Pub Date : 2024-08-31DOI: 10.1101/2024.08.29.24312591
Lucas McCullum, Samuel Mulder, Natalie West, Robert Aghoghovbia, Alaa Mohamed Shawky Ali, Hayden Scott, Travis C. Salzillo, Yao Ding, Alex Dresner, Ergys Subashi, Dan Ma, R. Jason Stafford, Ken-Pin Hwang, Clifton D. Fuller
Objective The purpose of this study was to investigate the technical feasibility of integrating the quantitative maps available from SyntheticMR into the head and neck adaptive radiation oncology workflow. While SyntheticMR has been investigated for diagnostic applications, no studies have investigated its feasibility and potential for MR-Simulation or MR-Linac workflow. Demonstrating the feasibility of using this technique will facilitate rapid quantitative biomarker extraction which can be leveraged to guide adaptive radiation therapy decision making.
{"title":"Technical Development and In Silico Implementation of SyntheticMR in Head and Neck Adaptive Radiation Therapy: A Prospective R-IDEAL Stage 0/1 Technology Development Report","authors":"Lucas McCullum, Samuel Mulder, Natalie West, Robert Aghoghovbia, Alaa Mohamed Shawky Ali, Hayden Scott, Travis C. Salzillo, Yao Ding, Alex Dresner, Ergys Subashi, Dan Ma, R. Jason Stafford, Ken-Pin Hwang, Clifton D. Fuller","doi":"10.1101/2024.08.29.24312591","DOIUrl":"https://doi.org/10.1101/2024.08.29.24312591","url":null,"abstract":"<strong>Objective</strong> The purpose of this study was to investigate the technical feasibility of integrating the quantitative maps available from SyntheticMR into the head and neck adaptive radiation oncology workflow. While SyntheticMR has been investigated for diagnostic applications, no studies have investigated its feasibility and potential for MR-Simulation or MR-Linac workflow. Demonstrating the feasibility of using this technique will facilitate rapid quantitative biomarker extraction which can be leveraged to guide adaptive radiation therapy decision making.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202889","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background Appendiceal tumors comprise a heterogeneous group of tumors which frequently disseminate to the peritoneum. Management of appendiceal tumors is lacking high quality data, given its rarity and heterogeneity. In general, appendiceal tumor treatment is extrapolated in part from colorectal cancer or pooled studies, without definitive evidence of disease-specific benefit. Many practices are controversial and vary widely between institutions. A national consensus update of best management practices for appendiceal malignancies was performed to better standardize care. Herein we present recommendations for management of appendiceal tumors with peritoneal involvement.
{"title":"Consensus guideline for the management of patients with appendiceal tumors: Part 2: Appendiceal tumors with peritoneal involvement","authors":"PSM Appendiceal Tumor Writing Group, PSM Consortium Group, Kiran K. Turaga","doi":"10.1101/2024.08.30.24309032","DOIUrl":"https://doi.org/10.1101/2024.08.30.24309032","url":null,"abstract":"<strong>Background</strong> Appendiceal tumors comprise a heterogeneous group of tumors which frequently disseminate to the peritoneum. Management of appendiceal tumors is lacking high quality data, given its rarity and heterogeneity. In general, appendiceal tumor treatment is extrapolated in part from colorectal cancer or pooled studies, without definitive evidence of disease-specific benefit. Many practices are controversial and vary widely between institutions. A national consensus update of best management practices for appendiceal malignancies was performed to better standardize care. Herein we present recommendations for management of appendiceal tumors with peritoneal involvement.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-30DOI: 10.1101/2024.08.29.24312245
Zahi I. Mitri, Allison L. Creason, Jayne M. Stommel, Daniel Bottomly, Tugba Y. Ozmen, Matthew J. Rames, Furkan Ozmen, Boyoung Jeong, Natalia Lukashchuk, Jack Ashton, Jeong Youn Lim, Shamilene Sivagnanam, Konjit Betra, Jinho Lee, Marilyne Labrie, SMMART Clinical Trials Program, Lisa M. Coussens, Christopher L. Corless, Shannon K. McWeeney, Gordon B. Mills
In syngeneic murine breast cancer models, poly ADP-ribose polymerase inhibitor (PARPi) and anti-PD-L1 combinations induce deep, sustained responses independent of BRCA1/2 mutation status. We therefore investigated this combination in the AMTEC clinical trial, in which a one-month olaparib run-in was followed by combined olaparib and durvalumab in participants with BRCA1/2 wild-type metastatic triple negative breast cancer. To characterize adaptive responses to olaparib monotherapy, paired biopsies taken before and during PARPi lead-in were deeply characterized by DNA, RNA, and protein multi-omic analyses, including spatially-resolved single cell proteomics for tumor and immune contexture. We identified multiple potential tumor-intrinsic and microenvironmental biomarkers from pre-treatment and on-olaparib biopsies that robustly predicted participant response to combined olaparib and durvalumab. Notably, the on-olaparib biopsy provided the greatest information content, suggesting that adaptation of malignant cells and the tumor ecosystem to PARPi can serve as a predictor of potential benefit from combined PARPi and anti-PD-L1 therapy.
{"title":"Adaptive Responses to PARP Inhibition Predict Response to Olaparib and Durvalumab: Multi-omic Analysis of Serial Biopsies in the AMTEC Trial","authors":"Zahi I. Mitri, Allison L. Creason, Jayne M. Stommel, Daniel Bottomly, Tugba Y. Ozmen, Matthew J. Rames, Furkan Ozmen, Boyoung Jeong, Natalia Lukashchuk, Jack Ashton, Jeong Youn Lim, Shamilene Sivagnanam, Konjit Betra, Jinho Lee, Marilyne Labrie, SMMART Clinical Trials Program, Lisa M. Coussens, Christopher L. Corless, Shannon K. McWeeney, Gordon B. Mills","doi":"10.1101/2024.08.29.24312245","DOIUrl":"https://doi.org/10.1101/2024.08.29.24312245","url":null,"abstract":"In syngeneic murine breast cancer models, poly ADP-ribose polymerase inhibitor (PARPi) and anti-PD-L1 combinations induce deep, sustained responses independent of <em>BRCA1/2</em> mutation status. We therefore investigated this combination in the AMTEC clinical trial, in which a one-month olaparib run-in was followed by combined olaparib and durvalumab in participants with <em>BRCA1/2</em> wild-type metastatic triple negative breast cancer. To characterize adaptive responses to olaparib monotherapy, paired biopsies taken before and during PARPi lead-in were deeply characterized by DNA, RNA, and protein multi-omic analyses, including spatially-resolved single cell proteomics for tumor and immune contexture. We identified multiple potential tumor-intrinsic and microenvironmental biomarkers from pre-treatment and on-olaparib biopsies that robustly predicted participant response to combined olaparib and durvalumab. Notably, the on-olaparib biopsy provided the greatest information content, suggesting that adaptation of malignant cells and the tumor ecosystem to PARPi can serve as a predictor of potential benefit from combined PARPi and anti-PD-L1 therapy.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-30DOI: 10.1101/2024.08.29.24312110
Marco M. Buttigieg, Caitlyn Vlasschaert, Alexander G. Bick, Robert J. Vanner, Michael J. Rauh
Clonal hematopoiesis (CH) – the expansion of somatically-mutated hematopoietic cells in blood – is common in solid cancers. CH is associated with systemic inflammation that may lead to cancer, but its impact on tumor biology is underexplored. Here, we report the effects of CH on the tumor microenvironment (TME) using 1,550 treatment-naïve patient samples from the CPTAC cohort. CH was present in 18.3% of patients, with one-third of CH mutations also detectable in tumor-derived DNA from the same individual (CH-Tum), reflecting CH-mutant leukocyte infiltration. The presence of CH-Tum was associated with worse survival across cancers, particularly for glioblastoma.
{"title":"Inflammatory reprogramming of the tumor microenvironment by infiltrating clonal hematopoiesis is associated with adverse outcomes in solid cancer","authors":"Marco M. Buttigieg, Caitlyn Vlasschaert, Alexander G. Bick, Robert J. Vanner, Michael J. Rauh","doi":"10.1101/2024.08.29.24312110","DOIUrl":"https://doi.org/10.1101/2024.08.29.24312110","url":null,"abstract":"Clonal hematopoiesis (CH) – the expansion of somatically-mutated hematopoietic cells in blood – is common in solid cancers. CH is associated with systemic inflammation that may lead to cancer, but its impact on tumor biology is underexplored. Here, we report the effects of CH on the tumor microenvironment (TME) using 1,550 treatment-naïve patient samples from the CPTAC cohort. CH was present in 18.3% of patients, with one-third of CH mutations also detectable in tumor-derived DNA from the same individual (CH-Tum), reflecting CH-mutant leukocyte infiltration. The presence of CH-Tum was associated with worse survival across cancers, particularly for glioblastoma.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"26 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-29DOI: 10.1101/2024.08.29.24312704
Alberto Langtry, Raul Rabadan, Lola Alonso, Casper van Eijck, Teresa Macarulla, Rita T Lawlor, Alfredo Carrato, Rafael Alvarez-Gallego, Mar Iglesias, Xavier Molero, J Matthias Löhr, Christopher W Michalski, José Perea, Michael O’Rorke, Víctor M Barberà, Adonina Tardón, Antoni Farré, Luís Muñoz-Bellvís, Tatjana Crnogorac-Jurcevic, Enrique Domínguez-Muñoz, Thomas Gress, William Greenhalf, Linda Sharp, Sergio Sabroso-Lasa, Ioan Filip, Gaby Strijk, Florian Castet, Joaquim Balsells, Eithne Costello, Jörg Kleeff, Bo Kong, Josefina Mora, Damian O’Driscoll, Aldo Scarpa, Weimin Ye, Francisco X. Real, Núria Malats, Evangelina López de Maturana, PanGenEU Investigators
Genetic susceptibility loci are associated with PDAC risk and survival, but the impact of germline HLA region variation remains largely unexplored. This study examined HLA I-II alleles within the PanGenEU study and validated our findings using external datasets (UK Biobank, TCGA, PAN-NGS trial, and Caris trial). HLA-A*02:01and HLA-B*49 alleles were linked to a decreased risk of PDAC, whereas HLA-B*39, HLA-DPB1*04, and HLA-A*26:01 were directly associated with increased risk. PDAC patients carrying the HLA-A*02:01 allele also showed lower mortality rates, with the effect being more pronounced in those with KRASG12V mutations, pointing to a host*tumor genetic interaction. This research highlights HLA-A*02:01, found in 20% of Europeans, as a marker for reduced PDAC risk and mortality, especially in KRASG12V mutated tumors. Results from this study could enhance personalized medicine for PDAC by identifying patients who may benefit from regular screenings through tailored risk assessments. Importantly, our findings are crucial for stratifying PDAC patients based on their genetic background and tumor mutational profile, which can guide treatment strategies.
{"title":"HLA-A*02:01 allele is associated with decreased risk and a longer survival in pancreatic cancer: Results from an exhaustive analysis of the HLA variation in PDAC","authors":"Alberto Langtry, Raul Rabadan, Lola Alonso, Casper van Eijck, Teresa Macarulla, Rita T Lawlor, Alfredo Carrato, Rafael Alvarez-Gallego, Mar Iglesias, Xavier Molero, J Matthias Löhr, Christopher W Michalski, José Perea, Michael O’Rorke, Víctor M Barberà, Adonina Tardón, Antoni Farré, Luís Muñoz-Bellvís, Tatjana Crnogorac-Jurcevic, Enrique Domínguez-Muñoz, Thomas Gress, William Greenhalf, Linda Sharp, Sergio Sabroso-Lasa, Ioan Filip, Gaby Strijk, Florian Castet, Joaquim Balsells, Eithne Costello, Jörg Kleeff, Bo Kong, Josefina Mora, Damian O’Driscoll, Aldo Scarpa, Weimin Ye, Francisco X. Real, Núria Malats, Evangelina López de Maturana, PanGenEU Investigators","doi":"10.1101/2024.08.29.24312704","DOIUrl":"https://doi.org/10.1101/2024.08.29.24312704","url":null,"abstract":"Genetic susceptibility loci are associated with PDAC risk and survival, but the impact of germline HLA region variation remains largely unexplored. This study examined <em>HLA</em> I-II alleles within the PanGenEU study and validated our findings using external datasets (UK Biobank, TCGA, PAN-NGS trial, and Caris trial). <em>HLA-A*02:01and HLA-B*49</em> alleles were linked to a decreased risk of PDAC, whereas <em>HLA-B*39</em>, <em>HLA-DPB1*04,</em> and <em>HLA-A*26:01</em> were directly associated with increased risk. PDAC patients carrying the <em>HLA-A*02:01</em> allele also showed lower mortality rates, with the effect being more pronounced in those with <em>KRAS</em><sup>G12V</sup> mutations, pointing to a host*tumor genetic interaction. This research highlights <em>HLA-A*02:01</em>, found in 20% of Europeans, as a marker for reduced PDAC risk and mortality, especially in <em>KRAS</em><sup>G12V</sup> mutated tumors. Results from this study could enhance personalized medicine for PDAC by identifying patients who may benefit from regular screenings through tailored risk assessments. Importantly, our findings are crucial for stratifying PDAC patients based on their genetic background and tumor mutational profile, which can guide treatment strategies.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-29DOI: 10.1101/2024.08.29.24312777
Annette Salomonsson, Daniel Ehinger, Mats Jönsson, Johan Botling, Patrick Micke, Hans Brunnström, Johan Staaf, Maria Planck
Introduction Many studies have aimed at identifying additional prognostic tools to guide treatment choices and patient surveillance in lung cancer by assessing the expression of individual proteins through immunohistochemistry (IHC) or, more recently, through gene expression-based signatures. As a proof-of-concept, we used a multi-cohort, gene expression-based discovery and validation strategy to identify genes with prognostic potential in lung adenocarcinoma. The clinical applicability of this strategy was further assessed by evaluating a selection of the markers by IHC.
{"title":"Gene expression-based identification of prognostic markers in lung adenocarcinoma","authors":"Annette Salomonsson, Daniel Ehinger, Mats Jönsson, Johan Botling, Patrick Micke, Hans Brunnström, Johan Staaf, Maria Planck","doi":"10.1101/2024.08.29.24312777","DOIUrl":"https://doi.org/10.1101/2024.08.29.24312777","url":null,"abstract":"<strong>Introduction</strong> Many studies have aimed at identifying additional prognostic tools to guide treatment choices and patient surveillance in lung cancer by assessing the expression of individual proteins through immunohistochemistry (IHC) or, more recently, through gene expression-based signatures. As a proof-of-concept, we used a multi-cohort, gene expression-based discovery and validation strategy to identify genes with prognostic potential in lung adenocarcinoma. The clinical applicability of this strategy was further assessed by evaluating a selection of the markers by IHC.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-28DOI: 10.1101/2024.08.27.24312529
Maria Semitekolou, Nikolaos Paschalidis, Domenico Lo Tartaro, Aikaterini Tsitsopoulou, Panagiota Stamou, Alexandros Mavroudis, Effrosyni Markaki, Athina Varveri, Ioannis Morianos, Matthieu Lavigne, Charalampos Fotsitzoudis, Sophia Magkouta, Konstantina Dede, Ioannis Kalomenidis, Konstantinos Samitas, Konstantinos Potaris, Andrea Cossarizza, Dimitrios Mavroudis, Sara De Biasi, Panayiotis Verginis
Immune checkpoint inhibitor immunotherapy has revolutionized the treatment of non-small cell lung cancer (NSCLC). Despite the immense success, still a significant proportion of patients do not develop durable responses, allowing disease progression accompanied by high mortality rates. Therefore, there is an imperative need for identification of reliable non-invasive predictive biomarkers to guide therapeutic decisions. Herein, we constructed a blood immunomap in NSCLC patients with metastatic disease, using a high-dimensional mass cytometry approach. Assessment of clinical responses to aPD1 immunotherapy revealed, among others, a significant expansion of CD8+PD-L1+ T cells in individuals not responding to immunotherapy. Of interest, CD8+PD-L1+ T cells were enriched in tumor biopsies and bronchoalveolar lavage of NSCLC individuals at early stages of disease as well as in pleural infusions of individuals with thoracic malignancies. Transcriptomic analysis revealed that CD8+PD-L1+ T cells exhibited a regulatory /exhausted phenotype, while various transcripts associated with the overall survival of NSCLC individuals, were mapped. Overall, our findings define an immunomap in the early stage and advanced NSCLC patients and identify immune-related events which may benefit the quest for identification of predictive biomarkers of immunotherapy responses.
免疫检查点抑制剂免疫疗法彻底改变了非小细胞肺癌（NSCLC）的治疗方法。尽管取得了巨大成功，但仍有相当一部分患者没有产生持久的反应，导致疾病进展并伴随着高死亡率。因此，迫切需要鉴定可靠的非侵入性预测生物标志物来指导治疗决策。在此，我们采用高维质谱方法构建了转移性 NSCLC 患者的血液免疫图谱。对 aPD1 免疫疗法临床反应的评估显示，在对免疫疗法无反应的个体中，CD8+PD-L1+ T 细胞显著扩增。值得关注的是，CD8+PD-L1+ T细胞在疾病早期阶段的NSCLC患者的肿瘤活检和支气管肺泡灌洗液中以及在胸腔恶性肿瘤患者的胸腔输液中富集。转录组分析表明，CD8+PD-L1+ T 细胞表现出调节/耗竭表型，而与 NSCLC 患者总体存活率相关的各种转录本也被绘制出来。总之，我们的研究结果定义了早期和晚期 NSCLC 患者的免疫图谱，并确定了与免疫相关的事件，这些事件可能有助于确定免疫疗法反应的预测性生物标记物。
{"title":"Blood immunomap for prediction of responses to aPD1 immunotherapy in metastatic non-small cell lung cancer","authors":"Maria Semitekolou, Nikolaos Paschalidis, Domenico Lo Tartaro, Aikaterini Tsitsopoulou, Panagiota Stamou, Alexandros Mavroudis, Effrosyni Markaki, Athina Varveri, Ioannis Morianos, Matthieu Lavigne, Charalampos Fotsitzoudis, Sophia Magkouta, Konstantina Dede, Ioannis Kalomenidis, Konstantinos Samitas, Konstantinos Potaris, Andrea Cossarizza, Dimitrios Mavroudis, Sara De Biasi, Panayiotis Verginis","doi":"10.1101/2024.08.27.24312529","DOIUrl":"https://doi.org/10.1101/2024.08.27.24312529","url":null,"abstract":"Immune checkpoint inhibitor immunotherapy has revolutionized the treatment of non-small cell lung cancer (NSCLC). Despite the immense success, still a significant proportion of patients do not develop durable responses, allowing disease progression accompanied by high mortality rates. Therefore, there is an imperative need for identification of reliable non-invasive predictive biomarkers to guide therapeutic decisions. Herein, we constructed a blood immunomap in NSCLC patients with metastatic disease, using a high-dimensional mass cytometry approach. Assessment of clinical responses to aPD1 immunotherapy revealed, among others, a significant expansion of CD8+PD-L1+ T cells in individuals not responding to immunotherapy. Of interest, CD8+PD-L1+ T cells were enriched in tumor biopsies and bronchoalveolar lavage of NSCLC individuals at early stages of disease as well as in pleural infusions of individuals with thoracic malignancies. Transcriptomic analysis revealed that CD8+PD-L1+ T cells exhibited a regulatory /exhausted phenotype, while various transcripts associated with the overall survival of NSCLC individuals, were mapped. Overall, our findings define an immunomap in the early stage and advanced NSCLC patients and identify immune-related events which may benefit the quest for identification of predictive biomarkers of immunotherapy responses.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"80 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-28DOI: 10.1101/2024.08.28.24312703
Myrthe M.M.R. Griffioen, Dennis S Metselaar
High-grade glioma (HGG) patients have a dismal prognosis, due to a lack of effective treatments. In order to change the fate of HGG patients and decrease the current treatment-related side effects, therapy focus has shifted in the past years to immunotherapy, such as chimeric antigen receptor (CAR)-based treatments. Recent developments in CAR-based therapy show promising results in adult glioma patients, and the first clinical trials for pediatric patients with HGG are in progress. However, there are significant differences between pediatric HGG (pHGG) and their adult counterparts, including the composition of the tumor immune microenvironment (TIME), which strongly influences CAR treatment responsiveness. Therefore, we here provide a systematic overview of CAR-based therapeutic targets in pHGG entities, focusing on clinical trials and preclinical research, and comparing them to adult glioma. We conclude that target expression, TIME and CAR treatment-related toxicities vary across pHGG entities and differ from adult HGG, which suggests the need for more tailored immunotherapeutic CAR approaches in pHGG. Overall, we provide a target roadmap for future development of CAR-based therapeutic strategies for pediatric HGG patients, who are in desperate need for novel therapies.
由于缺乏有效的治疗方法，高级别胶质瘤（HGG）患者的预后很差。为了改变 HGG 患者的命运，减少目前治疗相关的副作用，过去几年的治疗重点已转向免疫疗法，如基于嵌合抗原受体（CAR）的疗法。基于嵌合抗原受体（CAR）的疗法的最新进展显示，在成人胶质瘤患者中取得了良好的疗效，而针对儿童 HGG 患者的首批临床试验也正在进行中。然而，儿科 HGG（pHGG）与成人 HGG 存在明显差异，其中包括肿瘤免疫微环境（TIME）的组成，它对 CAR 治疗的反应性有很大影响。因此，我们在此系统概述了 pHGG 实体中基于 CAR 的治疗靶点，重点关注临床试验和临床前研究，并将其与成人胶质瘤进行比较。我们的结论是，不同 pHGG 实体的靶点表达、TIME 和 CAR 治疗相关毒性各不相同，而且与成人 HGG 也有区别，这表明 pHGG 需要更有针对性的 CAR 免疫治疗方法。总之，我们为急需新型疗法的儿科 HGG 患者提供了基于 CAR 的治疗策略的未来发展目标路线图。
{"title":"CAR-based therapeutic targets in pediatric high-grade glioma","authors":"Myrthe M.M.R. Griffioen, Dennis S Metselaar","doi":"10.1101/2024.08.28.24312703","DOIUrl":"https://doi.org/10.1101/2024.08.28.24312703","url":null,"abstract":"High-grade glioma (HGG) patients have a dismal prognosis, due to a lack of effective treatments. In order to change the fate of HGG patients and decrease the current treatment-related side effects, therapy focus has shifted in the past years to immunotherapy, such as chimeric antigen receptor (CAR)-based treatments. Recent developments in CAR-based therapy show promising results in adult glioma patients, and the first clinical trials for pediatric patients with HGG are in progress. However, there are significant differences between pediatric HGG (pHGG) and their adult counterparts, including the composition of the tumor immune microenvironment (TIME), which strongly influences CAR treatment responsiveness. Therefore, we here provide a systematic overview of CAR-based therapeutic targets in pHGG entities, focusing on clinical trials and preclinical research, and comparing them to adult glioma. We conclude that target expression, TIME and CAR treatment-related toxicities vary across pHGG entities and differ from adult HGG, which suggests the need for more tailored immunotherapeutic CAR approaches in pHGG. Overall, we provide a target roadmap for future development of CAR-based therapeutic strategies for pediatric HGG patients, who are in desperate need for novel therapies.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"106 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-26DOI: 10.1101/2024.08.25.24312509
David Reinecke, Nader Maarouf, Andrew Smith, Daniel Alber, John Markert, Nicolas K. Goff, Todd C. Hollon, Asadur Chowdury, Cheng Jiang, Xinhai Hou, Anna-Katharina Meissner, Gina Fuertjes, Maximilian I. Ruge, Daniel Ruess, Thomas Stehle, Abdulkader Al-Shughri, Lisa I. Koerner, Georg Widhalm, Thomas Roetzer-Pejrimovsky, John G. Golfinos, Matija Snuderl, Volker Neuschmelting, Daniel A. Orringer
Accurate intraoperative diagnosis is crucial for differentiating between primary CNS lymphoma (PCNSL) and other CNS entities, guiding surgical decision-making, but represents significant challenges due to overlapping histomorphological features, time constraints, and differing treatment strategies. We combined stimulated Raman histology (SRH) with deep learning to address this challenge. We imaged unprocessed, label-free tissue samples intraoperatively using a portable Raman scattering microscope, generating virtual H&E-like images within less than three minutes. We developed a deep learning pipeline called RapidLymphoma based on a self-supervised learning strategy to (1) detect PCNSL, (2) differentiate from other CNS entities, and (3) test the diagnostic performance in a prospective international multicenter cohort and two additional independent test cohorts. We trained on 54,000 SRH patch images sourced from surgical resections and stereotactic-guided biopsies, including various CNS tumor/non-tumor lesions. Training and test data were collected from four tertiary international medical centers. The final histopathological diagnosis served as ground-truth. In the prospective test cohort of PCNSL and non-PCNSL entities (n=160), RapidLymphoma achieved an overall balanced accuracy of 97.81%, non-inferior to frozen section analysis in detecting PCNSL (100% vs. 78.94%). The additional test cohorts (n=420, n=59) reached balanced accuracy rates of 95.44% and 95.57% in differentiating IDH-wildtype diffuse gliomas and various brain metastasis from PCNSL. Visual heatmaps revealed capabilities to detect class-specific histomorphological key features. RapidLymphoma proves reliable and valid for intraoperative PCNSL detection and differentiation from other CNS entities. It provides visual feedback within three minutes, enabling fast clinical decision-making and subsequent treatment strategy planning.
{"title":"Fast intraoperative detection of primary CNS lymphoma and differentiation from common CNS tumors using stimulated Raman histology and deep learning","authors":"David Reinecke, Nader Maarouf, Andrew Smith, Daniel Alber, John Markert, Nicolas K. Goff, Todd C. Hollon, Asadur Chowdury, Cheng Jiang, Xinhai Hou, Anna-Katharina Meissner, Gina Fuertjes, Maximilian I. Ruge, Daniel Ruess, Thomas Stehle, Abdulkader Al-Shughri, Lisa I. Koerner, Georg Widhalm, Thomas Roetzer-Pejrimovsky, John G. Golfinos, Matija Snuderl, Volker Neuschmelting, Daniel A. Orringer","doi":"10.1101/2024.08.25.24312509","DOIUrl":"https://doi.org/10.1101/2024.08.25.24312509","url":null,"abstract":"Accurate intraoperative diagnosis is crucial for differentiating between primary CNS lymphoma (PCNSL) and other CNS entities, guiding surgical decision-making, but represents significant challenges due to overlapping histomorphological features, time constraints, and differing treatment strategies. We combined stimulated Raman histology (SRH) with deep learning to address this challenge. We imaged unprocessed, label-free tissue samples intraoperatively using a portable Raman scattering microscope, generating virtual H&E-like images within less than three minutes. We developed a deep learning pipeline called RapidLymphoma based on a self-supervised learning strategy to (1) detect PCNSL, (2) differentiate from other CNS entities, and (3) test the diagnostic performance in a prospective international multicenter cohort and two additional independent test cohorts. We trained on 54,000 SRH patch images sourced from surgical resections and stereotactic-guided biopsies, including various CNS tumor/non-tumor lesions. Training and test data were collected from four tertiary international medical centers. The final histopathological diagnosis served as ground-truth. In the prospective test cohort of PCNSL and non-PCNSL entities (n=160), RapidLymphoma achieved an overall balanced accuracy of 97.81%, non-inferior to frozen section analysis in detecting PCNSL (100% vs. 78.94%). The additional test cohorts (n=420, n=59) reached balanced accuracy rates of 95.44% and 95.57% in differentiating IDH-wildtype diffuse gliomas and various brain metastasis from PCNSL. Visual heatmaps revealed capabilities to detect class-specific histomorphological key features.\u0000RapidLymphoma proves reliable and valid for intraoperative PCNSL detection and differentiation from other CNS entities. It provides visual feedback within three minutes, enabling fast clinical decision-making and subsequent treatment strategy planning.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"31 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-23DOI: 10.1101/2024.08.23.24312477
Norbert Vey, Anne-Sophie Chretien, Pierre-Yves Dumas, Christian Recher, Lauris Gastaud, Bruno Lioure, Claude-Eric Bulabois, Cecile Pautas, Jean-Pierre Marolleau, Stephane Lepretre, Emmanuel Raffoux, Xavier Thomas, Yosr Hicheri, Caroline Bonmati, Bruno Quesnel, Philippe Rousselot, Eric Jourdan, Jean-Valere Malfuson, Gaelle Guillerm, Jean-Henri Bourhis, Mario Ojeda-Uribe, Mathilde Hunault, Amira Ben Amara, Marie-Sarah Rouviere, Nicolas Boucherit, Pascale Andre, Claude Preudhomme, Nicolas Dulphy, Antoine Toubert, Norbert Ifrah, Daniel Olive, Herve Dombret
Lirilumab is a fully human monoclonal antibody designed to block killer inhibitory receptors (KIR), which are major immune checkpoints involved in the regulation of NK cell-mediated killing of HLA-I-expressing tumors. EFFIKIR is a multicenter randomized double-blind 3-arm placebo-controlled phase II trial with lirilumab as single-agent as maintenance therapy of elderly patients with AML in first complete remission (NCT01687387). Two dose schedules led to either continuous or intermittent KIR occupancy. 153 patients were randomized and 152 patients were treated after 3+7 induction therapy. The median follow-up was 36.6 months. Lirilumab was well tolerated, with no significant hematological toxicity. The median LFS were 17.6, 6.7 and 13.9 months in the 0.1mg/kg arm, 1mg/kg arm and placebo arm, respectively. An excess in early relapse led to early termination of treatment in the 1mg/kg arm. Extensive analysis of immune cell fate following KIR blockade evidenced a decrease of KIR+ NK cell absolute counts following KIR blockade, associated with a decrease of Bcl-2. Lirilumab also bound antigen-experienced CD8+ T cells, and induced a transient decrease of CD69 expression. Besides, lirilumab bound vδ2+ γδT cells with a high cytotoxic potential, and induced a decrease of DNAM-1 and Bcl-2, the latter being associated with a decrease of KIR+ γδT cell, and with a drastic reduction of time to relapse. Overall, the potentially deleterious effects on immune effectors may have resulted in the impairment of immune surveillance associated with an unexpected high rate of early relapse in the group of patients exposed to prolonged full KIR blockade.
{"title":"Randomized Phase 2 Trial of Lirilumab as maintenance Treatment in Acute Myeloid Leukemia: Results of the EFFIKIR Trial","authors":"Norbert Vey, Anne-Sophie Chretien, Pierre-Yves Dumas, Christian Recher, Lauris Gastaud, Bruno Lioure, Claude-Eric Bulabois, Cecile Pautas, Jean-Pierre Marolleau, Stephane Lepretre, Emmanuel Raffoux, Xavier Thomas, Yosr Hicheri, Caroline Bonmati, Bruno Quesnel, Philippe Rousselot, Eric Jourdan, Jean-Valere Malfuson, Gaelle Guillerm, Jean-Henri Bourhis, Mario Ojeda-Uribe, Mathilde Hunault, Amira Ben Amara, Marie-Sarah Rouviere, Nicolas Boucherit, Pascale Andre, Claude Preudhomme, Nicolas Dulphy, Antoine Toubert, Norbert Ifrah, Daniel Olive, Herve Dombret","doi":"10.1101/2024.08.23.24312477","DOIUrl":"https://doi.org/10.1101/2024.08.23.24312477","url":null,"abstract":"Lirilumab is a fully human monoclonal antibody designed to block killer inhibitory receptors (KIR), which are major immune checkpoints involved in the regulation of NK cell-mediated killing of HLA-I-expressing tumors. EFFIKIR is a multicenter randomized double-blind 3-arm placebo-controlled phase II trial with lirilumab as single-agent as maintenance therapy of elderly patients with AML in first complete remission (NCT01687387). Two dose schedules led to either continuous or intermittent KIR occupancy. 153 patients were randomized and 152 patients were treated after 3+7 induction therapy. The median follow-up was 36.6 months. Lirilumab was well tolerated, with no significant hematological toxicity. The median LFS were 17.6, 6.7 and 13.9 months in the 0.1mg/kg arm, 1mg/kg arm and placebo arm, respectively. An excess in early relapse led to early termination of treatment in the 1mg/kg arm. Extensive analysis of immune cell fate following KIR blockade evidenced a decrease of KIR+ NK cell absolute counts following KIR blockade, associated with a decrease of Bcl-2. Lirilumab also bound antigen-experienced CD8+ T cells, and induced a transient decrease of CD69 expression. Besides, lirilumab bound vδ2+ γδT cells with a high cytotoxic potential, and induced a decrease of DNAM-1 and Bcl-2, the latter being associated with a decrease of KIR+ γδT cell, and with a drastic reduction of time to relapse. Overall, the potentially deleterious effects on immune effectors may have resulted in the impairment of immune surveillance associated with an unexpected high rate of early relapse in the group of patients exposed to prolonged full KIR blockade.","PeriodicalId":501437,"journal":{"name":"medRxiv - Oncology","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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