM1D mutations have been shown to expand under selective pressure of DNA-damaging chemotherapy. However, whether PPM1D mutations promote the development of hematologic malignancies remains unclear.</p><p><strong>Experimental design: </strong>We characterized the clinical and genomic profiles of 112 PPM1D-mutated patients across the spectrum of myeloid disorders using a combination of bulk and single-cell analyses on diagnostic and longitudinal samples.</p><p><strong>Results: </strong>Among all patients, 78% had a history of primary cancer, with DNMT3A and TP53 being the most frequent co-mutated genes. In ten patients with high-grade serous ovarian cancer, longitudinal analysis showed variable dynamics of PPM1D-mutant clones, with 81% of clones expanding during exposure to alkylating agents. Clonal hierarchy estimation revealed that 44% of PPM1D-mutated acute myeloid leukemia (AML) patients had a PPM1D mutation in the founder clone, with rare TP53 co-mutations. Both TP53 wildtype and mutated AML patients had poor overall survival. Single cell DNA and surface protein analysis in seven patients confirmed that PPM1D mutations can arise in the founding clone, and were associated with expression of leukemic markers.</p><p><strong>Conclusions: </strong>PPM1D mutated CH clones can spontaneously regress after treatment discontinuation, however they can also be found in the dominant clone in AML/MDS.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751343","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 1, first-in-human, dose-escalation, expansion trial of cytokine encoding synthetic mRNA-mixture alone or with cemiplimab in advanced solid tumors.","authors":"Oliver Bechter, Carmen Loquai, Stephane Champiat, Jean-Francois Baurain, Jean-Jacques Grob, Jochen Utikal, Sylvie Rottey, Alfonso Berrocal, Jessica C Hassel, Ana Arance, Miguel F Sanmamed, Marye Boers-Sonderen, Brian Gastman, Christoffer Gebhardt, Brant Delafontaine, Ugur Sahin, Özlem Türeci, Patrick Brueck, Giovanni Abbadessa, Rahul Marpadga, Helen Lee, Yue Yang, Barbara Buday, Gianfranco Di Genova, Hong Wang, Binfeng Xia, Joon Sang Lee, Céleste Lebbe","doi":"10.1158/1078-0432.CCR-24-1983","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-1983","url":null,"abstract":"<p><strong>Purpose: </strong>We investigated SAR441000 (mixture of four mRNAs encoding interleukin [IL]-12, single chain interferon [IF]-α-2b, granulocyte-macrophage colony-stimulating factor, and IL-15 sushi domain) alone or in combination with cemiplimab in patients with advanced solid tumors.</p><p><strong>Patients and methods: </strong>SAR441000 was intratumorally administered weekly in a 4-week cycle in monotherapy and in a 3-week cycle at a pre-defined dose level (DL) with 350 mg cemiplimab (intravenously) every 3 weeks in combination therapy. The primary objective was to determine maximum tolerated or maximum administered dose (MAD), overall safety, tolerability, and objective response rate of SAR441000.</p><p><strong>Results: </strong>We enrolled 77 patients previously treated with anti-cancer therapies (escalation monotherapy: N=21; escalation combination: N=15; and expansion combination [PD-1 refractory melanoma]: N=41). MAD at DL8 was 4000 µg. The most common Grade ≥3 treatment-related adverse event was fatigue in escalation phase (monotherapy: 28.6%; combination therapy: 66.7%) and injection-site pain (31.7%) in expansion phase. In combination therapy, one patient in escalation and two in expansion phase achieved partial responses. At 4000 μg (highest dose) across all cohorts, the maximum fold change in plasma cytokine concentration was the highest and lowest for IFN-α-2 (74.9-folds) and IL-15 (1.96-folds), respectively. Increased blood IFN-γ and IP-10 levels were observed for most patients.</p><p><strong>Conclusions: </strong>Intratumoral administration of SAR441000 in combination with cemiplimab, was generally well tolerated with anti-tumor activity in loco-regional disease setting. Anecdotal evidence of pharmacodynamic immune-modulatory effect and distant non-injected lesion anti-tumor response was observed, without significant effect in patients with advanced solid tumors previously treated with anti-PD1 therapies.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729013","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":"Identification of Early-Stage Breast Cancer with Minimal Risk of Recurrence by Breast Cancer Index.","authors":"Marie-France Jilderda, Yi Zhang, Valerie Rebattu, Ranelle Salunga, Wilma Mesker, Jenna Wong, Linda de Munck, Tommy Fornander, Bo Nordenskjöld, Olle Stål, Amanda K L Anderson, Esther Bastiaannet, Kai Treuner, Gerrit-Jan Liefers","doi":"10.1158/1078-0432.CCR-24-3836","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-3836","url":null,"abstract":"<p><strong>Purpose: </strong>This study assessed the prognostic ability of Breast Cancer Index (BCI) to identify patients at minimal risk (<5%) of 10-year distant recurrence (DR) who are unlikely to benefit from adjuvant endocrine therapy.</p><p><strong>Experimental design: </strong>This prospective translational study included postmenopausal patients with early-stage, HR+ N0 breast cancer from the Stockholm (STO-3) trial who underwent surgery alone (\"untreated\") or surgery plus adjuvant tamoxifen (\"treated\") and the Netherlands Cancer Registry (NCR; surgery alone). The primary endpoint was time to DR. An adjusted BCI model with an additional cut-point was developed that stratified patients into 4 prognostic risk groups.</p><p><strong>Results: </strong>Across cohorts, 16%-22% of patients were classified as minimal risk of 10-year DR. In the Stockholm untreated cohort (n = 283), risks in the minimal, low, intermediate, and high risk groups were 2.3%, 15.5% (hazard ratio, 4.71 [95% CI, 1.09-20.29] versus minimal risk), 19.8% (6.97 [1.61-30.18]), and 35.9% (13.21 [3.07-56.76]), respectively (P < .001). In the Stockholm treated cohort (n = 317), risks were 4.3%, 5.0% (1.16 [0.35-3.85]), 11.7% (2.45 [0.74-8.14]), and 21.1% (5.27 [1.72-16.16]; P < .001). In the NCR cohort (n = 1245), risks were 4.5%, 7.5% (sub-distribution hazard ratio, 1.67 [95% CI, 0.81-3.45]), 10.3% (2.40 [1.14-5.03]), and 13.1% (3.13 [1.50-6.55]; P = .005). BCI risk scores provided additional independent information over standard prognostic factors (likelihood ratio, c2 = 7.98; P = .004).</p><p><strong>Conclusions: </strong>The adjusted BCI model identified women with early-stage, HR+ N0 breast cancer at minimal risk of DR who may consider de-escalating adjuvant endocrine therapy.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718019","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":"Modelling MRD changes in myeloma to understand treatment effects, predict outcomes, and investigate curative potential.","authors":"Walter M Gregory, Thomas J Prior, J Blake Bartlett, Pieter Sonneveld, Meletios A Dimopoulos, Philippe Moreau, Saad Usmani, Thierry Facon","doi":"10.1158/1078-0432.CCR-24-3475","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-3475","url":null,"abstract":"<p><strong>Purpose: </strong>We designed mathematical models to describe and quantify the mechanisms and dynamics of minimal residual disease (MRD) in order to better understand these MRD dynamics, to inform future treatment design, including when to stop or change treatment, and to extrapolate from current PFS times to predict future PFS curves.</p><p><strong>Experimental design: </strong>To model individual sequential MRD data from phase III clinical trials (MAIA, CASTOR, and POLLUX) using previously developed mathematical models which would be modified as necessary to accurately correspond with the actual MRD data. These models would then be used to extrapolate PFS curves ahead in time.</p><p><strong>Results: </strong>Patients with low MRD values either showed rapid disease regrowth or the MRD values remained low for a prolonged period. Treatment appeared to be most effective in terms of cell-kill within the first 6 to 12 months. Regrowth rates were correlated with estimated initial residual disease, particularly in MRD negative patients. Three-year model extrapolations of PFS were closely comparable to clinical trial data.</p><p><strong>Conclusions: </strong>This model could provide early prediction of PFS outcomes, which otherwise takes lengthy periods of time to observe with clinical trials. Patients showing rapid rebound from low MRD values may benefit from adding another treatment before reaching progressive disease. The MRD analyses and results presented, such as the results about efficacy occurring early in the first 6 to 12 months, may help guide the development and selection of optimal regimens. Longer follow-up periods and application to other trials and datasets are required to substantiate these findings.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718092","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 Proteogenomic View of Synchronous Endometrioid Endometrial and Ovarian Cancer.","authors":"Fabian Coscia, Annelaura B Nielsen, Melanie Weigert, Karen Watters, Melissa Javellana, Michael Anglesio, S Diane Yamada, Ricardo R Lastra, Matthias Mann, Ernst Lengyel","doi":"10.1158/1078-0432.CCR-24-1763","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-1763","url":null,"abstract":"<p><strong>Purpose: </strong>Increasing genomics-based evidence suggests that synchronous endometrial and ovarian cancer (SEOC) represents clonally related primary and metastatic tumors. A systematic analysis of the global protein landscape of SEOCs, heretofore lacking, could reveal functional and disease-specific consequences of known genetic alterations, the directionality of metastasis, and accurate histological markers to distinguish SEOCs from single-site tumors.</p><p><strong>Experimental design: </strong>We performed a systematic proteogenomic analysis of 29 patients diagnosed with SEOC at three international gynecologic oncology treatment centers (Chicago, Vancouver, Tübingen). For direct comparison to single-site tumors, we included 9 patients with single-site endometrioid ovarian and 26 patients with single-site endometrial endometrioid cancer. For all 64 patients, we performed sequencing of a 275-gene cancer panel combined with compartment-resolved mass spectrometry (MS) based proteomics of consecutive tissue sections to compare global (6,000+ proteins), tumor, and stromal proteomes.</p><p><strong>Results: </strong>DNA-based panel sequencing confirmed that most SEOCs are clonally related. Global proteome profiling uncovered pronounced differences between SEOCs and single tumors and underscored the importance of the stromal proteome in defining and identifying SEOCs. We identified molecularly unique SEOC stromal proteomes, which were globally more related to single endometrial cancers. We finally derived a proteomic predictor distinguishing SEOCs from single-site ovarian and uterine tumors.</p><p><strong>Conclusions: </strong>The integrated proteogenomic data show that SEOCs are distinguishable from endometrial endometrioid or endometrioid ovarian cancers. Based on their proteogenomic similarity to endometrial endometrioid cancers, we conclude that most synchronous endometrial and ovarian cancers represent primary endometrial endometrioid cancers that have metastasized to the ovary.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718045","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":"Neoadjuvant BMS-813160, nivolumab, gemcitabine and nab-paclitaxel for patients with pancreatic cancer","authors":"Patrick M. Grierson, Crystal Wolf, Rama Suresh, Andrea Wang-Gillam, Benjamin R. Tan, Lee Ratner, Peter Oppelt, Olivia Aranha, Ashley Frith, Katrina S. Pedersen, Jennifer Spann, Nicholas Boice, Amberly Brown, John M. Baer, Emily G. Butka, Faiz Ahmad, Yifei Xu, Jingxia Liu, David G. DeNardo, Kian-Huat Lim","doi":"10.1158/1078-0432.ccr-24-1821","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1821","url":null,"abstract":"Background: Targeting tumor-associated macrophages through C-C chemokine receptor type 2 (CCRs) in pancreatic ductal adenocarcinoma (PDAC) improves the efficacy of chemotherapy and restores T cell immunity in preclinical models. Methods: We conducted a phase I/II single institution study (NCT03496662) combining chemotherapy gemcitabine and nab-paclitaxel (GnP), CCR2/5 inhibitor BMS-813160 and nivolumab for four 28-day cycles for patients with borderline resectable (BR) or locally advanced (LA) PDAC. The recommended phase 2 dose (RP2D) of BMS-813160 was established in the 3+3 design. Primary endpoints were safety and objective response rate (ORR). Secondary endpoints included resection rate, median progression-free survival (mPFS) and overall survival (mOS). Results: 8 patients were treated with GnP alone (control arm) and 31 patients (29 response evaluable) were treated at RP2D. No grade 3/4 toxicities attributed to nivolumab or BMS-813160 were identified. After 4 cycles of study treatment (N=26), ORR was 35.7% and 16.7% among BR- and LA-PDAC patients respectively, compared to 0% of control patients. 78.6% BR- and 16.7% of LA-PDAC patients who completed study treatment underwent surgical resection. For intent-to-treat analyses, BR-PDAC patients had a mPFS and mOS of 14.6 and 20.4 months respectively; and for LA-PDAC patients, were 14.7 and 17 months, respectively. Biomarker analyses showed decreased intratumoral monocytes, macrophages, enhanced T cell proliferation and effector gene expression. Conclusions: Neoadjuvant BMS-813160/nivolumab/GnP was well tolerated and appears to achieve comparable ORR and resectability to historical data, however with prolonged PFS and OS in LA-PDAC patients, warranting a larger phase II study with a more efficacious CCR2-targeted therapeutic.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"45 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677646","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":"Riluzole in Combination with mFOLFOX6 and Bevacizumab in Treating Patients with Metastatic Colorectal Cancer: A Phase 1 Clinical Trial","authors":"Chunjie Li, Anne M. Noonan, John Hays, Sameek Roychowdhury, Pannaga Malalur, Rifat Elkhatib, Ashish Manne, Arjun Mittra, Shafia Rahman, Liwei Yan, Kasey Hill, Nicole Abbott, Mitch Phelps, Joo Young Na, Beiyuan Liang, Hayden Storts, Misbah Khan, Evan H. Zhang, Wayne Miles, Vedat Yildiz, Lai Wei, Jing J. Wang, Ning Jin","doi":"10.1158/1078-0432.ccr-24-3964","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3964","url":null,"abstract":"BACKGROUND: Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the US. 5-fluorouracil (5-FU)-based chemotherapies in combination with targeted agents remain the standard of care in patients with metastatic or locally advanced disease. New treatment strategies are needed for metastatic CRC patients with microsatellite stable disease. Preclinical studies showed that riluzole, an oral medicine for amyotrophic lateral sclerosis, inhibits glutamate release and synergizes with 5-FU to reduce cell viability in CRC cell lines. METHODS: In this single-arm, phase 1 trial of riluzole in combination with mFOLFOX6/bevacizumab for patients with metastatic CRC, the riluzole dose started at 50 mg twice daily, escalating to 100 mg twice daily or de-escalating to 50 mg once daily. Patients received riluzole for 16 weeks in combination with mFOLOFX6/bevacizumab for 8 cycles. Patients then either continued mFOLFOX6/bevacizumab or switched therapy. RESULTS: Twelve of the 14 patients enrolled were evaluable. All patients previously received FOLFOX, and 5 patients (41.7%) showed disease resistance to it. Two patients obtained partial responses, 9 had stable disease, and 1 had progressive disease. The objective response rate was 16.7%, and the disease control rate was 91.7%. The median duration of response was 4.9 months (95% CI 1.6-9.8). Median progression-free survival and overall survival were 4.89 and 12.98 months, respectively. CONCLUSION: Our study showed that riluzole plus mFOLFOX6/bevacizumab is well tolerated in patients with metastatic CRC and may have clinical activity in patients whose disease is resistant to FOLFOX.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"49 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143665863","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":"Detection of circulating tumor DNA using a tissue-free epigenomic assay is a highly prognostic biomarker in early-stage triple negative breast cancer","authors":"Foluso O. Ademuyiwa, Cynthia X. Ma, Katherine Weilbaecher, Rama Suresh, Lindsay L. Peterson, Ron Bose, Nusayba Bagegni, Caron E. Rigden, Ashley Frith, Katherine Clifton, Derek Dustin, Mingyang Cai, Liyang Xiong, Sai Chen, Andrew Davis","doi":"10.1158/1078-0432.ccr-24-3145","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3145","url":null,"abstract":"Purpose: Clinical tools to monitor treatment response and metastatic risk could improve early-stage triple-negative breast cancer (TNBC) care. While molecular residual disease (MRD) assays show promise, their use in the neoadjuvant setting requires rapid turnaround times. Tissue-informed approaches may be challenging for patients with limited biopsy samples. The objectives were to determine the surveillance sensitivity for detecting metastatic recurrence and evaluate the ctDNA response to neoadjuvant therapy using a tissue-free epigenomic assay. Patients and Methods: Patients with stage II or III TNBC undergoing neoadjuvant docetaxel and carboplatin chemotherapy on a clinical trial (NCT02124902) followed by surgery with or without adjuvant therapy were included in this study. Blood samples were prospectively collected prior to, during, and after completion of neoadjuvant therapy (NAT), and after surgery at pre-specified surveillance time points. Plasma samples were analyzed by Guardant Reveal. Results: A total of 119 TNBC patients were included in the analysis. ctDNA was detected in the post-surgical setting in 8.9% (7/79) of patients, with an 83% (5/6) patient-level surveillance sensitivity for metastatic recurrence and 99.5% (197/198) sample-level specificity. Post-surgical ctDNA detection was prognostic for shorter recurrence-free interval (RFI; HR 37.7, p&amp;lt;0.0001). ctDNA detection at the post-NAT pre-surgical time point was also associated with shorter RFI in patients with residual disease at surgery (HR 28.2, p&amp;lt;0.0001). Conclusions: In early-stage TNBC patients, a tissue-free, epigenomic assay and demonstrated high specificity and sensitivity for metastatic recurrence. ctDNA detection in the neoadjuvant setting indicated poor prognosis, highlighting its potential role across breast cancer care.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"92 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143672356","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":"Facts and hopes of CD40 agonists as a cancer immunotherapy","authors":"John C. McVey, Gregory L. Beatty","doi":"10.1158/1078-0432.ccr-24-1660","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1660","url":null,"abstract":"CD40 agonists are a promising class of immunotherapeutic agents that potentiate both innate and adaptive immunity. This review examines the established facts and prospects of CD40 agonists in cancer immunotherapy. CD40, a co-stimulatory receptor of the TNF receptor superfamily, is found on antigen-presenting cells. CD40 activation licenses dendritic cells to prime tumor-specific T cells, polarizes macrophages to a pro-inflammatory phenotype, activates B cells, and facilitates tumor fibrosis remodeling. Preclinical models demonstrate the significant potential of CD40 agonists to induce anti-tumor immunity, leading to the development of various CD40-activating therapeutics, including monoclonal antibodies, recombinant CD40L, and ectopic expression of CD40L via gene transfer. While clinical trials show modest antitumor activity, some patients experience durable responses, especially when CD40 agonists are combined with other therapies such as immune checkpoint inhibitors and chemotherapy. These combinations, tested in traditionally difficult-to-treat cancers like pancreatic cancer, provide hope for improved outcomes. Current research focuses on refining CD40 agonist therapies through novel combination strategies, improving patient selection, and the development of tumor-targeted CD40 agonists and Fc-engineered antibodies which aim to enhance efficacy while mitigating toxicity. However, significant challenges remain, particularly in identifying patients most likely to benefit from CD40 immunotherapy and understanding resistance mechanisms. Addressing these challenges is crucial for guiding effective combination strategies and optimizing treatment outcomes. By examining both established facts and ongoing developments, this review provides a comprehensive overview of the status and potential of CD40 agonists in cancer immunotherapy.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"22 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143672338","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":"Precision Endocrine Therapy in Endometrial Cancer: Has its time finally come?","authors":"Vikas Garg, Amit M. Oza","doi":"10.1158/1078-0432.ccr-24-3905","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3905","url":null,"abstract":"Endocrine therapy (ET) has been underexplored in endometrial cancer (EC). Emerging data suggest that combining ET with CDK4/6 inhibitors improve outcomes in EC. This commentary complements a recent CCR manuscript and reviews opportunities to improve precision ET, and the potential to overcome resistance mechanisms associated with ET failure.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"20 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143672339","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}