Clinical Cancer Research最新文献

{"title":"Safety and Tolerability of Letetresgene Autoleucel (Lete-cel; 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":"https://doi.org/10.1158/1078-0432.CCR-24-1591","url":null,"abstract":"<p><strong>Purpose: </strong>To evaluate safety, tolerability, and anti-tumor response of lete-cel, genetically modified autologous T-cells expressing a T-cell receptor specific for NY-ESO-1/LAGE-1a shared epitope, alone or in combination with pembrolizumab, in human leukocyte antigen HLA-A*02-positive (HLA-A*02:01-, HLA-A*02:05-, and/or HLA-A*02:06-) patients with New York esophageal squamous cell carcinoma 1 (NY-ESO-1)- and/or LAGE-1a-positive non-small cell lung cancer (NSCLC).</p><p><strong>Experimental design: </strong>Study 208749 was a single-arm study of lete-cel alone. Study 208471 was a multi-arm study of lete-cel alone or in combination with pembrolizumab in patients with advanced or recurrent NSCLC.</p><p><strong>Results: </strong>Over 2500 patients were screened for target expression. In the multi-arm study, 738 (45%) of 1638 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 (AEs) were reported in either study. Cytopenias and cytokine release syndrome were the most common treatment-emergent AEs. Combining pembrolizumab with lete-cel did not appear to increase toxicity over lete-cel alone. Limited anti-tumor 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. Anti-tumor activity was observed in a limited number of patients.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":"https://doi.org/10.1158/1078-0432.CCR-24-2582","url":null,"abstract":"<p><strong>Purpose: </strong>The prognosis of patients with unresectable hepatocellular carcinoma (uHCC) and compensated cirrhosis is influenced by cancer progression. Data on the incidence and the prognostic role of clinical hepatic decompensation following immune checkpoint inhibitor therapy are lacking. We aimed to assess whether early clinical hepatic decompensation (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 IMbrave150 trial were analyzed. Cumulative incidence of CHD was assessed by competing risks analysis against HCC radiological progression. Early CHD and HCC radiological progression were assessed as predictors of OS by time-dependent Cox model.</p><p><strong>Results: </strong>The 3- and 12-month rates of CHD were 7% and 12%, respectively, while the 3- and 12-month rates of HCC radiological progression were 23% and 52%. Albumin-bilirubin(ALBI)grade 2 (Sub-distribution hazard ratio[sHR] 1.79, 95%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 radiological 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 uHCC undergoing systemic treatment. Within well-compensated participants, ALBI, 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":""},"PeriodicalIF":10.0,"publicationDate":"2024-11-22","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":"A phase II open label, randomized clinical trial of atezolizumab with or without human recombinant IL-7 (CYT107) in advanced urothelial cancer.","authors":"Randy F Sweis, Gurkamal S Chatta, Rohit K Jain, Helen Moon, Scott Edward Delacroix, Alana Fang, Leonard D'Amico, Angela Shaulov Kask, Martin A Cheever, Steven Fling, Elad Sharon, Andreanne Lacroix, Judith C Kaiser, Russell K Pachynski, Evan Y Yu","doi":"10.1158/1078-0432.CCR-24-1728","DOIUrl":"10.1158/1078-0432.CCR-24-1728","url":null,"abstract":"<p><strong>Purpose: </strong>Advanced urothelial cancer generally has high mortality despite modern anti-PD-1/L1 antibody-based combinations. Augmenting checkpoint inhibitor-mediated immune responses with lymphocyte growth factors may improve outcomes. We conducted a randomized phase II study (CITN-14) in 47 patients to explore whether human recombinant IL-7 (CYT107) could be safely combined with PD-L1 inhibition to enhance responses.</p><p><strong>Patients and methods: </strong>Patients with urothelial cancer following platinum chemotherapy were randomized to atezolizumab alone or with CYT107 weekly for four doses. The primary objective was clinical efficacy by objective response rate (ORR). Secondary objectives included safety, toxicity, and other clinical outcomes. Correlative endpoints included peripheral immunophenotyping and quantification of cytokines.</p><p><strong>Results: </strong>CYT107 plus atezolizumab was well-tolerated, without dose-limiting toxicities (DLTs), and lower grade 3-4 treatment-related adverse events (TRAEs) compared to atezolizumab. The ORR was 26.3% for the combination versus 23.8% for atezolizumab alone (p = 0.428). The complete response (CR) rate was 10.5% for the combination versus 4.8% for monotherapy. Three patients on the combination had responses >21 months versus one with monotherapy. CD4+ and CD8+ T lymphocyte expansion occurred in patients with response to combination therapy, with the greatest effect in T memory stem cell (Tscm) cells. Responding patients had elevated baseline CCL4 and decreased VEGF-A and TNF.</p><p><strong>Conclusions: </strong>Combining CYT107 with atezolizumab was safe and resulted in lymphocyte expansion, a doubling of the CR rate, and durable responses exceeding 2 years, however, the ORR was similar to atezolizumab alone. Increased and sustained doses of CYT107 coupled with patient selection strategies should be further investigated.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142686251","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 Z 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":"https://doi.org/10.1158/1078-0432.CCR-24-0841","url":null,"abstract":"<p><strong>Purpose: </strong>Preclinical data motivate clinical evaluation of inhibitors of mitogen-activated protein kinase-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>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 addition of paclitaxel until disease progression or toxicity. Serum drug levels were measured, and pharmacodynamic endpoints included immunohistochemistry, 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>Conclusion: </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":""},"PeriodicalIF":10.0,"publicationDate":"2024-11-22","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":"Quantitative and Morphology-Based Deep Convolutional Neural Network Approaches for Osteosarcoma Survival Prediction in the Neoadjuvant and Metastatic Setting.","authors":"Nicolas Coudray, Michael A. Occidental, Jose G. Mantilla, Adalberto Claudio Quiros, Ke Yuan, Jan Balko, Aristotelis Tsirigos, George Jour","doi":"10.1158/1078-0432.ccr-24-2599","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2599","url":null,"abstract":"Purpose: Necrosis quantification in the neoadjuvant setting using pathology slide review is the most important validated prognostic marker in conventional osteosarcoma. Herein, we explored three deep learning strategies on histology samples to predict outcome for OSA in the neoadjuvant setting. Experimental Design: Our study relies on a training cohort from New York University (New York, NY) and an external cohort from Charles university (Prague, Czechia). We trained and validated the performance of a supervised approach that integrates neural network predictions of necrosis/tumor content, and compared predicted overall survival (OS) using Kaplan-Meier curves. Furthermore, we explored morphology-based supervised and self-supervised approaches to determine whether intrinsic histomorphological features could serve as a potential marker for OS in the setting of neoadjuvant. Results: Excellent correlation between the trained network and the pathologists was obtained for the quantification of necrosis content (R2=0.899, r=0.949, p &amp;lt; 0.0001). OS prediction cutoffs were consistent between pathologists and the neural network (22% and 30% of necrosis, respectively). Morphology-based supervised approach predicted OS with p-value=0.0028, HR=2.43 [1.10-5.38]. The self-supervised approach corroborated the findings with clusters enriched in necrosis, fibroblastic stroma, and osteoblastic morphology associating with better OS (lg2HR; -2.366; -1.164; -1.175; 95% CI=[-2.996; -0.514]). Viable/partially viable tumor and fat necrosis were associated with worse OS (lg2HR;1.287;0.822;0.828; 95% CI=[0.38-1.974]). Conclusions: Neural networks can be used to automatically estimate the necrosis to tumor ratio, a quantitative metric predictive of survival. Furthermore, we identified alternate histomorphological biomarkers specific to the necrotic and tumor regions themselves which can be used as predictors.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"5 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Phase II Basket Trial of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART) SWOG S1609: Vulvar Cancers","authors":"Young Kwang Chae, Lucy Corthell, Sandip Pravin. Patel, Robert Edwards, Jennifer M. Scalici, Hye Sung Kim, Liam IL-Young Chung, Megan Othus, Christine M. McLeod, Helen X. Chen, Elad Sharon, Howard Streicher, Christopher W. Ryan, Charles D. Blanke, Razelle Kurzrock","doi":"10.1158/1078-0432.ccr-24-1957","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1957","url":null,"abstract":"Background: Dual PD-1/CTLA-4 inhibition shows promise in various malignancies. The SWOG S1609 DART trial presents initial results of ipilimumab/nivolumab in vulvar cancers. Methods: DART is a prospective/open-label/multicenter (1,016 US sites)/multi-cohort phase II clinical trial of ipilimumab (1mg/kg intravenously every 6 weeks) plus nivolumab (240mg intravenously every 2 weeks). The primary endpoint was objective response rate [ORR, confirmed complete and partial responses (CR and PR, respectively)] per RECISTv1.1; progression-free survival (PFS), overall survival (OS), clinical benefit rate [CBR; overall response plus stable disease (SD) ≥6 months], and toxicity are secondary endpoints. Results: Sixteen evaluable patients (median age, 55.5 years; 0-6 prior therapies; no prior immunotherapy) were analyzed, all of whom had squamous cell carcinoma histology. ORR was 18.8% (3/16), CBR was 25% (4/16), and CBR plus unconfirmed PR rate was 31% (5/16); PFS was 34.1, 16.7. 15.5, 7.2 and 7.0 months for these five patients. The median PFS and OS were 2.2 and 7.6 months. The most common adverse events were diarrhea, fatigue, pruritus, anorexia, and nausea (25%, n=4 each). Grade 3-4 adverse events occurred in 25% of patients (n=4). There was 1 grade 1-2 adverse event (6.7%) that led to discontinuation, and 1 (6.7%) grade 5 death adverse event. Conclusion: Ipilimumab plus nivolumab in vulvar cancers resulted in an objective response in three out of 16 patients, all of whom had durable responses lasting over one year. Notably, two additional patients experienced durable SD and unconfirmed PR. Correlative studies to determine response and resistance markers are ongoing.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"108 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673888","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":"Hormone Receptor Positive HER2-negative/MammaPrint High-2 Breast Cancers Closely Resemble Triple Negative Breast Cancers","authors":"Alejandro Rios-Hoyo, Kaitlyn Xiong, Jiawei Dai, Christina Yau, Michal Marczyk, Rolando Garcia-Milian, Denise M. Wolf, Laura A. Huppert, Rita Nanda, Gillian L. Hirst, Erin F. Cobain, Laura J. van 't Veer, Laura J. Esserman, Lajos Pusztai","doi":"10.1158/1078-0432.ccr-24-1553","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1553","url":null,"abstract":"Purpose: The MammaPrint prognostic assay categorizes breast cancers into high- and low-risk subgroups, and the high-risk group can be further subdivided into high 1 (MP-H1), and very high-risk high-2 (MP/H-2). The aim of this analysis was to assess clinical and molecular differences between the hormone receptor positive/HER2-negative (HR+) MP-H1, -H2, and triple negative (TN) MP-H1 and -H2 cancers. Experimental design: Pre-treatment gene expression data from 742 HER2 negative breast cancers enrolled in the I-SPY2 neoadjuvant trial was used. Prognostic risk categories were assigned using the MammaPrint assay. Transcriptional similarities across the 4 receptor and prognostic groups were assessed using principal component analyses and by identifying differentially expressed genes. We also examined pathologic complete response (pCR) rates and event-free survivals (EFS) by risk group. Results: Principal component analysis showed that HR+/MP-H2 tumors clustered with TN/MP-H2 cancers. Only 125 genes showed differential expression between the HR+/MP-H2 and TN/MP-H2 cancers while 1,465 genes were differentially expressed between HR+/MP-H2 and -H1. Gene set analysis revealed similarly high expression of cell cycle, DNA repair, and immune-infiltration related pathways in HR+/MP-H2 and TN/MP-H2 cancers. HR+/MP-H2 cancers also showed low estrogen receptor (ER)-related gene expression. pCR rates were similarly high in TN/MP-H2 and HR+/MP-H2 cancers (42% vs 30.5%, p=0.11), and MP-H2 cancers with residual cancer had similarly poor EFS regardless of ER status. Conclusions: In conclusion, HR+/MP-H2 cancers closely resemble TN breast cancers in transcriptional and clinical features and benefit from similar treatment strategies.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"14 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Phase II Study of Fulvestrant plus Abemaciclib in Hormone Receptor-Positive Advanced or Recurrent Endometrial Cancer","authors":"Angela K. Green, Qin Zhou, Alexia Iasonos, William A. Zammarrelli, Britta Weigelt, Lora H. Ellenson, Rashmi Chhetri-Long, Pooja Shah, Jade Loh, Vania Hom, Pier Selenica, Joseph Erinjeri, Iva Petkovska, Sarat Chandarlapaty, Seth Cohen, Rachel Grisham, Jason Konner, Maria M. Rubinstein, William Tew, Tiffany Troso-Sandoval, Carol Aghajanian, Vicky Makker","doi":"10.1158/1078-0432.ccr-24-1999","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1999","url":null,"abstract":"Purpose: Inhibition of the cyclin D-cyclin dependent kinase (CDK)4/6-INK4-retinoblastoma pathway can overcome acquired or de novo treatment resistance to endocrine monotherapy. Responses to endocrine monotherapy in advanced endometrial cancer (EC) are suboptimal, perhaps due to genomic alterations that promote estrogen receptor (ER)-independent cyclin D1-CDK4/6 activation. We hypothesized that addition of abemaciclib, a CDK4/6 kinase inhibitor, to antiestrogen therapy with fulvestrant will be an effective therapeutic strategy in patients with advanced or recurrent EC. Methods: In this phase II study, patients with advanced or recurrent EC received 150 mg of abemaciclib orally twice daily with 500 mg of fulvestrant intramuscularly monthly with a 2-week loading dose. Eligibility included ER or progesterone receptor expression ³1% by immunohistochemistry, measurable disease, £2 prior lines of chemotherapy, and £1 prior line of hormonal therapy. The primary endpoint was objective response rate (ORR) by RECIST v1.1. Results: Twenty-seven patients initiated therapy and 25 were evaluable for efficacy. Eleven patients achieved partial response; 10 responses (91%) were in copy number-low/no specific molecular profile tumors, 1 (9%) was in a microsatellite instability-high tumor, and no responses were observed in copy number-high/TP53abnormal tumors. The ORR was 44% (90% CI, 27.0%-62.1%). Median duration of response was 15.6 months. Median progression-free survival was 9.0 months (90% CI: 1.8-20.4). The most common grade ³3 treatment-related adverse events were neutropenia (26%) and anemia (19%); no new safety signals were identified. Conclusions: The combination of abemaciclib and fulvestrant has promising activity with durable responses in advanced or recurrent EC; a randomized trial is planned.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"251 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673896","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":"Analysis of shared variants between cancer biospecimens","authors":"Michael B. Foote, James Robert. White, Walid K. Chatila, Guillem Argilés, Steve Lu, Benoit Rousseau, Oliver Artz, Paul Johannet, Henry Walch, Mitesh Patel, Michelle F. Lamendola-Essel, David Casadevall, Somer Abdelfattah, Shrey Patel, Rona Yaeger, Andrea Cercek, Clara Montagut, Michael Berger, Nikolaus Schultz, Luis A. Diaz","doi":"10.1158/1078-0432.ccr-24-1583","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1583","url":null,"abstract":"Purpose: Mutational data from multiple solid and liquid biospecimens of a single patient is often integrated to track cancer evolution. However, there is no accepted framework to resolve if individual samples from the same individual share variants due to common identity versus coincidence. Experimental Design: Utilizing 8,000 patient tumors from The Cancer Genome Atlas (TCGA) across 33 cancer types, we estimated background rates of co-occurrence rates of mutations between discrete pairs of samples across cancers and by cancer type. We developed a mutational profile similarity score (MPS) that uses a large background database to produce confidence estimates that two tumors share a unique, related molecular profile. The MPS algorithm was applied to randomly paired tumor profiles, including patients who underwent repeat solid tumor biopsies sequenced with MSK-IMPACT (n=53,113). We also evaluated the MPS in sample pairs from single patients with multiple cancers (n=2,012), as well as patients with plasma and solid-tumor variant profiles (n=884 patients). Results: In unrelated tumors, nucleotide-specific variants are shared in 1.3% (cancer-type agnostic) and in 10-13% (cancer-type specific) of cases. The mutational profile similarity (MPS) method contextualized shared variants to specify whether patients had a single cancer versus multiple distinct cancers. When multiple tumors were compared from the same patient, and an initial clinicopathologic diagnosis was discordant with molecular findings, the MPS anticipated future diagnosis changes in 28% of examined cases. Conclusions: Use of a novel shared variant framework can provide information to clarify the molecular relationship between compared biospecimens with minimal required input.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"11 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673880","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":"Clinical Pharmacology of Cytokine Release Syndrome with T-cell Engaging Bispecific Antibodies: Current Insights and Drug Development Strategies.","authors":"Kendra K Radtke, Brendan C Bender, Zao Li, David C Turner, Sumedha Roy, Anton Belousov, Chi-Chung Li","doi":"10.1158/1078-0432.CCR-24-2247","DOIUrl":"10.1158/1078-0432.CCR-24-2247","url":null,"abstract":"<p><p>Cytokine release syndrome (CRS) is a common acute toxicity in T-cell therapies, including T-cell engaging bispecific antibodies (T-BiSp). Effective CRS management and prevention is crucial in T-BiSp development. Required hospitalization for 7 of the 9 approved T-BiSp and the need for clinical intervention in severe cases highlight the importance of mitigation strategies to reduce healthcare burden and improve patient outcome. In this review, we discuss the emerging evidence on CRS mitigation, management, and prediction. We cover different strategies for dose optimization, current and emerging (pre)treatment strategies, quantitative pharmacology tools employed during drug development, and biomarkers and predictive factors. Insights are gleaned on step-up dosing and formulation effects on CRS and CRS relationships with cytokine dynamics and drug levels gathered through review of T-BiSp licensing applications and emerging data from conferences and publications.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667404","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}