Benjamin E Warner,Japan Patel,Renwei Wang,Jennifer Adams-Haduch,Yu-Tang Gao,Woon-Puay Koh,Ka Wo Wong,Alan K S Chiang,Jian-Min Yuan,Kathy H Y Shair
{"title":"The Epstein-Barr virus nuclear antigen 1 variant associated with nasopharyngeal carcinoma defines the sequence criteria for serologic risk prediction.","authors":"Benjamin E Warner,Japan Patel,Renwei Wang,Jennifer Adams-Haduch,Yu-Tang Gao,Woon-Puay Koh,Ka Wo Wong,Alan K S Chiang,Jian-Min Yuan,Kathy H Y Shair","doi":"10.1158/1078-0432.ccr-24-1142","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1142","url":null,"abstract":"PURPOSEAntibodies to select Epstein-Barr virus (EBV) proteins can diagnose early-stage nasopharyngeal carcinoma (NPC). We have previously shown that IgA against EBV nuclear antigen 1 (EBNA1) can predict incident NPC in high- and intermediate-risk cohorts 4 years pre-diagnosis. Here, we tested EBNA1 variants, with mutants, to define the sequence requirements for an NPC risk assay.DESIGNMammalian-expressed constructs were developed to represent EBNA1 variants 487V and 487A which can differ by ≥15 amino acids in the N- and C-termini. Denatured lysates were evaluated by a refined IgA and IgG immunoblot assay in a case-control study using pre-diagnostic NPC sera from two independent cohorts in Singapore and Shanghai, P.R. China.RESULTSAt 95% sensitivity, 487V yielded a 94.9% specificity compared to 86.1% for 487A. EBNA1 deleted for the conserved glycine-alanine repeats (GAr) reduced false positives by 22.8%. NPC sera reacted more strongly to the C-terminus than healthy controls, but the C-terminal construct (a.a. 390-641) showed lower specificity (84.8%) than the EBNA1 GAr deleted construct (92.4%) at 95% sensitivity.CONCLUSIONAlthough EBNA1 IgA was present in healthy sera, most epitopes localized to the immunodominant GAr. We conclude that a refined EBNA1 antigen deleted for the GAr but with residues consistently detected in Southeast Asian NPC tumors is optimal for risk prediction with an extended sojourn time of 7.5 years. Furthermore, distinct EBNA1 serologic profiles enhanced the utility of the EBNA1 IgA assay for risk stratification. This illustrates the importance of serologically relevant EBNA1 sequences for NPC risk prediction and early detection.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142174538","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}
Yoshiko Nakano,Roland P Kuiper,Kim E Nichols,Christopher C Porter,Harry Lesmana,Julia Meade,Christian P Kratz,Lucy A Godley,Luke D Maese,Maria Isabel Achatz,Payal P Khincha,Sharon A Savage,Andrea S Doria,Mary-Louise C Greer,Vivian Y Chang,Lisa L Wang,Sharon E Plon,Michael F Walsh
{"title":"Update on Recommendations for Cancer Screening and Surveillance in Children with Genomic Instability Disorders.","authors":"Yoshiko Nakano,Roland P Kuiper,Kim E Nichols,Christopher C Porter,Harry Lesmana,Julia Meade,Christian P Kratz,Lucy A Godley,Luke D Maese,Maria Isabel Achatz,Payal P Khincha,Sharon A Savage,Andrea S Doria,Mary-Louise C Greer,Vivian Y Chang,Lisa L Wang,Sharon E Plon,Michael F Walsh","doi":"10.1158/1078-0432.ccr-24-1098","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1098","url":null,"abstract":"Genomic instability disorders are characterized by DNA or chromosomal instability resulting in various clinical manifestations including developmental anomalies, immunodeficiency, and increased risk to develop cancers beginning in childhood. Many of these genomic instability disorders also present with exquisite sensitivity to anticancer treatments such as ionizing radiation and chemotherapy, which may further increase the risk of second cancers. In July 2023, the American Association of Cancer Research held the second Childhood Cancer Predisposition Workshop where multidisciplinary international experts discussed, reviewed, and updated recommendations for children with cancer predisposition syndromes. This article will discuss childhood cancer risks and surveillance recommendations for the group of genomic instability disorders with predominantly recessive inheritance, including the DNA repair disorders ataxia telangiectasia, Nijmegen breakage syndrome, Fanconi anemia, Xeroderma Pigmentosum, Bloom syndrome, and Rothmund-Thomson syndrome, as well as the telomere biology disorders and mosaic variegated aneuploidy. Recognition of children with genomic instability disorders is important in order to make the proper diagnosis, enable genetic counseling, and inform cancer screening, cancer risk reduction, and choice of anti-cancer therapy.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142174607","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}
Olivier Rixe,John L Villano,Robert Wesolowski,Anne M Noonan,Vinay K Puduvalli,Trisha M Wise-Draper,Richard Curry,Emrullah Yilmaz,Charlie Cruze,Besim Ogretmen,Gilles Tapolsky,Ray Takigiku
{"title":"A first-in-human phase 1 study of BXQ-350, a first-in-class sphingolipid metabolism regulator, in patients with advanced/recurrent solid tumors or high-grade gliomas.","authors":"Olivier Rixe,John L Villano,Robert Wesolowski,Anne M Noonan,Vinay K Puduvalli,Trisha M Wise-Draper,Richard Curry,Emrullah Yilmaz,Charlie Cruze,Besim Ogretmen,Gilles Tapolsky,Ray Takigiku","doi":"10.1158/1078-0432.ccr-24-1721","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1721","url":null,"abstract":"PURPOSEBXQ-350, a nanovesicle formulation of Saposin C, is an allosteric sphingolipid metabolism regulator that increases pro-apoptotic ceramide and decreases oncogenic sphingosine-1-phosphate (S1P) levels. We conducted a first-in-human, phase 1 study of BXQ-350.PATIENTS AND METHODSAdults (≥18 years old) with advanced/recurrent, treatment-refractory solid tumors or high-grade gliomas received BXQ-350 intravenously in five dose cohorts (0.7-2.4 mg/kg) in a 3+3 dose-escalation and expansion design. Primary endpoints during dose escalation were dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD); primary objective in expansion parts was assessment of anti-tumor activity (RECIST v1.1/RANO criteria).RESULTSEighty-six patients were enrolled. DLTs were not observed during dose escalation (n=18), and a MTD was not identified. An additional 68 patients received the 2.4 mg/kg dose. Nine patients (10%) discontinued due to adverse events (AEs). The most common treatment-related AEs were nausea (24%) and fatigue (23%). Eight patients had a progression-free survival (PFS) ≥6 months. Two of these achieved a partial response, and six had stable disease, among whom three had a reduction in ≥1 target lesion. Of those with PFS ≥6 months, seven remained on study for >12 months, five for >24 months, and after seven years, two remained on study without disease progression.CONCLUSIONSBXQ-350 was well tolerated as monotherapy at doses up to 2.4 mg/kg. It provided some lasting clinical benefit in patients with recurrent solid malignancies across several tumor types, consistent with a decreased systemic S1P/ceramide metabolic rheostat. BXQ-350 warrants further clinical investigation alone and combined with standard-of-care for advanced solid tumors.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142174537","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}
Caner Ercan,Salvatore Lorenzo Renne,Luca Di Tommaso,Charlotte K Y Ng,Salvatore Piscuoglio,Luigi M Terracciano
{"title":"Hepatocellular Carcinoma Immune Microenvironment Analysis: A Comprehensive Assessment with Computational and Classical Pathology.","authors":"Caner Ercan,Salvatore Lorenzo Renne,Luca Di Tommaso,Charlotte K Y Ng,Salvatore Piscuoglio,Luigi M Terracciano","doi":"10.1158/1078-0432.ccr-24-0960","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-0960","url":null,"abstract":"PURPOSEThe spatial variability and clinical relevance of the tumour immune microenvironment (TIME) are still poorly understood for hepatocellular carcinoma (HCC). Here we aim to develop a deep learning (DL)-based image analysis model for the spatial analysis of immune cell biomarkers, and microscopically evaluate the distribution of immune infiltration.EXPERIMENTAL DESIGNNinety-two HCC surgical liver resections and 51 matched needle biopsies were histologically classified according to their immunophenotypes: inflamed, immune-excluded, and immune-desert. To characterise the TIME on immunohistochemistry (IHC)-stained slides, we designed a multi-stage DL algorithm, IHC-TIME, to automatically detect immune cells and their localisation in TIME in tumour-stromal, centre-border segments.RESULTSTwo models were trained to detect and localise the immune cells on IHC-stained slides. The framework models, i.e. immune cell detection models and tumour-stroma segmentation, reached 98% and 91% accuracy, respectively. Patients with inflamed tumours showed better recurrence-free survival than those with immune-excluded or immune desert tumours. Needle biopsies were found to be 75% accurate in representing the immunophenotypes of the main tumour. Finally, we developed an algorithm that defines immunophenotypes automatically based on the IHC-TIME analysis, achieving an accuracy of 80%.CONCLUSIONSOur DL-based tool can accurately analyse and quantify immune cells on IHC-stained slides of HCC. The microscopical classification of the TIME can stratify HCCs according to the patient prognosis. Needle biopsies can provide valuable insights for TIME-related prognostic prediction, albeit with specific constraints. The computational pathology tool provides a new way to study the HCC TIME.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142174535","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":"TAK1 Promotes an Immunosuppressive Tumor Microenvironment through Cancer-Associated Fibroblast Phenotypic Conversion in Pancreatic Ductal Adenocarcinoma.","authors":"Nan Sheng,Koji Shindo,Kenoki Ohuchida,Tomohiko Shinkawa,Bo Zhang,Haimin Feng,Takeo Yamamoto,Taiki Moriyama,Naoki Ikenaga,Kohei Nakata,Yoshinao Oda,Masafumi Nakamura","doi":"10.1158/1078-0432.ccr-24-1004","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1004","url":null,"abstract":"PURPOSEWe aim to clarify the precise function of Transformed growth factor-beta 1 activated kinase-1 (TAK1) in cancer-associated fibroblasts (CAFs) within human pancreatic ductal adenocarcinoma (PDAC) by investigating its role in cytokine-mediated signaling pathways.EXPERIMENTAL DESIGNThe expression of TAK1 in pancreatic cancer was confirmed by TCGA data and human pancreatic cancer specimens. CAFs from freshly resected PDAC specimens were cultured and used in a three-dimensional model for direct and indirect co-culture with PDAC tumors to investigate TAK1 function. Additionally, organoids from KPC (LSL-K-RasLSLG12D/+; LSL-p53R172H/+; Pdx1-Cre) mice were mixed with CAFs and injected subcutaneously into C57BL/6 mice to explore in vivo functional interactions of TAK1.RESULTSTCGA data revealed significant upregulation of TAK1 in PDAC, associating with a positive correlation with the T-cell exhaustion signature. Knockdown of TAK1 in CAFs decreased the iCAF signature and increased the myCAF signature both in vitro and in vivo. The absence of TAK1 hindered CAF proliferation, blocked several inflammatory factors via multiple pathways associated with immunosuppression, and hindered EMT, outgrowth in vitro in spheroid co-cultures with PDAC cells. Additionally, TAK1 inhibitor restrained tumor growth, increased CD4+ and CD8+ T cell abundance, and reduced immunosuppressive cells present in vivo.CONCLUSIONSBlocking the TAK1+CAF phenotype leads to the conversion of protumorigenic CAFs to antitumorigenic CAFs. This highlights TAK1 as a potential therapeutic target, particularly in CAFs, and represents a novel avenue for combined immunotherapy in PDAC.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142174536","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}
Tobias Tix,Mohammad Alhomoud,Roni Shouval,Edward R Scheffer Cliff,Miguel-Angel Perales,David M Cordas Dos Santos,Kai Rejeski
{"title":"Second primary malignancies after CAR T-cell therapy: A systematic review and meta-analysis of 5,517 lymphoma and myeloma patients.","authors":"Tobias Tix,Mohammad Alhomoud,Roni Shouval,Edward R Scheffer Cliff,Miguel-Angel Perales,David M Cordas Dos Santos,Kai Rejeski","doi":"10.1158/1078-0432.ccr-24-1798","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-1798","url":null,"abstract":"PURPOSECAR T-cell therapy is a potent immunotherapy for hematologic malignancies, but patients can develop long-term adverse events including second primary malignancies (SPMs) that impact morbidity and mortality. To delineate the frequency and subtypes of SPMs following CAR-T in lymphoma and myeloma, we performed a systematic review and meta-analysis.DESIGNA literature search was conducted in the MEDLINE, Embase, and CENTRAL (Cochrane) databases. Following extraction of SPM cases and assignment of malignant origin, we analyzed SPM point estimates using random effect models.RESULTSWe identified 326 SPMs across 5,517 patients from 18 clinical trials (CT) and 7 real-world studies (RWS). With a median follow-up of 21.7 months, the overall SPM point estimate was 5.8% (95%CI 4.7-7.2). SPM estimates were associated with treatment setting (CT>RWS), duration of follow-up, and number of prior treatment lines, which were each confirmed as independent study-level risk factors of SPM in a meta-regression model. A subgroup meta-analysis of the four trials that randomized CAR-T versus standard-of-care revealed a similar risk of SPM with either treatment strategy (p=0.92). In a distribution analysis of SPM subtypes, hematologic malignancies were the most common (37%), followed by solid tumors (27%) and non-melanoma skin cancers (16%). T-cell malignancies represented a small minority of events (1.5%). We noted disease- and product-specific variations in SPM distribution.CONCLUSIONSThese data raise awareness of SPM as a clinically relevant long-term adverse event in patients receiving CAR T-cell therapy. However, our findings do not indicate that SPM frequency is higher with CAR-T versus previous standard-of-care strategies.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142170689","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}
Harper Hubbeling, Doris Leithner, Emily A. Silverman, Jessica Flynn, Sean Devlin, Gunjan Shah, Beatrice Fregonese, Beatriz Wills, Akshay Bedmutha, Ana Alarcon Tomas, Allison Parascondola, Amethyst Saldia, Ivan Landego, Carla Hajj, Alexander P. Boardman, Parastoo B. Dahi, Arnab Ghosh, Sergio Giralt, Richard J. Lin, Jae Park, Michael Scordo, Gilles Salles, Joachim Yahalom, M. Lia. Palomba, Heiko Schöder, Miguel-Angel Perales, Roni Shouval, Brandon S. Imber
{"title":"Metabolic tumor volume response after bridging therapy determines chimeric antigen receptor T-cell outcomes in large B cell lymphoma","authors":"Harper Hubbeling, Doris Leithner, Emily A. Silverman, Jessica Flynn, Sean Devlin, Gunjan Shah, Beatrice Fregonese, Beatriz Wills, Akshay Bedmutha, Ana Alarcon Tomas, Allison Parascondola, Amethyst Saldia, Ivan Landego, Carla Hajj, Alexander P. Boardman, Parastoo B. Dahi, Arnab Ghosh, Sergio Giralt, Richard J. Lin, Jae Park, Michael Scordo, Gilles Salles, Joachim Yahalom, M. Lia. Palomba, Heiko Schöder, Miguel-Angel Perales, Roni Shouval, Brandon S. Imber","doi":"10.1158/1078-0432.ccr-24-0830","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-0830","url":null,"abstract":"Purpose: Greater disease burden is a well-established predictor of poorer outcomes following chimeric antigen receptor T-cell therapy (CART). While bridging therapy (BT) is widely used between leukapheresis and CAR T infusion, limited data has evaluated the impact of BT on CART outcomes. In this study, we hypothesized that the quantitative dynamics of radiomic cytoreduction during bridging are prognostic. Patients and Methods: Patients with large B-cell lymphoma (LBCL) treated with CD19-CART from 2016-2022 were included. Metabolic tumor volume (MTV) was determined for all patients on pre-leukapheresis PET and on post-BT/pre-infusion PET in those who received BT. Patients were stratified into ‘High’ and ‘Low’ disease burden using an MTV cutpoint of 65.4cc established by maximally selected log-rank statistic for progression free survival (PFS). Results: Of 191 patients treated with CART, 144 (75%) received BT. In the BT cohort, 56% had any reduction in MTV post-BT. On multivariate analysis, MTV trajectory across the bridging period remained significantly associated with PFS (p<0.001), however notably patients with improved MTV (High->Low) had equivalent PFS compared to those with initially and persistently low MTV (Low->Low) (HR for High->Low MTV: 2.74, CI: 0.82-9.18). There was a reduction in any Grade ICANS in the High->Low MTV cohort as compared to High->High (13 vs. 41%, p=0.05). Conclusions: This is the first study to use radiomics to quantify disease burden pre- and post-BT in a large real world LBCL cohort. We demonstrate that effective BT can enable initially high-disease burden patients to achieve post-CART outcomes comparable to low-disease burden patients.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142170754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The intrauterine device: how to deploy this strategy in the molecular world?","authors":"Paul Johannet,Claire F Friedman","doi":"10.1158/1078-0432.ccr-24-2034","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2034","url":null,"abstract":"Progestin-based therapy can safely be offered to a subset of patients with atypical endometrial hyperplasia or Grade 1 endometrioid endometrial cancer who desire fertility preservation. A recent study shows that levonorgestrel intrauterine device confers durable clinical benefit and identifies possible immune mechanisms of relapse and resistance.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":11.5,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142165873","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}
Kevin L Ma, Tara C Mitchell, Meaghan Dougher, Cimarron E Sharon, Gabriella N Tortorello, David E Elder, Eric E Morgan, Phyllis A Gimotty, Alexander C Huang, Ravi K Amaravadi, Lynn M Schuchter, Ahron Flowers, John T Miura, Giorgos C Karakousis, Xiaowei Xu
{"title":"Tumor-infiltrating lymphocytes in necrotic tumors after melanoma neoadjuvant anti-PD1 therapy correlate with pathological response and recurrence-free survival.","authors":"Kevin L Ma, Tara C Mitchell, Meaghan Dougher, Cimarron E Sharon, Gabriella N Tortorello, David E Elder, Eric E Morgan, Phyllis A Gimotty, Alexander C Huang, Ravi K Amaravadi, Lynn M Schuchter, Ahron Flowers, John T Miura, Giorgos C Karakousis, Xiaowei Xu","doi":"10.1158/1078-0432.CCR-23-3775","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-23-3775","url":null,"abstract":"<p><strong>Purpose: </strong>Neoadjuvant anti-PD1 therapy in melanoma may increase tumor-infiltrating lymphocytes (TILs), and more TILs are associated with better treatment response. A major pathological response (MPR) in melanoma after neoadjuvant anti-PD1 therapy usually comprises tumor necrosis and fibrosis. The role of TILs in necrotic tumor necrosis (nTILs) has not been explored.</p><p><strong>Experimental design: </strong>We performed CD3 and CD8 immunohistochemical stains on 41 melanomas with geographic necrosis. 14 were immunotherapy-naïve, and 27 had been treated with one dose of neoadjuvant anti-PD-1 in two clinical trials. CD3+ and CD8+ nTILs were graded as absent/minimal or moderate/brisk. The percentage of necrotic areas in the tumor bed before and after treatment was quantified. Endpoints were MPR and 5-year recurrence-free survival (RFS).</p><p><strong>Results: </strong>In the immunotherapy-naïve cohort, 3/14 (21%) specimens had moderate/brisk CD3+, and 2/14 (14%) had moderate/brisk CD8+ nTILs. In the treated cohort, 16/27 (59%) specimens had moderate/brisk CD3+, and 15/27 (56%) had moderate/brisk CD8+ nTILs, higher than the naïve cohort (CD3, p=0.046; CD8, p=0.018). Tumor necrosis was significantly increased after anti-PD1 therapy (p=0.007). In the treated cohort, moderate/brisk CD3+ and CD8+ nTILs correlated with MPR (p=0.042, p=0.019, respectively). Treated patients with moderate/brisk CD3+ nTILs had higher 5-year RFS than those with absent/minimal nTILs (69% versus 0%; p=0.006). This persisted on multivariate analysis (HR 0.16, 95% CI 0.03-0.84, p=0.03), adjusted for pathologic response, which was borderline significant (HR 0.26, 95% CI 0.07-1.01, p=0.051).</p><p><strong>Conclusions: </strong>CD3+ and CD8+ nTILs are associated with pathological response and 5-year RFS in melanoma patients after neoadjuvant anti-PD1 therapy.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":10.0,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153269","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}
Jaleh Fallah, Brian L Heiss, Hee-Koung Joeng, Chana Weinstock, Xin Gao, William F Pierce, Benjamin Chukwurah, Vishal Bhatnagar, Mallorie H Fiero, Laleh Amiri-Kordestani, Richard Pazdur, Paul G Kluetz, Daniel L Suzman
{"title":"FDA Approval Summary: Belzutifan for Patients with Advanced Renal Cell Carcinoma.","authors":"Jaleh Fallah, Brian L Heiss, Hee-Koung Joeng, Chana Weinstock, Xin Gao, William F Pierce, Benjamin Chukwurah, Vishal Bhatnagar, Mallorie H Fiero, Laleh Amiri-Kordestani, Richard Pazdur, Paul G Kluetz, Daniel L Suzman","doi":"10.1158/1078-0432.CCR-24-1199","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-1199","url":null,"abstract":"<p><p>On December 14, 2023, the United States Food and Drug Administration (FDA) approved belzutifan (Welireg, Merck & Co., Inc.) for patients with advanced renal cell carcinoma (RCC) following a programmed death receptor-1 or programmed death-ligand 1 (PD-1/PD-L1) inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI). FDA granted traditional approval based on LITESPARK-005 (NCT04195750), an open-label, randomized, head-to-head trial of 746 patients with advanced RCC that progressed following both a PD-1/PD-L1 inhibitor and a VEGF-TKI. Patients were randomized (1:1) to receive belzutifan or everolimus. The primary endpoints were progression-free survival (PFS) assessed by blinded independent central review (BICR) and overall survival (OS). A statistically significant improvement in PFS was demonstrated for belzutifan compared with everolimus [hazard ratio (HR)=0.75 (95% CI: 0.63, 0.90); 1-sided p-value=0.0008]. Kaplan-Meier curves reflected non-proportional hazards with similar median PFS estimates of 5.6 months (95% CI: 3.9, 7.0) in the belzutifan arm and 5.6 months (95% CI: 4.8, 5.8) in the everolimus arm. While not reaching full maturity, OS results appeared to show a favorable trend in the belzutifan arm compared to everolimus [HR=0.88 (95% CI: 0.73, 1.07)]. The confirmed objective response rate by BICR was 22% and 3.6% in belzutifan and everolimus arms, respectively. Observed toxicities differed between treatment arms, but drug discontinuations and interruptions due to treatment-emergent adverse events were lower on the belzutifan arm compared to the everolimus arm, and a descriptive analysis of patient-reported symptom and functional outcomes was suggestive of favorable tolerability for belzutifan compared to everolimus.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":null,"pages":null},"PeriodicalIF":10.0,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153268","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}