Pub Date : 2024-08-26DOI: 10.1097/CJI.0000000000000540
Jichun Sun, Panpan Luo, Yuge Guo, Yang He, Chunjiang Wang
Haemophagocytic lymphohistiocytosis (HLH) is a rare and fatal immune-related event of nivolumab. The clinical features of nivolumab-induced HLH are unclear. The aim of this study was to investigate the clinical features, treatment, and outcome of nivolumab-induced HLH to provide information for prevention and treatment. We collected nivolumab-induced HLH-related case reports for retrospective analysis by searching the Chinese and English databases from inception to March 31, 2024. HLH developed in 24 patients, with a median age of 57 years (range: 26, 86). The onset of HLH symptoms ranged from 3 days to 68 weeks after administration, with a median time of 5.5 weeks. Fever (87.5%) was the most common symptom and could be accompanied by splenomegaly (66.7%) and hepatomegaly (20.8%). Laboratory tests revealed hemocytopenia, hypertriglyceridemia, hypofibrinogenemia, hyperferritinemia, increased sCD25, and decreased natural killer cell activity. Bone marrow biopsy showed hemophagocytosis (62.5%). After discontinuing nivolumab, HLH patients receiving systemic steroids, tocilizumab, and anakinra showed positive results. As a rare adverse reaction of nivolumab, HLH requires rapid diagnosis and appropriate treatment based on clinical symptoms and laboratory tests. Tocilizumab and anakinra can be used as an effective treatment against the steroid HLH.
{"title":"Clinical Features, Treatment, and Outcomes of Nivolumab-Induced Hemophagocytic Lymphohistiocytosis.","authors":"Jichun Sun, Panpan Luo, Yuge Guo, Yang He, Chunjiang Wang","doi":"10.1097/CJI.0000000000000540","DOIUrl":"https://doi.org/10.1097/CJI.0000000000000540","url":null,"abstract":"<p><p>Haemophagocytic lymphohistiocytosis (HLH) is a rare and fatal immune-related event of nivolumab. The clinical features of nivolumab-induced HLH are unclear. The aim of this study was to investigate the clinical features, treatment, and outcome of nivolumab-induced HLH to provide information for prevention and treatment. We collected nivolumab-induced HLH-related case reports for retrospective analysis by searching the Chinese and English databases from inception to March 31, 2024. HLH developed in 24 patients, with a median age of 57 years (range: 26, 86). The onset of HLH symptoms ranged from 3 days to 68 weeks after administration, with a median time of 5.5 weeks. Fever (87.5%) was the most common symptom and could be accompanied by splenomegaly (66.7%) and hepatomegaly (20.8%). Laboratory tests revealed hemocytopenia, hypertriglyceridemia, hypofibrinogenemia, hyperferritinemia, increased sCD25, and decreased natural killer cell activity. Bone marrow biopsy showed hemophagocytosis (62.5%). After discontinuing nivolumab, HLH patients receiving systemic steroids, tocilizumab, and anakinra showed positive results. As a rare adverse reaction of nivolumab, HLH requires rapid diagnosis and appropriate treatment based on clinical symptoms and laboratory tests. Tocilizumab and anakinra can be used as an effective treatment against the steroid HLH.</p>","PeriodicalId":15996,"journal":{"name":"Journal of Immunotherapy","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142055743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-30DOI: 10.1097/CJI.0000000000000536
Luise Froessl, Puja Panwar, Subir Bhatia, Jonathan Dowell
We report the case of corneal transplant rejection in a 77-year-old male receiving durvalumab as consolidative therapy for stage IIIB non-small cell lung cancer (NSCLC). Following successful chemoradiation and initiation of durvalumab, the patient underwent a right corneal transplant for corneal dystrophy. Six months after an initially stable post-transplant course, he developed progressive visual decline culminating in graft failure 1 year later despite treatment with prednisone eye drops. This case adds to the limited evidence implicating immune checkpoint inhibitors (ICIs) in corneal graft rejection, emphasizing the need for multidisciplinary evaluation and close monitoring of corneal transplant recipients undergoing ICI therapy.
{"title":"Corneal Transplant Rejection Following Durvalumab Therapy in a Patient With NSCLC: A Case Report.","authors":"Luise Froessl, Puja Panwar, Subir Bhatia, Jonathan Dowell","doi":"10.1097/CJI.0000000000000536","DOIUrl":"https://doi.org/10.1097/CJI.0000000000000536","url":null,"abstract":"<p><p>We report the case of corneal transplant rejection in a 77-year-old male receiving durvalumab as consolidative therapy for stage IIIB non-small cell lung cancer (NSCLC). Following successful chemoradiation and initiation of durvalumab, the patient underwent a right corneal transplant for corneal dystrophy. Six months after an initially stable post-transplant course, he developed progressive visual decline culminating in graft failure 1 year later despite treatment with prednisone eye drops. This case adds to the limited evidence implicating immune checkpoint inhibitors (ICIs) in corneal graft rejection, emphasizing the need for multidisciplinary evaluation and close monitoring of corneal transplant recipients undergoing ICI therapy.</p>","PeriodicalId":15996,"journal":{"name":"Journal of Immunotherapy","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141792608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-09DOI: 10.1097/CJI.0000000000000531
Guojie Chen, WenYa Li, Ruomu Ge, Ting Guo, Yuhan Zhang, Chenglin Zhou, Mei Lin
Hepatocellular carcinoma (HCC) is the most common type of liver cancer and is associated with high morbidity and mortality rates. The aims of this study were to investigate the immune-promoting action of nucleolar and spindle-associated protein 1 (NUSAP1) and identify an immunotherapy target for HCC. The Cancer Genome Atlas (TCGA) was used to analyze interaction molecules and immune correlation. The interaction between NUSAP1 and SHC binding and spindle associated 1 (SHCBP1) was examined. The role of the SHCBP1/Janus kinase 2/signal transducer and activator of transcription 3 (SHCBP1/JAK2/STAT3) pathway in this process was explored. After co-culture with HCC cell lines, the differentiation of peripheral blood mononuclear cells (PBMCs) into dendritic cells (DC) was evaluated by measuring the expression of surface factors CD1a and CD86. Pathological tissues from 50 patients with HCC were collected to validate the results of cell experiments. The expression levels of CD1a and CD86 in tissues were also determined. The results show that NUSAP1 interacted with SHCBP1 and was positively correlated with DC. In HCC cell lines, an interaction was observed between NUSAP1 and SHCBP1. It was verified that NUSAP1 inhibited the JAK2/STAT3 phosphorylation pathway by blocking SHCBP1. After co-culture, the levels of CD1a and CD86 in PBMC were elevated. In the clinical specimens, CD1a and CD86 expression levels were significantly higher in the high-NUSAP1 group versus the low-NUSAP1 group. In Summary, NUSAP1 enhanced immunity by inhibiting the SHCBP1/JAK2/STAT3 phosphorylation pathway and promoted DC generation and HCC apoptosis. NUSAP1 may be a target of immunotherapy for HCC.
{"title":"NUSAP1 Promotes Immunity and Apoptosis by the SHCBP1/JAK2/STAT3 Phosphorylation Pathway to Induce Dendritic Cell Generation in Hepatocellular Carcinoma.","authors":"Guojie Chen, WenYa Li, Ruomu Ge, Ting Guo, Yuhan Zhang, Chenglin Zhou, Mei Lin","doi":"10.1097/CJI.0000000000000531","DOIUrl":"https://doi.org/10.1097/CJI.0000000000000531","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) is the most common type of liver cancer and is associated with high morbidity and mortality rates. The aims of this study were to investigate the immune-promoting action of nucleolar and spindle-associated protein 1 (NUSAP1) and identify an immunotherapy target for HCC. The Cancer Genome Atlas (TCGA) was used to analyze interaction molecules and immune correlation. The interaction between NUSAP1 and SHC binding and spindle associated 1 (SHCBP1) was examined. The role of the SHCBP1/Janus kinase 2/signal transducer and activator of transcription 3 (SHCBP1/JAK2/STAT3) pathway in this process was explored. After co-culture with HCC cell lines, the differentiation of peripheral blood mononuclear cells (PBMCs) into dendritic cells (DC) was evaluated by measuring the expression of surface factors CD1a and CD86. Pathological tissues from 50 patients with HCC were collected to validate the results of cell experiments. The expression levels of CD1a and CD86 in tissues were also determined. The results show that NUSAP1 interacted with SHCBP1 and was positively correlated with DC. In HCC cell lines, an interaction was observed between NUSAP1 and SHCBP1. It was verified that NUSAP1 inhibited the JAK2/STAT3 phosphorylation pathway by blocking SHCBP1. After co-culture, the levels of CD1a and CD86 in PBMC were elevated. In the clinical specimens, CD1a and CD86 expression levels were significantly higher in the high-NUSAP1 group versus the low-NUSAP1 group. In Summary, NUSAP1 enhanced immunity by inhibiting the SHCBP1/JAK2/STAT3 phosphorylation pathway and promoted DC generation and HCC apoptosis. NUSAP1 may be a target of immunotherapy for HCC.</p>","PeriodicalId":15996,"journal":{"name":"Journal of Immunotherapy","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141558934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01Epub Date: 2024-04-30DOI: 10.1097/CJI.0000000000000517
Kexin Chang, QingFang Yue, Long Jin, Pengyu Fan, Yi Liu, Fei Cao, Yuan Zhang
The involvement of M2-like tumor-associated macrophages (TAMs) in the advancement and treatment of cancer has been widely documented. This study aimed to develop a new signature associated with M2-like TAMs to predict the prognosis and treatment response in individuals diagnosed with breast cancer (BC). Weighted gene co-expression network analysis (WGCNA) was used to identity for M2-like TAM-related modular genes. The M2-like TAM-related modular subtype was identified using unsupervised clustering. WGCNA identified 722 M2-like TAM genes, 204 of which were associated with recurrence-free survival (RFS). Patients in cluster 1 exhibited upregulated cancer-related pathways, a higher proportion of triple-negative breast cancer (TNBC) subtypes, lower expression of immune checkpoints, and worse prognosis. Cluster 2 was characterized by upregulated immune-related pathways, a higher proportion of luminal A subtypes, and higher expression of immune checkpoints. A prognostic signature was created and confirmed using an independent dataset. A well-built nomogram can accurately forecast the survival outcomes for every individual. Furthermore, patients classified as low-risk exhibited a more favorable outlook, elevated tumor microenvironment (TME) score, and superior reaction to immunotherapy. In conclusion, we discovered 2 different types of M2-like TAMs and developed a prognostic signature revealing the diversity of M2-like TAMs in BC and their correlation with immune status and prognosis. This feature can predict the prognosis and immunotherapeutic effects of BC and offer novel concepts and approaches for tailoring BC treatment.
M2样肿瘤相关巨噬细胞(TAMs)参与癌症的发展和治疗已被广泛记录。本研究旨在开发一种与M2样肿瘤相关巨噬细胞相关的新特征,以预测乳腺癌(BC)患者的预后和治疗反应。研究采用加权基因共表达网络分析(WGCNA)来识别与M2样TAM相关的模块基因。通过无监督聚类确定了M2样TAM相关模块亚型。WGCNA 确定了 722 个 M2-like TAM 基因,其中 204 个基因与无复发生存率(RFS)相关。群组1的患者表现出癌症相关通路上调、三阴性乳腺癌(TNBC)亚型比例较高、免疫检查点表达较低以及预后较差等特征。群组2的特点是免疫相关通路上调、管腔A亚型比例较高以及免疫检查点表达较高。我们创建了一个预后特征,并通过一个独立的数据集进行了确认。建立良好的提名图可以准确预测每个人的生存结果。此外,被归类为低风险的患者前景更乐观,肿瘤微环境(TME)评分更高,对免疫疗法的反应更佳。总之,我们发现了两种不同类型的M2样TAMs,并建立了一个预后特征,揭示了M2样TAMs在BC中的多样性及其与免疫状态和预后的相关性。这一特征可以预测 BC 的预后和免疫治疗效果,并为定制 BC 治疗提供了新的概念和方法。
{"title":"Comprehensive Molecular Analyses of an M2-Like Tumor-Associated Macrophage for Predicting the Prognosis and Immunotherapy in Breast Cancer.","authors":"Kexin Chang, QingFang Yue, Long Jin, Pengyu Fan, Yi Liu, Fei Cao, Yuan Zhang","doi":"10.1097/CJI.0000000000000517","DOIUrl":"10.1097/CJI.0000000000000517","url":null,"abstract":"<p><p>The involvement of M2-like tumor-associated macrophages (TAMs) in the advancement and treatment of cancer has been widely documented. This study aimed to develop a new signature associated with M2-like TAMs to predict the prognosis and treatment response in individuals diagnosed with breast cancer (BC). Weighted gene co-expression network analysis (WGCNA) was used to identity for M2-like TAM-related modular genes. The M2-like TAM-related modular subtype was identified using unsupervised clustering. WGCNA identified 722 M2-like TAM genes, 204 of which were associated with recurrence-free survival (RFS). Patients in cluster 1 exhibited upregulated cancer-related pathways, a higher proportion of triple-negative breast cancer (TNBC) subtypes, lower expression of immune checkpoints, and worse prognosis. Cluster 2 was characterized by upregulated immune-related pathways, a higher proportion of luminal A subtypes, and higher expression of immune checkpoints. A prognostic signature was created and confirmed using an independent dataset. A well-built nomogram can accurately forecast the survival outcomes for every individual. Furthermore, patients classified as low-risk exhibited a more favorable outlook, elevated tumor microenvironment (TME) score, and superior reaction to immunotherapy. In conclusion, we discovered 2 different types of M2-like TAMs and developed a prognostic signature revealing the diversity of M2-like TAMs in BC and their correlation with immune status and prognosis. This feature can predict the prognosis and immunotherapeutic effects of BC and offer novel concepts and approaches for tailoring BC treatment.</p>","PeriodicalId":15996,"journal":{"name":"Journal of Immunotherapy","volume":" ","pages":"205-215"},"PeriodicalIF":3.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140863716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01Epub Date: 2024-03-27DOI: 10.1097/CJI.0000000000000514
John P Antonelli, Myiah Quach, Aparna Mahajan, Jennifer Pleva, Vincent T Ma
Summary: Anti-programmed cell death protein 1 (PD-1) therapy is considered effective in the treatment of metastatic or locally advanced cutaneous squamous cell carcinoma but the use of these agents in solid organ transplant recipients (SOTRs) is often taken with caution. While anti-tumor effects without graft rejection have been reported, studies have shown high rates of fatal graft rejection with immune checkpoint therapy. In this case report, we present an SOTR patient with life-threatening, acute hypoxic respiratory failure due to rapidly progressive metastatic cutaneous squamous cell carcinoma with lung and pleural involvement. Modification of their immunosuppressive regimen and treatment with front-line anti-PD-1 inhibitor, pembrolizumab, led to rapid clinical response with near complete resolution of metastatic pulmonary disease and no long-term evidence of graft rejection. Our case report shows that front-line treatment with PD-1 inhibitors can be safely administered in SOTR patients with rapid metastatic disease control.
{"title":"Rapid Life-Saving Response to Anti-PD-1 in a Solid Organ Transplant Recipient With Metastatic Cutaneous Squamous Cell Carcinoma: A Case Report and Review.","authors":"John P Antonelli, Myiah Quach, Aparna Mahajan, Jennifer Pleva, Vincent T Ma","doi":"10.1097/CJI.0000000000000514","DOIUrl":"10.1097/CJI.0000000000000514","url":null,"abstract":"<p><strong>Summary: </strong>Anti-programmed cell death protein 1 (PD-1) therapy is considered effective in the treatment of metastatic or locally advanced cutaneous squamous cell carcinoma but the use of these agents in solid organ transplant recipients (SOTRs) is often taken with caution. While anti-tumor effects without graft rejection have been reported, studies have shown high rates of fatal graft rejection with immune checkpoint therapy. In this case report, we present an SOTR patient with life-threatening, acute hypoxic respiratory failure due to rapidly progressive metastatic cutaneous squamous cell carcinoma with lung and pleural involvement. Modification of their immunosuppressive regimen and treatment with front-line anti-PD-1 inhibitor, pembrolizumab, led to rapid clinical response with near complete resolution of metastatic pulmonary disease and no long-term evidence of graft rejection. Our case report shows that front-line treatment with PD-1 inhibitors can be safely administered in SOTR patients with rapid metastatic disease control.</p>","PeriodicalId":15996,"journal":{"name":"Journal of Immunotherapy","volume":" ","pages":"216-219"},"PeriodicalIF":3.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140293743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01Epub Date: 2024-03-14DOI: 10.1097/CJI.0000000000000510
Theresa Ruf, Farnaz Rahimi, David Anz, Amanda Tufman, Suzanna Salzer, Sarah Zierold, Dirk Tomsitz, Lars E French, Lucie Heinzerling
The wide use of immune checkpoint inhibitors has increased the frequency of immune-related adverse events (irAEs). While many are managed with corticosteroids or hormone substitution, up to 14.9% of irAEs are steroid-refractory or steroid-dependent and thus require second-line treatment. These should reduce irAE-related morbidity and mortality and induce a few side effects of their own while maintaining the antitumor response. There is little comparative data on second-line therapies for irAEs. Two cases of irAEs could not be sufficiently managed with corticosteroids and subsequently received treatment with extracorporeal photopheresis (ECP), including one patient with immune-related erosive oral lichen planus and one patient with immune-related colitis. In both cases, the irAE resolved with ECP in combination with immunosuppressive drugs, that is 4 weeks and 10 weeks after the start of ECP, respectively. To investigate this approach, a prospective clinical study that compares ECP and other second-line therapies for the treatment of steroid-refractory and steroid-dependent irAEs with regard to immunophenotype and therapy response has been designed. ECP could be a treatment option for steroid-refractory and steroid-dependent irAEs, given its good safety profile and lack of adverse effects on antitumor response. Comparative prospective studies are needed to generate an evidence base.
{"title":"Extracorporeal Photopheresis as a Treatment Option for Immune-Related Adverse Events: Two Case Reports and a Prospective Study.","authors":"Theresa Ruf, Farnaz Rahimi, David Anz, Amanda Tufman, Suzanna Salzer, Sarah Zierold, Dirk Tomsitz, Lars E French, Lucie Heinzerling","doi":"10.1097/CJI.0000000000000510","DOIUrl":"10.1097/CJI.0000000000000510","url":null,"abstract":"<p><p>The wide use of immune checkpoint inhibitors has increased the frequency of immune-related adverse events (irAEs). While many are managed with corticosteroids or hormone substitution, up to 14.9% of irAEs are steroid-refractory or steroid-dependent and thus require second-line treatment. These should reduce irAE-related morbidity and mortality and induce a few side effects of their own while maintaining the antitumor response. There is little comparative data on second-line therapies for irAEs. Two cases of irAEs could not be sufficiently managed with corticosteroids and subsequently received treatment with extracorporeal photopheresis (ECP), including one patient with immune-related erosive oral lichen planus and one patient with immune-related colitis. In both cases, the irAE resolved with ECP in combination with immunosuppressive drugs, that is 4 weeks and 10 weeks after the start of ECP, respectively. To investigate this approach, a prospective clinical study that compares ECP and other second-line therapies for the treatment of steroid-refractory and steroid-dependent irAEs with regard to immunophenotype and therapy response has been designed. ECP could be a treatment option for steroid-refractory and steroid-dependent irAEs, given its good safety profile and lack of adverse effects on antitumor response. Comparative prospective studies are needed to generate an evidence base.</p>","PeriodicalId":15996,"journal":{"name":"Journal of Immunotherapy","volume":" ","pages":"227-231"},"PeriodicalIF":3.2,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140119768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2024-02-06DOI: 10.1097/CJI.0000000000000506
Karlijn de Joode, Alfonso Rojas Mora, Ron H N van Schaik, Alfred Zippelius, Astrid van der Veldt, Camille Léa Gerard, Heinz Läubli, Olivier Michielin, Roger von Moos, Markus Joerger, Mitchell P Levesque, Stefanie Aeppli, Johanna Mangana, Cristina Mangas, Nadine Trost, Stefan Meyer, Sandra Leoni Parvex, Ron Mathijssen, Yannis Metaxas
Single nucleotide polymorphisms (SNPs) in the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) gene, an inhibitor of T-cell priming, are associated with auto and alloimmunity. Studies implied a role for these SNPs as surrogate markers for immunotherapy-outcome in patients with melanoma. However, no predictive SNPs are defined to date. We analyzed different CTLA-4 SNPs in a large multicenter cohort of patients with ipilimumab-treated melanoma and investigated possible correlations with treatment-related outcomes. Archival blood and/or tumor tissue samples were collected from 361 patients with advanced-stage ipilimumab-treated (±nivolumab) in 6 Swiss and Dutch hospitals. Matrix-assisted laser desorption/ionization-time of flight mass spectrometry based DNA genotyping was performed for 10 different CTLA-4 SNPs: 49A>G, CT60G>A, Jo27T>C, Jo30G>A, Jo31G>T, -658C>T, -1722T>C, -1661A>G, 318C>T, and C>T rs1863800. Associations between different allele genotypes and occurrence of grade ≥3 adverse events (AEs) and survival were tested using univariable logistic regressions or Cox proportional hazard models. 262/361 (73%) patients could be analyzed; 65% of those were males, the median age was 58 years, 39% showed a partial or complete response, and 65% had ≥1 AEs. A TT-genotype of -1722T>C SNP was significantly associated with a lower incidence of grade ≥3 AEs ( P = 0.049), whereas the GG-genotype of CT60G>A correlated with a higher incidence of grade ≥3 AEs ( P = 0.026). The TT-genotype of Jo27T>C SNP ( P = 0.056) and GG-genotype of Jo31G>T ( P = 0.046) were associated with overall survival. CTLA-4 SNPs might predict treatment-related outcomes in patients with melanoma receiving ipilimumab. Confirmatory studies are needed to fully exploit those findings as predictive biomarkers for ipilimumab AEs.
{"title":"Effects of CTLA-4 Single Nucleotide Polymorphisms on Toxicity of Ipilimumab-Containing Regimens in Patients With Advanced Stage Melanoma.","authors":"Karlijn de Joode, Alfonso Rojas Mora, Ron H N van Schaik, Alfred Zippelius, Astrid van der Veldt, Camille Léa Gerard, Heinz Läubli, Olivier Michielin, Roger von Moos, Markus Joerger, Mitchell P Levesque, Stefanie Aeppli, Johanna Mangana, Cristina Mangas, Nadine Trost, Stefan Meyer, Sandra Leoni Parvex, Ron Mathijssen, Yannis Metaxas","doi":"10.1097/CJI.0000000000000506","DOIUrl":"10.1097/CJI.0000000000000506","url":null,"abstract":"<p><p>Single nucleotide polymorphisms (SNPs) in the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) gene, an inhibitor of T-cell priming, are associated with auto and alloimmunity. Studies implied a role for these SNPs as surrogate markers for immunotherapy-outcome in patients with melanoma. However, no predictive SNPs are defined to date. We analyzed different CTLA-4 SNPs in a large multicenter cohort of patients with ipilimumab-treated melanoma and investigated possible correlations with treatment-related outcomes. Archival blood and/or tumor tissue samples were collected from 361 patients with advanced-stage ipilimumab-treated (±nivolumab) in 6 Swiss and Dutch hospitals. Matrix-assisted laser desorption/ionization-time of flight mass spectrometry based DNA genotyping was performed for 10 different CTLA-4 SNPs: 49A>G, CT60G>A, Jo27T>C, Jo30G>A, Jo31G>T, -658C>T, -1722T>C, -1661A>G, 318C>T, and C>T rs1863800. Associations between different allele genotypes and occurrence of grade ≥3 adverse events (AEs) and survival were tested using univariable logistic regressions or Cox proportional hazard models. 262/361 (73%) patients could be analyzed; 65% of those were males, the median age was 58 years, 39% showed a partial or complete response, and 65% had ≥1 AEs. A TT-genotype of -1722T>C SNP was significantly associated with a lower incidence of grade ≥3 AEs ( P = 0.049), whereas the GG-genotype of CT60G>A correlated with a higher incidence of grade ≥3 AEs ( P = 0.026). The TT-genotype of Jo27T>C SNP ( P = 0.056) and GG-genotype of Jo31G>T ( P = 0.046) were associated with overall survival. CTLA-4 SNPs might predict treatment-related outcomes in patients with melanoma receiving ipilimumab. Confirmatory studies are needed to fully exploit those findings as predictive biomarkers for ipilimumab AEs.</p>","PeriodicalId":15996,"journal":{"name":"Journal of Immunotherapy","volume":" ","pages":"190-194"},"PeriodicalIF":3.9,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139692022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01Epub Date: 2024-03-11DOI: 10.1097/CJI.0000000000000508
Haci Arak, Suna Erkiliç, Şendağ Yaslikaya, Eda Eylemer Mocan, Gökmen Aktaş, Melek Özdemir, Hüseyin Salih Semiz, Saadettin Kiliçkap, Faruk Recep Özalp, Özlem Nuray Sever, Goncagül Akdağ, Ahmet Burak Ağaoğlu, Melike Özçelik, Murat Sari, Murat Arcagök, Hicran Anik, Şaziye Burçak Yayla, Nadiye Sever, Fatma Pinar Açar, İsmail Bayrakçi, Serdar Turhal, Murat Ayhan, Tülay Kuş
Our aim was to assess the efficacy of adjuvant programmed cell death protein-1 (PD-1) inhibitors and compare the other adjuvant treatments in patients with surgically resected stage III or IV acral melanoma. This study is a multicenter, retrospective analysis. We included 114 patients with stage III or IV acral malignant melanoma who underwent surgery within the past 10 years. We analyzed the effect of adjuvant programmed cell death protein-1 inhibitors on disease-free survival (DFS). The mean follow-up was 40 months, during which 69 (59.5%) patients experienced recurrence. Among the participants, 64 (56.1%) received systemic adjuvant therapy. Specifically, 48.4% received anti-PD-1 therapy, 29.7% received interferon, 14.1% received tezozolomide, and 7.8% received B-Raf proto-oncogene/mitogen-activated protein kinase inhibitors. Patients who received adjuvant therapy had a median DFS of 24 (10.9-37.2) months, whereas those who did not receive adjuvant therapy had a median DFS of 15 (9.8-20.2) months. Multivariate analysis for DFS revealed that the receipt of adjuvant therapy and lymph node metastasis stage were independent significant parameters ( P = 0.021, P = 0.018, respectively). No statistically significant difference was observed for DFS between programmed cell death protein-1 inhibitor treatment and other adjuvant treatments. Regarding overall survival (OS), patients who received adjuvant treatment had a median OS of 71 (30.4-111.7) months, whereas those who did not receive adjuvant treatment had a median OS of 38 (16.7-59.3; P = 0.023) months. In addition, there were no significant differences in OS observed between various adjuvant treatment agents ( P = 0.122). In our study, we have shown that adjuvant therapy had a positive effect on both DFS and OS in patients with stages III-IV acral melanoma who underwent curative intent surgery. Notably, we found no significant differences between anti-PD-1 therapy and other adjuvant therapies.
我们的目的是评估程序性细胞死亡蛋白-1(PD-1)抑制剂的辅助疗效,并比较其他辅助疗法对手术切除的III期或IV期尖锐湿疣患者的疗效。本研究是一项多中心回顾性分析。我们纳入了114名在过去10年内接受过手术的III期或IV期口角恶性黑色素瘤患者。我们分析了程序性细胞死亡蛋白-1抑制剂辅助治疗对无病生存期(DFS)的影响。平均随访时间为 40 个月,期间有 69 例(59.5%)患者复发。其中,64人(56.1%)接受了全身辅助治疗。具体来说,48.4%的患者接受了抗PD-1治疗,29.7%的患者接受了干扰素治疗,14.1%的患者接受了替佐唑胺治疗,7.8%的患者接受了B-Raf原癌基因/介原激活蛋白激酶抑制剂治疗。接受辅助治疗的患者的中位生存期为24(10.9-37.2)个月,而未接受辅助治疗的患者的中位生存期为15(9.8-20.2)个月。DFS的多变量分析显示,接受辅助治疗和淋巴结转移分期是独立的重要参数(分别为P = 0.021和P = 0.018)。在DFS方面,程序性细胞死亡蛋白-1抑制剂治疗与其他辅助治疗之间没有统计学差异。在总生存期(OS)方面,接受辅助治疗的患者的中位OS为71(30.4-111.7)个月,而未接受辅助治疗的患者的中位OS为38(16.7-59.3;P = 0.023)个月。此外,不同辅助治疗药物的中位生存期也无明显差异(P = 0.122)。在我们的研究中,我们发现辅助治疗对接受治愈性手术的 III-IV 期盲灶黑色素瘤患者的 DFS 和 OS 均有积极影响。值得注意的是,我们发现抗PD-1疗法与其他辅助疗法之间没有明显差异。
{"title":"The Effectiveness of Adjuvant PD-1 Inhibitors in Patients With Surgically Resected Stage III/IV Acral Melanoma.","authors":"Haci Arak, Suna Erkiliç, Şendağ Yaslikaya, Eda Eylemer Mocan, Gökmen Aktaş, Melek Özdemir, Hüseyin Salih Semiz, Saadettin Kiliçkap, Faruk Recep Özalp, Özlem Nuray Sever, Goncagül Akdağ, Ahmet Burak Ağaoğlu, Melike Özçelik, Murat Sari, Murat Arcagök, Hicran Anik, Şaziye Burçak Yayla, Nadiye Sever, Fatma Pinar Açar, İsmail Bayrakçi, Serdar Turhal, Murat Ayhan, Tülay Kuş","doi":"10.1097/CJI.0000000000000508","DOIUrl":"10.1097/CJI.0000000000000508","url":null,"abstract":"<p><p>Our aim was to assess the efficacy of adjuvant programmed cell death protein-1 (PD-1) inhibitors and compare the other adjuvant treatments in patients with surgically resected stage III or IV acral melanoma. This study is a multicenter, retrospective analysis. We included 114 patients with stage III or IV acral malignant melanoma who underwent surgery within the past 10 years. We analyzed the effect of adjuvant programmed cell death protein-1 inhibitors on disease-free survival (DFS). The mean follow-up was 40 months, during which 69 (59.5%) patients experienced recurrence. Among the participants, 64 (56.1%) received systemic adjuvant therapy. Specifically, 48.4% received anti-PD-1 therapy, 29.7% received interferon, 14.1% received tezozolomide, and 7.8% received B-Raf proto-oncogene/mitogen-activated protein kinase inhibitors. Patients who received adjuvant therapy had a median DFS of 24 (10.9-37.2) months, whereas those who did not receive adjuvant therapy had a median DFS of 15 (9.8-20.2) months. Multivariate analysis for DFS revealed that the receipt of adjuvant therapy and lymph node metastasis stage were independent significant parameters ( P = 0.021, P = 0.018, respectively). No statistically significant difference was observed for DFS between programmed cell death protein-1 inhibitor treatment and other adjuvant treatments. Regarding overall survival (OS), patients who received adjuvant treatment had a median OS of 71 (30.4-111.7) months, whereas those who did not receive adjuvant treatment had a median OS of 38 (16.7-59.3; P = 0.023) months. In addition, there were no significant differences in OS observed between various adjuvant treatment agents ( P = 0.122). In our study, we have shown that adjuvant therapy had a positive effect on both DFS and OS in patients with stages III-IV acral melanoma who underwent curative intent surgery. Notably, we found no significant differences between anti-PD-1 therapy and other adjuvant therapies.</p>","PeriodicalId":15996,"journal":{"name":"Journal of Immunotherapy","volume":" ","pages":"182-189"},"PeriodicalIF":3.9,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11073564/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139706978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Summary: T-cell-directed cancer therapies such as T-cell-engaging bispecifics (TCBs) are commonly associated with cytokine release syndrome and associated clinical signs that can limit their tolerability and therapeutic benefit. Strategies for reducing cytokine release are therefore needed. Here, we report on studies performed in cynomolgus monkeys to test different approaches for mitigating cytokine release with TCBs. A "priming dose" as well as subcutaneous dosing reduced cytokine release compared with intravenous dosing but did not affect the intended T-cell response to the bispecific. As another strategy, cytokines or cytokine responses were blocked with an anti-IL-6 antibody, dexamethasone, or a JAK1/TYK2-selective inhibitor, and the effects on toxicity as well as T-cell responses to a TCB were evaluated. The JAK1/TYK2 inhibitor and dexamethasone prevented CRS-associated clinical signs on the day of TCB administration, but the anti-IL-6 had little effect. All interventions allowed for functional T-cell responses and expected damage to target-bearing tissues, but the JAK1/TYK2 inhibitor prevented the upregulation of activation markers on T cells, suggesting the potential for suppression of T-cell responses. Our results suggest that short-term prophylactic dexamethasone treatment may be an effective option for blocking cytokine responses without affecting desired T-cell responses to TCBs.
摘要:T细胞定向癌症疗法,如T细胞激活双特异性药物(TCBs),通常与细胞因子释放综合征和相关临床症状有关,这可能会限制其耐受性和治疗效果。因此需要减少细胞因子释放的策略。在此,我们报告了在眼镜猴身上进行的研究,这些研究测试了使用细胞因子抑制剂减少细胞因子释放的不同方法。与静脉注射相比,"启动剂量 "和皮下注射可减少细胞因子的释放,但不会影响T细胞对双特异性的预期反应。另一种策略是用抗 IL-6 抗体、地塞米松或 JAK1/TYK2 选择性抑制剂阻断细胞因子或细胞因子反应,并评估其对毒性以及 T 细胞对 TCB 反应的影响。JAK1/TYK2抑制剂和地塞米松能防止在注射TCB当天出现CRS相关临床症状,但抗IL-6的效果甚微。所有干预措施都能使T细胞产生功能性反应,并对靶组织造成预期损伤,但JAK1/TYK2抑制剂能阻止T细胞活化标志物的上调,这表明它有可能抑制T细胞反应。我们的研究结果表明,短期预防性地塞米松治疗可能是阻断细胞因子反应而不影响T细胞对TCB的预期反应的有效选择。
{"title":"Nonclinical Investigation of Cytokine Mitigation Strategies for T-cell-Engaging Bispecifics in the Cynomolgus Macaque.","authors":"Cris Kamperschroer, Magali Guffroy, Amy Shen, Melba Dokmanovich, Makeida Stubbs, Lynn M O'Donnell","doi":"10.1097/CJI.0000000000000512","DOIUrl":"10.1097/CJI.0000000000000512","url":null,"abstract":"<p><strong>Summary: </strong>T-cell-directed cancer therapies such as T-cell-engaging bispecifics (TCBs) are commonly associated with cytokine release syndrome and associated clinical signs that can limit their tolerability and therapeutic benefit. Strategies for reducing cytokine release are therefore needed. Here, we report on studies performed in cynomolgus monkeys to test different approaches for mitigating cytokine release with TCBs. A \"priming dose\" as well as subcutaneous dosing reduced cytokine release compared with intravenous dosing but did not affect the intended T-cell response to the bispecific. As another strategy, cytokines or cytokine responses were blocked with an anti-IL-6 antibody, dexamethasone, or a JAK1/TYK2-selective inhibitor, and the effects on toxicity as well as T-cell responses to a TCB were evaluated. The JAK1/TYK2 inhibitor and dexamethasone prevented CRS-associated clinical signs on the day of TCB administration, but the anti-IL-6 had little effect. All interventions allowed for functional T-cell responses and expected damage to target-bearing tissues, but the JAK1/TYK2 inhibitor prevented the upregulation of activation markers on T cells, suggesting the potential for suppression of T-cell responses. Our results suggest that short-term prophylactic dexamethasone treatment may be an effective option for blocking cytokine responses without affecting desired T-cell responses to TCBs.</p>","PeriodicalId":15996,"journal":{"name":"Journal of Immunotherapy","volume":" ","pages":"160-171"},"PeriodicalIF":3.9,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140335947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Summary: Immune checkpoint blockade therapy is a pivotal approach in treating malignant tumors. TIGIT has emerged as a focal point of interest among the diverse targets for tumor immunotherapy. Nonetheless, there is still a lack of comprehensive understanding regarding the immune microenvironment alterations following TIGIT blockade treatment. To bridge this knowledge gap, we performed single-cell sequencing on mice both before and after the administration of anti-TIGIT therapy. Our analysis revealed that TIGIT was predominantly expressed on T cells and natural killer (NK) cells. The blockade of TIGIT exhibited inhibitory effects on Treg cells by downregulating the expression of Foxp3 and reducing the secretion of immunosuppressive cytokines. In addition, TIGIT blockade facilitated the activation of NK cells, leading to an increase in cell numbers, and promoted cDC1 maturation through the secretion of XCL1 and Flt3L. This activation, in turn, stimulated the TCR signaling of CD8 + T cells, thereby enhancing their antitumor effect. Consequently, anti-TIGIT therapy demonstrated substantial potential for cancer immunotherapy. Our research provided novel insights into future therapeutic strategies targeting TIGIT for patients with cancer.
{"title":"TIGIT Blockade Reshapes the Tumor Microenvironment Based on the Single-cell RNA-Sequencing Analysis.","authors":"Yanyan Lang, Hao Huang, Hongwei Jiang, Shaoxian Wu, Yaping Chen, Bin Xu, Yingting Liu, Dawei Zhu, Xiao Zheng, Lujun Chen, Jingting Jiang","doi":"10.1097/CJI.0000000000000511","DOIUrl":"10.1097/CJI.0000000000000511","url":null,"abstract":"<p><strong>Summary: </strong>Immune checkpoint blockade therapy is a pivotal approach in treating malignant tumors. TIGIT has emerged as a focal point of interest among the diverse targets for tumor immunotherapy. Nonetheless, there is still a lack of comprehensive understanding regarding the immune microenvironment alterations following TIGIT blockade treatment. To bridge this knowledge gap, we performed single-cell sequencing on mice both before and after the administration of anti-TIGIT therapy. Our analysis revealed that TIGIT was predominantly expressed on T cells and natural killer (NK) cells. The blockade of TIGIT exhibited inhibitory effects on Treg cells by downregulating the expression of Foxp3 and reducing the secretion of immunosuppressive cytokines. In addition, TIGIT blockade facilitated the activation of NK cells, leading to an increase in cell numbers, and promoted cDC1 maturation through the secretion of XCL1 and Flt3L. This activation, in turn, stimulated the TCR signaling of CD8 + T cells, thereby enhancing their antitumor effect. Consequently, anti-TIGIT therapy demonstrated substantial potential for cancer immunotherapy. Our research provided novel insights into future therapeutic strategies targeting TIGIT for patients with cancer.</p>","PeriodicalId":15996,"journal":{"name":"Journal of Immunotherapy","volume":" ","pages":"172-181"},"PeriodicalIF":3.9,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140305883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}