Journal for Immunotherapy of Cancer最新文献

{"title":"Body mass index and type 2 diabetes mellitus as metabolic determinants of immune checkpoint inhibitors response in melanoma.","authors":"Yu Jen Alexander Jan, Cho-Han Chiang, Soravis Osataphan, Aleigha R Lawless, Kerry L Reynolds, Ryan J Sullivan","doi":"10.1136/jitc-2024-009769","DOIUrl":"https://doi.org/10.1136/jitc-2024-009769","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint inhibitors (ICIs) have improved survival outcomes in melanoma. Studies exploring the correlations between body mass index (BMI), type 2 diabetes (T2DM) and the outcomes of ICI treatment have yielded inconsistent results. In this study, we aim to investigate the effects of BMI and T2DM on survival outcomes of patients with melanoma receiving ICIs.</p><p><strong>Methods: </strong>A retrospective multicenter cohort of patients with melanoma treated with ICIs was analyzed. Overall survival was evaluated with Kaplan-Meier survival analysis, univariate Cox and multivariate Cox proportional hazards model. Propensity-score matching (1:1) analysis between overweight and non-overweight groups was done and survival analyses and Cox analyses were performed again. Subgroup analyses and secondary analyses stratifying patients with different weights and T2DM statuses were also performed.</p><p><strong>Results: </strong>A total of 2,078 patients were included, of whom 1,412 were overweight (BMI≥25 kg/m²) and 666 were non-overweight (BMI<25 kg/m²). Overweight patients had better overall survival compared with non-overweight (median 71.7 vs 36.7 months, p<0.001). Patients with T2DM had worse overall survival compared with patients without T2DM (median 28.5 vs 67.3 months, p<0.001). After propensity-score matching (666 overweight were matched to 666 non-overweight), overweight patients remained to have better overall survival compared with non-overweight (median 67.7 vs 36.7 months, p<0.001). Patients with T2DM had worse survival in univariate Cox (HR 1.71, (95% CI: 1.20 to 2.43)) and multivariate Cox (HR 1.58, (95% CI: 1.08 to 2.31)) analyses. Overweight patients without T2DM had the best survival outcomes compared with other weight and T2DM combinations.</p><p><strong>Conclusion: </strong>In patients with melanoma treated with ICIs, being overweight had better survival outcomes compared with non-overweight. Having T2DM was associated with worse survival compared with those without T2DM. Further studies are needed to investigate the underlying mechanisms of these associations.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":null,"pages":null},"PeriodicalIF":10.3,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142604634","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":"TMED inhibition suppresses cell surface PD-1 expression and overcomes T cell dysfunction.","authors":"David W Vredevoogd, Georgi Apriamashvili, Pierre L Levy, Sanju Sinha, Zowi R Huinen, Nils L Visser, Beaunelle de Bruijn, Julia Boshuizen, Susan E van Hal-van Veen, Maarten A Ligtenberg, Onno B Bleijerveld, Chun-Pu Lin, Judit Díaz-Gómez, Santiago Duro Sánchez, Ettai Markovits, Juan Simon Nieto, Alex van Vliet, Oscar Krijgsman, Gal Markel, Michal J Besser, Maarten Altelaar, Eytan Ruppin, Daniel S Peeper","doi":"10.1136/jitc-2024-010145","DOIUrl":"https://doi.org/10.1136/jitc-2024-010145","url":null,"abstract":"<p><strong>Background: </strong>Blockade of the programmed cell death protein 1 (PD-1) immune checkpoint (ICB) is revolutionizing cancer therapy, but little is known about the mechanisms governing its expression on CD8 T cells. Because PD-1 is induced during activation of T cells, we set out to uncover regulators whose inhibition suppresses PD-1 abundance without adversely impacting on T cell activation.</p><p><strong>Methods: </strong>To identify PD-1 regulators in an unbiased fashion, we performed a whole-genome, fluorescence-activated cell sorting (FACS)-based CRISPR-Cas9 screen in primary murine CD8 T cells. A dual-readout design using the activation marker CD137 allowed us to uncouple genes involved in PD-1 regulation from those governing general T cell activation.</p><p><strong>Results: </strong>We found that the inactivation of one of several members of the TMED/EMP24/GP25L/p24 family of transport proteins, most prominently TMED10, reduced PD-1 cell surface abundance, thereby augmenting T cell activity. Another client protein was cytotoxic T lymphocyte-associated protein 4 (CTLA-4), which was also suppressed by TMED inactivation. Treatment with TMED inhibitor AGN192403 led to lysosomal degradation of the TMED-PD-1 complex and reduced PD-1 abundance in tumor-infiltrating CD8 T cells (TIL) in mice, thus reversing T cell dysfunction. Clinically corroborating these findings, single-cell RNA analyses revealed a positive correlation between TMED expression in CD8 TIL, and both a T cell dysfunction signature and lack of ICB response. Similarly, patients receiving a TIL product with high TMED expression had a shorter overall survival.</p><p><strong>Conclusion: </strong>Our results uncover a novel mechanism of PD-1 regulation, and identify a pharmacologically tractable target whose inhibition suppresses PD-1 abundance and T cell dysfunction.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":null,"pages":null},"PeriodicalIF":10.3,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142604638","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":"WWOX tuning of oleic acid signaling orchestrates immunosuppressive macrophage polarization and sensitizes hepatocellular carcinoma to immunotherapy.","authors":"Shaoqing Liu, Shiguang Yang, Min Xu, Qiang Zhou, Jialei Weng, Zhiqiu Hu, Minghao Xu, Wenxin Xu, Yong Yi, Yi Shi, Qiongzhu Dong, Mien-Chie Hung, Ning Ren, Chenhao Zhou","doi":"10.1136/jitc-2024-010422","DOIUrl":"10.1136/jitc-2024-010422","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint inhibitors (ICIs) are therapeutically effective for hepatocellular carcinoma (HCC) but are individually selective. This study examined the role of specific common fragile sites (CFSs) related gene in HCC immunotherapy.</p><p><strong>Methods: </strong>We analyzed HCC tissues using next-generation sequencing and flow cytometry via time-of-flight technology. A humanized orthotopic HCC mouse model, an in vitro co-culture system, untargeted metabolomics and a DNA pulldown assay were used to examine the function and mechanism of WWOX in the tumor immune response.</p><p><strong>Results: </strong>WWOX was the most upregulated CFS-related gene in HCC patients responsive to ICIs. WWOX deficiency renders HCC resistant to PD-1 treatment in humanized orthotopic HCC mouse model. Macrophage infiltration is increased and CD8 T-cell subset infiltration is decreased in WWOX-deficient HCC patients. HCC-derived oleic acid (OA) promotes macrophage conversion to an immunosuppressive phenotype. Mechanistically, WWOX deficiency promoted OA synthesis primarily via competitive binding of NME2 with KAT1, which promoted acetylation of NME2 at site 31 and inhibited NME2 binding to the SCD5 promoter region. Pharmacological blockade of SCD5 enhanced the antitumor effects of anti-PD-1 therapy.</p><p><strong>Conclusions: </strong>WWOX is a key factor for immune escape in HCC patients, which suggests its use as a biomarker for stratified treatment with ICIs in clinical HCC patients.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":null,"pages":null},"PeriodicalIF":10.3,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11552608/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of <i>CD47</i> gene expression in colorectal cancer: a comprehensive molecular profiling study.","authors":"Hiroyuki Arai, Nishant Gandhi, Francesca Battaglin, Jingyuan Wang, Sandra Algaze, Priya Jayachandran, Shivani Soni, Wu Zhang, Yan Yang, Joshua Millstein, Jae Ho Lo, Davendra Sohal, Richard Goldberg, Michael J Hall, Aaron James Scott, Jimmy J Hwang, Emil Lou, Benjamin A Weinberg, John Marshall, Sanjay Goel, Joanne Xiu, W Michael Korn, Heinz-Josef Lenz","doi":"10.1136/jitc-2024-010326","DOIUrl":"https://doi.org/10.1136/jitc-2024-010326","url":null,"abstract":"<p><strong>Background: </strong>In patients with colorectal cancer (CRC), the therapeutic effects of conventional immune checkpoint inhibitors targeting the adaptive immune system are largely limited to those with microsatellite instability-high tumors. Meanwhile, new immunotherapies targeting the innate immune system are attracting increasing attention. CD47 is a representative innate immune checkpoint involved in the evasion of tumor cell phagocytosis by macrophages. This large-scale study comprehensively examined the molecular significance of <i>CD47</i> gene expression in CRC.</p><p><strong>Methods: </strong>We analyzed the next-generation sequencing data of DNA and RNA from 14,287 CRC cases included in the data set of a commercial Clinical Laboratory Improvement Amendments-certified laboratory (Caris Life Sciences). The cases were divided into two groups based on the median value of <i>CD47</i> gene expression levels. The molecular and immune profiles between the groups were compared, and the relationship between <i>CD47</i> expression and survival outcomes was further examined.</p><p><strong>Results: </strong>In <i>CD47</i>-high tumors, the proportion of consensus molecular subtypes 1 and 4 was significantly higher than in <i>CD47</i>-low tumors. The expression levels of damage-associated molecular pattern-related genes showed a positive correlation with <i>CD47</i> expression levels. Major oncogenic pathways, such as mitogen-activated protein kinase, phosphoinositide 3-kinase, angiogenesis, and transforming growth factor beta, were significantly activated in <i>CD47</i>-high tumors. Additionally, the expression levels of a panel of adaptive immune checkpoint genes and estimates of immune cells constituting the tumor microenvironment (TME) were significantly higher in <i>CD47</i>-high tumors.</p><p><strong>Conclusions: </strong><i>CD47</i> expression in CRC was associated with the activation of several oncogenic pathways and an immune-engaged TME. Our findings may provide valuable information for considering new therapeutic strategies targeting innate immune checkpoints in CRC.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":null,"pages":null},"PeriodicalIF":10.3,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582929","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":"Intratumoral and peritumoral radiomics of MRIs predicts pathologic complete response to neoadjuvant chemoimmunotherapy in patients with head and neck squamous cell carcinoma.","authors":"Peiliang Lin, Wenqian Xie, Yong Li, Chenjia Zhang, Huiqian Wu, Huan Wan, Ming Gao, Faya Liang, Ping Han, Renhui Chen, Gui Cheng, Xuekui Liu, Song Fan, Xiaoming Huang","doi":"10.1136/jitc-2024-009616","DOIUrl":"10.1136/jitc-2024-009616","url":null,"abstract":"<p><strong>Background: </strong>For patients with locally advanced head and neck squamous cell carcinoma (HNSCC), combined programmed death receptor-1 inhibitor and chemotherapy improved response rate to neoadjuvant therapy. However, treatment response varies among patients. There is no tool to predict pathologic complete response (pCR) with high accuracy for now. To develop a tool based on radiomics features of MRI to predict pCR to neoadjuvant chemoimmunotherapy (NACI) may provide valuable assistance in treatment regimen determination for HNSCC.</p><p><strong>Methods: </strong>From January 2021 to April 2024, a total of 172 patients with HNSCC from three medical center, who received NACI followed by surgery, were included and allocated into a training set (n=84), an internal validation set (n=37) and an external validation set (n=51). Radiomics features were extracted from intratumoral and different peritumoral areas, and radiomics signature (Rad-score) for each area was constructed. A radiomics-clinical nomogram was developed based on Rad-scores and clinicopathological characteristics, tested in the validation sets, and compared with clinical nomogram and combined positive score (CPS) in predicting pCR.</p><p><strong>Results: </strong>The radiomics-clinical nomogram, incorporating peritumoral Rad-score, intratumoral Rad-score and CPS, achieved the highest accuracy with areas under the receiver operating characteristic curve of 0.904 (95% CI, 0.835 to 0.972) in the training cohort, 0.860 (95% CI, 0.722 to 0.998) in the internal validation cohort, and 0.849 (95% CI, 0.739 to 0.959) in the external validation cohort, respectively, which outperformed the clinical nomogram and CPS in predict pCR to NACI for HNSCC.</p><p><strong>Conclusion: </strong>A nomogram developed based on intratumoral and peritumoral MRI radiomics features outperformed CPS, a widely employed biomarker, in predict pCR to NACI for HNSCC, which would provide incremental value in treatment regimen determination.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":null,"pages":null},"PeriodicalIF":10.3,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11552555/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In situ endoscopic photodynamic therapy combined with immature DC vaccination induces a robust T cell response against peritoneal carcinomatosis.","authors":"Charline Degavre, Anouk Lepez, Sebastien Ibanez, Clémence François, Katarzyna Głowacka, Céline Guilbaud, Florine Laloux-Morris, Hrag Esfahani, Davide Brusa, Caroline Bouzin, Olivier Feron","doi":"10.1136/jitc-2024-009752","DOIUrl":"10.1136/jitc-2024-009752","url":null,"abstract":"<p><strong>Background: </strong>Immunogenic cell death (ICD) and ferroptosis have recently emerged as key factors in the anticancer immune response. Among the treatments able to induce ICD and the associated release of danger signals is photodynamic therapy (PDT). Ferroptosis for its part results from lipid peroxidation and is induced by CD8⁺ T cells to kill nearby cancer cells on IFN-γ production. We aimed to combine the two concepts, that is, to evaluate whether the strong pro-oxidant effects of PDT may promote ferroptosis and antigen release and to develop a procedure for in situ PDT to prepare the soil for highly endocytotic immature dendritic cell (iDC) adoptive transfer. This approach was implemented for managing peritoneal carcinomatosis, a lesion often associated with poor outcomes.</p><p><strong>Methods: </strong>We used three-dimensional (3D) heterotypic spheroids made of cancer cells, exposed them to a white light-activated OR141 photosensitizer (PS), and subsequently complexified them by adding iDC and naive lymphocytes. We next used a model of mouse peritoneal carcinomatosis and administered PDT using laparoscopy to locally induce photoactivation using the endoscope light. The immune response following adoptive transfer of iDC was tracked both in vivo and ex vivo using isolated immune cells from in situ vaccinated mice.</p><p><strong>Results: </strong>Cancer cells undergoing PDT-induced cell death significantly increased ICD markers and the infiltration of iDCs in spheroids, relying on ferroptosis. These actions induced the sequential activation of CD8⁺ and CD4⁺ T cells as revealed by a significant spheroid 3D structure deterioration and, remarkably, were not recapitulated by conventional ferroptosis inducer RSL3. Using LED light from an endoscope for in situ photoactivation of PS enabled us to apply the vaccination modality in mice with peritoneal tumors. Consecutive intraperitoneal injection of iDCs resulted in delayed tumor growth, increased survival rates, and prevented tumor relapse on rechallenge. CD8⁺ T cell response was supported by depletion experiments, nodal detection of early activated T cells, and ex vivo T cell-induced cytotoxicity toward spheroids.</p><p><strong>Conclusions: </strong>The combination of in situ PDT locally delivered by an endoscope light and iDC administration induces a durable memory immune response against peritoneal carcinomatosis thereby opening new perspectives for the treatment of a life-threatening condition.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":null,"pages":null},"PeriodicalIF":10.3,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11552574/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer-associated fibroblasts shape early myeloid cell response to chemotherapy-induced immunogenic signals in next generation tumor organoid cultures.","authors":"Julijan Kabiljo, Anna Theophil, Jakob Homola, Annalena F Renner, Nathalie Stürzenbecher, Daphni Ammon, Rebecca Zirnbauer, Simone Stang, Loan Tran, Johannes Laengle, Askin Kulu, Anna Chen, Markus Fabits, Velina S Atanasova, Oliver Pusch, Wolfgang Weninger, Henning Walczak, Dietmar Herndler Brandstetter, Gerda Egger, Helmut Dolznig, Anna Kusienicka, Matthias Farlik, Michael Bergmann","doi":"10.1136/jitc-2024-009494","DOIUrl":"10.1136/jitc-2024-009494","url":null,"abstract":"<p><strong>Background: </strong>Patient-derived colorectal cancer (CRC) organoids (PDOs) solely consisting of malignant cells led to major advances in the understanding of cancer treatments. Yet, a major limitation is the absence of cells from the tumor microenvironment, thereby prohibiting potential investigation of treatment responses on immune and structural cells. Currently there are sparse reports describing the interaction of PDOs, cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) in complex primary co-culture assay systems.</p><p><strong>Methods: </strong>Primary PDOs and patient matched CAF cultures were generated from surgical resections. Co-culture systems of PDOs, CAFs and monocytic myeloid cells were set up to recapitulate features seen in patient tumors. Single-cell transcriptomics and flow cytometry was used to show effects of culture systems on TAM populations in the co-culture assays under chemotherapeutic and oncolytic viral treatment.</p><p><strong>Results: </strong>In contrast to co-cultures of tumor cells and monocytes, CAF/monocyte co-cultures and CAF/monocyte/tumor cell triple cultures resulted in a partial differentiation into macrophages and a phenotypic switch, characterized by the expression of major immunosuppressive markers comparable to TAMs in CRC. Oxaliplatin and 5-fluorouracil, the standard-of-care chemotherapy for CRC, induced polarization of macrophages to a pro-inflammatory phenotype comparable to the immunogenic effects of treatment with an oncolytic virus. Monitoring phagocytosis as a functional proxy to macrophage activation and subsequent onset of an immune response, revealed that chemotherapy-induced cell death, but not virus-mediated cell death, is necessary to induce phagocytosis of CRC cells. Moreover, CAFs enhanced the phagocytic activity in chemotherapy treated CRC triple cultures.</p><p><strong>Conclusions: </strong>Primary CAF-containing triple cultures successfully model TAM-like phenotypes <i>ex vivo</i> and allow the assessment of their functional and phenotypic changes in response to treatments following a precision medicine approach.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":null,"pages":null},"PeriodicalIF":10.3,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11535717/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multicenter validation of an RNA-based assay to predict anti-PD-1 disease control in patients with recurrent or metastatic head and neck squamous cell carcinoma: the PREDAPT study.","authors":"Kevin C Flanagan, Jon Earls, Jeffrey Hiken, Rachel L Wellinghoff, Michelle M Ponder, Howard L McLeod, William H Westra, Vera Vavinskaya, Leisa Sutton, Ida Deichaite, Orlan K Macdonald, Karim Welaya, James Wade, Georges Azzi, Andrew W Pippas, Jennifer Slim, Bruce Bank, Xingwei Sui, Steven E Kossman, Todd D Shenkenberg, Warren L Alexander, Katharine A Price, Jessica Ley, David N Messina, Jarret I Glasscock, A Dimitrios Colevas, Ezra E W Cohen, Douglas Adkins, Eric J Duncavage","doi":"10.1136/jitc-2024-009573","DOIUrl":"10.1136/jitc-2024-009573","url":null,"abstract":"<p><strong>Background: </strong>Despite advances in cancer care and detection, >65% of patients with squamous cell cancer of the head and neck (HNSCC) will develop recurrent and/or metastatic disease. The prognosis for these patients is poor with a 5-year overall survival of 39%. Recent treatment advances in immunotherapy, including immune checkpoint inhibitors like pembrolizumab and nivolumab, have resulted in clinical benefit in a subset of patients. There is a critical clinical need to identify patients who benefit from these antiprogrammed cell death protein 1 (anti-PD-1) immune checkpoint inhibitors.</p><p><strong>Methods: </strong>Here, we report findings from a multicenter observational study, PREDicting immunotherapy efficacy from Analysis of Pre-treatment Tumor biopsies (PREDAPT), conducted across 17 US healthcare systems. PREDAPT aimed to validate OncoPrism-HNSCC, a clinical biomarker assay predictive of disease control in patients with recurrent or metastatic HNSCC treated with anti-PD-1 immune checkpoint inhibitors as a single agent (monotherapy) and in combination with chemotherapy (chemo-immunotherapy). The test used RNA-sequencing data and machine learning models to score each patient and place them into groups of low, medium, or high.</p><p><strong>Results: </strong>The OncoPrism-HNSCC prediction significantly correlated with disease control in both the monotherapy cohort (n=62, p=0.004) and the chemo-immunotherapy cohort (n=50, p=0.01). OncoPrism-HNSCC also significantly predicted progression-free survival in both cohorts (p=0.015 and p=0.037, respectively). OncoPrism-HNSCC had more than threefold higher specificity than programmed death-ligand 1 combined positive score and nearly fourfold higher sensitivity than tumor mutational burden for predicting disease control.</p><p><strong>Conclusions: </strong>Here, we demonstrate the clinical validity of the OncoPrism-HNSCC assay in identifying patients with disease control in response to anti-PD-1 immune checkpoint inhibitors.</p><p><strong>Trial registration number: </strong>NCT04510129.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":null,"pages":null},"PeriodicalIF":10.3,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11535711/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Myeloid subsets impede the efficacy of anti-PD1 therapy in patients with advanced gastric cancer (WJOG10417GTR study).","authors":"Hirokazu Shoji, Chie Kudo-Saito, Kengo Nagashima, Hiroshi Imazeki, Kai Tsugaru, Naoki Takahashi, Takeshi Kawakami, Yusuke Amanuma, Takeru Wakatsuki, Naohiro Okano, Yukiya Narita, Yoshiyuki Yamamoto, Rika Kizawa, Kei Muro, Kazunori Aoki, Narikazu Boku","doi":"10.1136/jitc-2024-010174","DOIUrl":"10.1136/jitc-2024-010174","url":null,"abstract":"<p><strong>Background: </strong>Gastric cancer (GC) is one of the most common and deadly malignant diseases worldwide. Despite revolutionary advances, the therapeutic efficacy of anti-PD1/PDL1 monoclonal antibodies in advanced GC is still low due to the emergence of innate and acquired resistance to treatment. Myeloid cells represent the majority of human immune cells. Therefore, their increase, decrease, and abnormality could have a significant impact on the patient's immune system and the progression of cancer, and reprogramming, inhibiting, and eliminating the tumor-supportive types may improve the immunological situation and efficacy of immunotherapy. However, the significance of myeloid cells in anti-PD1/PDL1 therapy remains unclear in GC. In the WJOG10417GTR study on GC, we sought to identify myeloid determinants that could predict anti-PD1 therapeutic efficacy and also serve as potential therapeutic targets.</p><p><strong>Methods: </strong>We collected tumor tissues and peripheral blood from 96 patients with advanced GC before and 1 month after anti-PD1 nivolumab monotherapy, and the isolated whole leucocytes were analyzed by flow cytometry for various immune cell populations, including many myeloid subsets. Then, the relationship between the cellular levels and progression-free survival (PFS) or overall survival (OS) was statistically analyzed.</p><p><strong>Results: </strong>We found that high levels of several myeloid subsets expressing molecules that have been targeted in drug discovery but not yet approved for clinical use were significantly associated with shorter PFS/OS as compared with low levels: PDL1⁺ and CTLA4⁺ myeloid subsets within tumors at baseline, PDL1⁺, B7H3⁺ and CD115⁺ myeloid subsets in peripheral blood at baseline, and LAG3⁺, CD155⁺ and CD115⁺ myeloid subsets in peripheral blood at post-treatment.</p><p><strong>Conclusions: </strong>This study revealed that these myeloid subsets are significant risk factors in nivolumab therapy for advanced GC. Targeting them may be useful as diagnostic biomarkers to predict potential anti-PD1 therapeutic efficacy, and also as therapeutic targets for accelerating the development of new drugs to improve clinical outcomes in immunotherapy for GC.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":null,"pages":null},"PeriodicalIF":10.3,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11535716/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reporting of late-onset immune-related adverse events with immune checkpoint inhibitors in VigiBase.","authors":"Roberta Noseda, Francesca Bedussi, Valentina Giunchi, Michele Fusaroli, Emanuel Raschi, Alessandro Ceschi","doi":"10.1136/jitc-2024-009902","DOIUrl":"10.1136/jitc-2024-009902","url":null,"abstract":"<p><strong>Background: </strong>To date, evidence on late-onset immune-related adverse events (irAEs) with immune checkpoint inhibitors (ICIs) is limited to a small number of clinical cases. This study aimed to identify drug- and patient-related characteristics potentially associated with the reporting of late-onset irAEs with ICIs in VigiBase, the WHO global database of individual case safety reports (ICSRs).</p><p><strong>Methods: </strong>Observational study comparing deduplicated ICSRs with ICIs reporting late-onset irAEs (occurred >90 days after ICI discontinuation) versus ICSRs with ICIs not reporting late-onset irAEs, collected in VigiBase from 2011 to December 31, 2022. Logistic regression was used to model the relationship between drug-related and patient-related characteristics of ICSRs and the reporting of late-onset irAEs. Significance was determined for variables with the lower bound of the 95% CI of the reporting OR (ROR) higher than 1 and a p value <0.05.</p><p><strong>Results: </strong>The study population consisted of 6006 ICSRs with ICI-related irAEs (4574, 76.2%, originated from Europe; 3900, 64.9%, involved males; median patient age was 67 years, IQR 59-74 years). Of these, 344 (5.7%) ICSRs reported a total of 388 late-onset irAEs, among which the most frequent were thyroiditis (n=45), pneumonitis (n=37), interstitial lung disease (n=25), hepatitis (n=23) and vitiligo (n=19). Median time to onset since ICI discontinuation was 167 days (IQR 115-294 days), with negligible proportion (3.2%) of co-reported antineoplastic agents during the discontinuation period. Logistic regression models showed disproportionate reporting of late-onset irAEs with ICI combination therapy (ROR 2.33, 95% CI 1.19 to 4.57), reporting of multiple irAEs (ROR 3.96, 95% CI 2.85 to 5.52), reporting of cutaneous irAEs (ROR 1.83, 95% CI 1.24 to 2.71), and melanoma (ROR 1.47, 95% CI 1.04 to 2.06).</p><p><strong>Conclusions: </strong>This global pharmacovigilance study provides the largest case series of late-onset irAEs with ICIs to date and identifies characteristics of ICSRs associated with disproportionate reporting. Dedicated prospective observational studies focused on long-term sequelae, quality of life and survival of patients developing late-onset irAEs with ICIs should be planned to confirm whether these reporting characteristics are predictors of actual occurrence. Furthermore, translational research should be encouraged to clarify the molecular mechanisms underlying late-onset irAE development.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":null,"pages":null},"PeriodicalIF":10.3,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11535709/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}