Pub Date : 2025-02-01Epub Date: 2024-12-26DOI: 10.1007/s10637-024-01494-4
Shaoli Zhao, Wei Sun, Jichun Sun, Liping Peng, Chunjiang Wang
Psoriasis is an uncommon immune-mediated adverse event linked to nivolumab, and its clinical characteristics remain inadequately defined. This study aims to investigate the clinical features and patterns of nivolumab-induced psoriasis, providing insights for the identification and management of this condition. Case reports and case series of nivolumab related psoriasis were gathered by searching Chinese and English databases for retrospective analysis until June 30, 2024. A total of fifty-five patients (80.0% male) were included, with a median age of 65 years (range 41, 89). Among these, thirty-eight (69.1%) patients experienced new-onset psoriasis, while 17 (30.9%) patients exhibited exacerbation of pre-existing psoriasis. The median time to onset of psoriasis was 28 days (range 3, 360). The predominant clinical types identified were plaque psoriasis (65.5%), psoriatic arthritis (20.0%) and palmoplantar psoriasis (16.4%). Twenty-five (45.5%) patients discontinued nivolumab, whereas 19 (34.5%) patients continued the treatment. Following clinical intervention, 52 (94.5%) patients reported symptom improvement. It is crucial to closely monitor patients receiving nivolumab for the emergence of psoriasis to ensure timely identification and diagnosis. Those diagnosed with psoriasis should be provided with appropriate treatment, whether topical or systemic, tailored to their specific clinical circumstances.
{"title":"Clinical features, treatment, and outcomes of nivolumab induced psoriasis.","authors":"Shaoli Zhao, Wei Sun, Jichun Sun, Liping Peng, Chunjiang Wang","doi":"10.1007/s10637-024-01494-4","DOIUrl":"10.1007/s10637-024-01494-4","url":null,"abstract":"<p><p>Psoriasis is an uncommon immune-mediated adverse event linked to nivolumab, and its clinical characteristics remain inadequately defined. This study aims to investigate the clinical features and patterns of nivolumab-induced psoriasis, providing insights for the identification and management of this condition. Case reports and case series of nivolumab related psoriasis were gathered by searching Chinese and English databases for retrospective analysis until June 30, 2024. A total of fifty-five patients (80.0% male) were included, with a median age of 65 years (range 41, 89). Among these, thirty-eight (69.1%) patients experienced new-onset psoriasis, while 17 (30.9%) patients exhibited exacerbation of pre-existing psoriasis. The median time to onset of psoriasis was 28 days (range 3, 360). The predominant clinical types identified were plaque psoriasis (65.5%), psoriatic arthritis (20.0%) and palmoplantar psoriasis (16.4%). Twenty-five (45.5%) patients discontinued nivolumab, whereas 19 (34.5%) patients continued the treatment. Following clinical intervention, 52 (94.5%) patients reported symptom improvement. It is crucial to closely monitor patients receiving nivolumab for the emergence of psoriasis to ensure timely identification and diagnosis. Those diagnosed with psoriasis should be provided with appropriate treatment, whether topical or systemic, tailored to their specific clinical circumstances.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"42-49"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142894714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01Epub Date: 2024-12-16DOI: 10.1007/s10637-024-01487-3
LinRui Ma, WeiKang Meng, WenJuan Jiang
{"title":"Vebreltinib: a promising milestone in targeted therapy for METex14-mutant NSCLC.","authors":"LinRui Ma, WeiKang Meng, WenJuan Jiang","doi":"10.1007/s10637-024-01487-3","DOIUrl":"10.1007/s10637-024-01487-3","url":null,"abstract":"","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"1-2"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11868279/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01Epub Date: 2025-01-09DOI: 10.1007/s10637-024-01492-6
Meihui Li, Xinyuan Wang, Jiali Gong, Hongyang Lu
A novel molecular classification for small cell lung cancer (SCLC) has been established utilizing the transcription factors achaete-scute homologue 1 (ASCL1), neurogenic differentiation factor 1 (NeuroD1), POU class 2 homeobox 3 (POU2F3), and yes-associated protein 1 (YAP1). This classification was predicated on the transcription factors. Conversely, there is a paucity of information regarding the distribution of these markers in other subtypes of pulmonary neuroendocrine tumors (PNET). Clinical and survival data for PNET patients were gathered from January 2008 to December 2020. Immunohistochemical analysis was employed to evaluate the expression. The relationship between YAP1 expression and outcomes in patients with pulmonary large cell neuroendocrine carcinoma (LCNEC) was examined. Data from low-grade PNET patients who had previously undergone immunotherapy were retrospectively gathered and analyzed. The ASCL1 positive rate was markedly elevated in SCLC (7.1% vs. 60%; P < 0.001) and LCNEC patients (7.1% vs. 38.5%; P = 0.034) compared to PC patients. The YAP1-positive rate was elevated in LCNEC compared to SCLC (43.6% vs. 20%, P = 0.028) and pulmonary carcinoid (PC) patients (43.6% vs. 21.4%; P = 0.021). The DLL3-positive rate in SCLC patients was greater than in SCLC and PC patients (37.1% vs. 23.1% vs. 0%; P = 0.028, P = 0.021). A significant level of tumor heterogeneity was noted, with SCLC and LCNEC patients exhibiting markedly higher heterogeneity than PC patients (65.7% vs. 56.3% vs. 21.4%; P = 0.005, P = 0.025). In patients with LCNEC, YAP1 positivity exhibited no correlation with PD-L1 expression (17.1% vs. 45.7%, P = 0.518). Tumor heterogeneity was also noted in transformed SCLC, with no significant differences in the expression levels of transcription factors between transformed and traditional SCLC. In 13 LCNEC patients with a history of ICI application, YAP1 exhibited no significant effect on PFS (P = 0.331) or OS (P = 0.17) in the subgroup analysis of LCNEC patients. Among the 14 patients with low-grade PNET who underwent immunotherapy, the disease control rate was 85.7%. Patients with high-grade PNET have high levels of expression of ASCL1 and DLL3, whereas patients with LCNEC have high levels of expression of YAP1. With regard to the transcription factor level, it was found that patients with SCLC and LCNEC had a much higher degree of tumor heterogeneity than those with PC. In patients with LCNEC who were receiving monotherapy of ICIs or chemotherapy in combination with ICIs, the expression of YAP1 did not appear to have any clear impact on the prognosis. This is due to the limited sample size of the study, which requires additional investigation. When compared to the expression of TFs in regular SCLC, the expression of TFs in converted SCLC is comparable.
利用转录因子achaete- scail同源物1 (ASCL1)、神经源性分化因子1 (NeuroD1)、POU2类同源盒3 (POU2F3)和ye -associated protein 1 (YAP1),建立了一种新的小细胞肺癌(SCLC)分子分类方法。这种分类是基于转录因子的。相反,关于这些标志物在其他肺神经内分泌肿瘤(PNET)亚型中的分布的信息缺乏。收集2008年1月至2020年12月PNET患者的临床和生存数据。采用免疫组化分析评价其表达。探讨肺大细胞神经内分泌癌(LCNEC)患者YAP1表达与预后的关系。回顾性收集和分析先前接受免疫治疗的低级别PNET患者的数据。ASCL1阳性率在SCLC中显著升高(7.1% vs. 60%;P
{"title":"The analysis of molecular classification of pulmonary neuroendocrine tumors and relationship between YAP1 and efficacy.","authors":"Meihui Li, Xinyuan Wang, Jiali Gong, Hongyang Lu","doi":"10.1007/s10637-024-01492-6","DOIUrl":"10.1007/s10637-024-01492-6","url":null,"abstract":"<p><p>A novel molecular classification for small cell lung cancer (SCLC) has been established utilizing the transcription factors achaete-scute homologue 1 (ASCL1), neurogenic differentiation factor 1 (NeuroD1), POU class 2 homeobox 3 (POU2F3), and yes-associated protein 1 (YAP1). This classification was predicated on the transcription factors. Conversely, there is a paucity of information regarding the distribution of these markers in other subtypes of pulmonary neuroendocrine tumors (PNET). Clinical and survival data for PNET patients were gathered from January 2008 to December 2020. Immunohistochemical analysis was employed to evaluate the expression. The relationship between YAP1 expression and outcomes in patients with pulmonary large cell neuroendocrine carcinoma (LCNEC) was examined. Data from low-grade PNET patients who had previously undergone immunotherapy were retrospectively gathered and analyzed. The ASCL1 positive rate was markedly elevated in SCLC (7.1% vs. 60%; P < 0.001) and LCNEC patients (7.1% vs. 38.5%; P = 0.034) compared to PC patients. The YAP1-positive rate was elevated in LCNEC compared to SCLC (43.6% vs. 20%, P = 0.028) and pulmonary carcinoid (PC) patients (43.6% vs. 21.4%; P = 0.021). The DLL3-positive rate in SCLC patients was greater than in SCLC and PC patients (37.1% vs. 23.1% vs. 0%; P = 0.028, P = 0.021). A significant level of tumor heterogeneity was noted, with SCLC and LCNEC patients exhibiting markedly higher heterogeneity than PC patients (65.7% vs. 56.3% vs. 21.4%; P = 0.005, P = 0.025). In patients with LCNEC, YAP1 positivity exhibited no correlation with PD-L1 expression (17.1% vs. 45.7%, P = 0.518). Tumor heterogeneity was also noted in transformed SCLC, with no significant differences in the expression levels of transcription factors between transformed and traditional SCLC. In 13 LCNEC patients with a history of ICI application, YAP1 exhibited no significant effect on PFS (P = 0.331) or OS (P = 0.17) in the subgroup analysis of LCNEC patients. Among the 14 patients with low-grade PNET who underwent immunotherapy, the disease control rate was 85.7%. Patients with high-grade PNET have high levels of expression of ASCL1 and DLL3, whereas patients with LCNEC have high levels of expression of YAP1. With regard to the transcription factor level, it was found that patients with SCLC and LCNEC had a much higher degree of tumor heterogeneity than those with PC. In patients with LCNEC who were receiving monotherapy of ICIs or chemotherapy in combination with ICIs, the expression of YAP1 did not appear to have any clear impact on the prognosis. This is due to the limited sample size of the study, which requires additional investigation. When compared to the expression of TFs in regular SCLC, the expression of TFs in converted SCLC is comparable.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"108-117"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142949028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: The RELAY-Brain trial examined the clinical utility and survival impacts of ramucirumab (RAM) combined with epidermal growth factor receptor (EGFR)-TKI in patients with EGFR-mutated non-small-cell lung cancer (NSCLC) with brain metastases. Although RAM combined with erlotinib (ERL) is known to have clinical benefits, the benefits in patients with baseline brain metastases remain unclear. This report examined the long-term follow-up data (Japan Registry of Clinical Trials: jRCTs2051190027) of the same patients, analyzing relevant biomarkers from tumor and plasma samples.
Patients and methods: The six patients enrolled in the RELAY-Brain trial received RAM plus ERL or osimertinib (OSM). Our long-term follow-up observational study assessed patient survival, treatment status, and genetic biomarkers. Tumor and plasma samples were analyzed at baseline, during treatment, and at disease progression using next-generation sequencing and droplet digital PCR, to identify gene alterations and EGFR-TKI-resistant mutations.
Results: After median follow-up of 44.2 months, the first site of disease progression in three of the patients was the brain metastases. In the RAM + ERL group, two patients with the T790M mutation subsequently received OSM. Progression-free survival (PFS) and overall survival ranged from 10.46 to 42.07 months and from 30.14 to 52.25 months, respectively. Gene alterations included TP53 mutations in three patients and ERBB2 and PIK3CA mutations in two. TP53 mutations were associated with shorter PFS.
Conclusion: RAM with ERL or OSM achieved significant clinical benefits for patients with EGFR-mutated NSCLC with asymptomatic brain metastases. These positive outcomes and the identification of related biomarkers support the therapeutic potential of these combinations.
{"title":"Efficacy of ramucirumab combined with erlotinib or osimertinib in untreated EGFR-mutated NSCLC patients with asymptomatic brain metastases: insights from molecular biomarkers in the RELAY-brain trial.","authors":"Hiroyasu Kaneda, Haruko Daga, Asuka Okada, Yuki Nakatani, Yoko Tani, Takako Oka, Kenji Sawa, Kazuko Sakai, Kazuto Nishio, Tomoya Kawaguchi","doi":"10.1007/s10637-025-01505-y","DOIUrl":"10.1007/s10637-025-01505-y","url":null,"abstract":"<p><strong>Background: </strong>The RELAY-Brain trial examined the clinical utility and survival impacts of ramucirumab (RAM) combined with epidermal growth factor receptor (EGFR)-TKI in patients with EGFR-mutated non-small-cell lung cancer (NSCLC) with brain metastases. Although RAM combined with erlotinib (ERL) is known to have clinical benefits, the benefits in patients with baseline brain metastases remain unclear. This report examined the long-term follow-up data (Japan Registry of Clinical Trials: jRCTs2051190027) of the same patients, analyzing relevant biomarkers from tumor and plasma samples.</p><p><strong>Patients and methods: </strong>The six patients enrolled in the RELAY-Brain trial received RAM plus ERL or osimertinib (OSM). Our long-term follow-up observational study assessed patient survival, treatment status, and genetic biomarkers. Tumor and plasma samples were analyzed at baseline, during treatment, and at disease progression using next-generation sequencing and droplet digital PCR, to identify gene alterations and EGFR-TKI-resistant mutations.</p><p><strong>Results: </strong>After median follow-up of 44.2 months, the first site of disease progression in three of the patients was the brain metastases. In the RAM + ERL group, two patients with the T790M mutation subsequently received OSM. Progression-free survival (PFS) and overall survival ranged from 10.46 to 42.07 months and from 30.14 to 52.25 months, respectively. Gene alterations included TP53 mutations in three patients and ERBB2 and PIK3CA mutations in two. TP53 mutations were associated with shorter PFS.</p><p><strong>Conclusion: </strong>RAM with ERL or OSM achieved significant clinical benefits for patients with EGFR-mutated NSCLC with asymptomatic brain metastases. These positive outcomes and the identification of related biomarkers support the therapeutic potential of these combinations.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"147-156"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143023473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-30DOI: 10.1007/s10637-025-01506-x
Lixia Ma, Yu Zhang, Yong Fang, Chunyi Hao, Qingxia Fan, Da Jiang, Liqin Lu, Fang Su, Chen Yang, Zhenru Liu, Ji Tian, Xiyang Sun, Shuguang Sun, Ying Cheng
Background: Immune checkpoint inhibitors (ICIs) combined with anti-vascular endothelial growth factor (VEGF) have been the standard first-line treatment of hepatocellular carcinoma (HCC). However, the efficacy of this combination in post-line treatment is still unknown. This study aimed to evaluate the efficacy and safety of the combination of anti-PD-L1 envafolimab and novel humanized anti-VEGF suvemcitug as second-line treatment for patients with HCC.
Methods: This open-label, prospective phase II clinical study (NCT05148195) comprised safety run-in stage and dose expansion stage of HCC cohort. Eligible patients were aged ≥ 18 years and had undergone at least a prior line of treatment. Patients received fixed-dose envafolimab and suvemcitug until termination of disease progression, unacceptable toxicities, or withdrawal. The primary endpoint of safety run-in stage was recommended dose (RD), and dose expansion stage was objective response rate (ORR).
Results: As of August 10, 2023, no dose-limiting toxicity was observed in six patients in the safety-run-in stage, and 2 mg/kg dose every 3 weeks was declared the RD of suvemcitug. Among 20 patients with HCC, the median age was 54.5 (range, 42-70) years. Of these patients, 20 (100.0%) received ≥ one prior line treatment, with 20 (100%) received tyrosine kinase inhibitor (TKI) treatment and 8 (40.0%) received prior ICI treatment. The ORR was 10.0% (95% confidence interval (CI), 1.2-31.7), DCR was 65.0% (95% CI, 40.8-84.6), and DoR was not reached (NR). With a median follow-up of 13.9 months, the median progression-free survival (PFS) and median overall survival (OS) were 4.3 months (95% CI, 1.4-8.1) and 10.7 months (95% CI, 6.0-not evaluable [NE]), respectively. Treatment-related adverse events (TRAEs) of grade ≥ 3 occurred in 40% patients, with proteinuria (20.0%, 4/20) being the most frequent. The ORR of no lung metastasis, prior first-line treatment and IO naïve treatment subgroup was 16.7%.
Conclusions: The combination of envafolimab and suvemcitug showed a tolerable safety profile and promising antitumor activity in HCC patients who failed later-line treatment.
{"title":"Anti-PD-L1 envafolimab combined with anti-VEGF suvemcitug in pretreated solid tumors and hepatocellular carcinoma: an open-label phase II study with safety run-in stage.","authors":"Lixia Ma, Yu Zhang, Yong Fang, Chunyi Hao, Qingxia Fan, Da Jiang, Liqin Lu, Fang Su, Chen Yang, Zhenru Liu, Ji Tian, Xiyang Sun, Shuguang Sun, Ying Cheng","doi":"10.1007/s10637-025-01506-x","DOIUrl":"https://doi.org/10.1007/s10637-025-01506-x","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint inhibitors (ICIs) combined with anti-vascular endothelial growth factor (VEGF) have been the standard first-line treatment of hepatocellular carcinoma (HCC). However, the efficacy of this combination in post-line treatment is still unknown. This study aimed to evaluate the efficacy and safety of the combination of anti-PD-L1 envafolimab and novel humanized anti-VEGF suvemcitug as second-line treatment for patients with HCC.</p><p><strong>Methods: </strong>This open-label, prospective phase II clinical study (NCT05148195) comprised safety run-in stage and dose expansion stage of HCC cohort. Eligible patients were aged ≥ 18 years and had undergone at least a prior line of treatment. Patients received fixed-dose envafolimab and suvemcitug until termination of disease progression, unacceptable toxicities, or withdrawal. The primary endpoint of safety run-in stage was recommended dose (RD), and dose expansion stage was objective response rate (ORR).</p><p><strong>Results: </strong>As of August 10, 2023, no dose-limiting toxicity was observed in six patients in the safety-run-in stage, and 2 mg/kg dose every 3 weeks was declared the RD of suvemcitug. Among 20 patients with HCC, the median age was 54.5 (range, 42-70) years. Of these patients, 20 (100.0%) received ≥ one prior line treatment, with 20 (100%) received tyrosine kinase inhibitor (TKI) treatment and 8 (40.0%) received prior ICI treatment. The ORR was 10.0% (95% confidence interval (CI), 1.2-31.7), DCR was 65.0% (95% CI, 40.8-84.6), and DoR was not reached (NR). With a median follow-up of 13.9 months, the median progression-free survival (PFS) and median overall survival (OS) were 4.3 months (95% CI, 1.4-8.1) and 10.7 months (95% CI, 6.0-not evaluable [NE]), respectively. Treatment-related adverse events (TRAEs) of grade ≥ 3 occurred in 40% patients, with proteinuria (20.0%, 4/20) being the most frequent. The ORR of no lung metastasis, prior first-line treatment and IO naïve treatment subgroup was 16.7%.</p><p><strong>Conclusions: </strong>The combination of envafolimab and suvemcitug showed a tolerable safety profile and promising antitumor activity in HCC patients who failed later-line treatment.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143065559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-01Epub Date: 2024-11-27DOI: 10.1007/s10637-024-01484-6
Xiaoxin Zhang, Jianhua Deng, Renjie Wu, Jian Hu
The immune checkpoint inhibitor therapy represented by blocking programmed cell death protein 1/ programmed cell death-ligand 1 (PD-1/PD-L1) has made significant progress in melanoma treatment. However, the response rate and therapeutic effect of immunotherapy alone are still not ideal for melanoma. In this study, we aimed to evaluate the defects of treating anti-PD-L1 alone and the therapeutic effect and molecular mechanism of combined therapy with anti-PD-L1 and MnCl2. We detected the changes of immune cell populations after anti-PD-L1 treatment in melanoma xenograft mouse model. Further, we evaluated the regulatory effect of MnCl2 on dendritic cells (DCs) maturation in vitro. Next, we tested the therapeutic effect and regulatory effect on the tumor microenvironment with anti-PD-L1 and MnCl2 via combining treatment with anti-PD-L1 and MnCl2. Anti-PD-L1 therapy has a certain tumor suppressive function, but the effect is not ideal. The results of flow cytometry showed that the number of CD4+ T cells and CD8+ T cells significantly increased after anti-PD-L1 treatment. However, the number of DCs remained basically unchanged after anti-PD-L1 treatment. In vitro, we confirmed that MnCl2 significantly promoted DCs maturation vis activating cGAS-STING signaling pathway. The combination of anti-PD-L1 and MnCl2 displayed the best tumor suppression effect in melanoma xenograft mouse model. In tumor microenvironment, the infiltration of T cells and the maturation of DCs were significantly promoted, demonstrating a strong anti-tumor immune response. In summary, we conclude that combining anti-PD-L1 with MnCl2 is a promising therapeutic strategy for melanoma.
{"title":"Manganese improves anti-PD-L1 immunotherapy via eliciting type I interferon signaling in melanoma.","authors":"Xiaoxin Zhang, Jianhua Deng, Renjie Wu, Jian Hu","doi":"10.1007/s10637-024-01484-6","DOIUrl":"10.1007/s10637-024-01484-6","url":null,"abstract":"<p><p>The immune checkpoint inhibitor therapy represented by blocking programmed cell death protein 1/ programmed cell death-ligand 1 (PD-1/PD-L1) has made significant progress in melanoma treatment. However, the response rate and therapeutic effect of immunotherapy alone are still not ideal for melanoma. In this study, we aimed to evaluate the defects of treating anti-PD-L1 alone and the therapeutic effect and molecular mechanism of combined therapy with anti-PD-L1 and MnCl<sub>2</sub>. We detected the changes of immune cell populations after anti-PD-L1 treatment in melanoma xenograft mouse model. Further, we evaluated the regulatory effect of MnCl<sub>2</sub> on dendritic cells (DCs) maturation in vitro. Next, we tested the therapeutic effect and regulatory effect on the tumor microenvironment with anti-PD-L1 and MnCl<sub>2</sub> via combining treatment with anti-PD-L1 and MnCl<sub>2</sub>. Anti-PD-L1 therapy has a certain tumor suppressive function, but the effect is not ideal. The results of flow cytometry showed that the number of CD4<sup>+</sup> T cells and CD8<sup>+</sup> T cells significantly increased after anti-PD-L1 treatment. However, the number of DCs remained basically unchanged after anti-PD-L1 treatment. In vitro, we confirmed that MnCl<sub>2</sub> significantly promoted DCs maturation vis activating cGAS-STING signaling pathway. The combination of anti-PD-L1 and MnCl<sub>2</sub> displayed the best tumor suppression effect in melanoma xenograft mouse model. In tumor microenvironment, the infiltration of T cells and the maturation of DCs were significantly promoted, demonstrating a strong anti-tumor immune response. In summary, we conclude that combining anti-PD-L1 with MnCl<sub>2</sub> is a promising therapeutic strategy for melanoma.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"685-693"},"PeriodicalIF":3.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142728747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Studies have shown that the Zinc finger homeobox 4 (ZFHX4) might be a factor in the prognosis of malignancies. However, little is known about the association between the ZFHX4 mutation and the effectiveness of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) and melanoma. Three public ICIs-treated NSCLC cohorts were divided into discovery cohort (n=75) and validation cohort (n=62), which were used to evaluate the relationship between ZFHX4 mutation and ICIs effectiveness in NSCLC. Seven ICIs-treated melanoma cohorts (n = 418) were used to analyze the relationship between ZFHX4 mutation and immunotherapy efficacy in melanoma. NSCLC and skin cutaneous melanoma (SKCM) cohorts from The Cancer Genome Atlas (TCGA) were used to investigate underlying mechanism. Patients with ZFHX4 mutant-type (ZFHX4-Mut) showed a superior objective response rate (ORR) (P < 0.01) and longer progression-free survival (PFS) (P < 0.05) than patients with ZFHX4 wild-type (ZFHX4-WT) in NSCLC cohorts. In the melanoma cohorts, patients carrying ZFHX4-Mut had a higher ORR (P = 0.042) and longer overall survival (OS) (P = 0.011). Besides, patients with NSCLC and melanoma harboring ZFHX4-Mut had a higher tumor mutation burden (TMB) (P<0.001) and tumor neoantigen burden (TNB) (P<0.001) than those harboring ZFHX4-WT. ZFHX4 mutation was associated with higher levels of plasma B cells, activated CD4+ memory T cells, and CD8+ T cells. Seven DNA damage repair pathways were significantly enriched in the ZFHX4-Mut group. ZFHX4 mutation could serve as a predicter for the efficacy of ICIs therapy in NSCLC and melanoma.
{"title":"Predictive value of ZFHX4 mutation for the efficacy of immune checkpoint inhibitors in non-small cell lung cancer and melanoma.","authors":"Cong Fu, Haoran Gu, Lin Sun, Zhouyu Wang, Qin Zhang, Ningning Luo, Dongsheng Chen, Tong Zhou","doi":"10.1007/s10637-024-01477-5","DOIUrl":"10.1007/s10637-024-01477-5","url":null,"abstract":"<p><p>Studies have shown that the Zinc finger homeobox 4 (ZFHX4) might be a factor in the prognosis of malignancies. However, little is known about the association between the ZFHX4 mutation and the effectiveness of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) and melanoma. Three public ICIs-treated NSCLC cohorts were divided into discovery cohort (n=75) and validation cohort (n=62), which were used to evaluate the relationship between ZFHX4 mutation and ICIs effectiveness in NSCLC. Seven ICIs-treated melanoma cohorts (n = 418) were used to analyze the relationship between ZFHX4 mutation and immunotherapy efficacy in melanoma. NSCLC and skin cutaneous melanoma (SKCM) cohorts from The Cancer Genome Atlas (TCGA) were used to investigate underlying mechanism. Patients with ZFHX4 mutant-type (ZFHX4-Mut) showed a superior objective response rate (ORR) (P < 0.01) and longer progression-free survival (PFS) (P < 0.05) than patients with ZFHX4 wild-type (ZFHX4-WT) in NSCLC cohorts. In the melanoma cohorts, patients carrying ZFHX4-Mut had a higher ORR (P = 0.042) and longer overall survival (OS) (P = 0.011). Besides, patients with NSCLC and melanoma harboring ZFHX4-Mut had a higher tumor mutation burden (TMB) (P<0.001) and tumor neoantigen burden (TNB) (P<0.001) than those harboring ZFHX4-WT. ZFHX4 mutation was associated with higher levels of plasma B cells, activated CD4+ memory T cells, and CD8+ T cells. Seven DNA damage repair pathways were significantly enriched in the ZFHX4-Mut group. ZFHX4 mutation could serve as a predicter for the efficacy of ICIs therapy in NSCLC and melanoma.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"623-634"},"PeriodicalIF":3.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142377924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-01Epub Date: 2024-09-21DOI: 10.1007/s10637-024-01473-9
Seyda Gungordu, Erhan Aptullahoglu
Despite available treatments for acute lymphoblastic leukemia (ALL), the disease's high clinical variability necessitates new therapeutic strategies, particularly for patients with high-risk features. The tumor suppressor protein p53, encoded by the TP53 gene and known as the guardian of the genome, plays a crucial role in preventing tumor development. Over 90% of ALL cases initially harbor wild-type TP53. Reactivation of p53, which is encoded from the wild type TP53 but lost its function for several reasons, is an attractive therapeutic approach in cancer treatment. p53 can be activated in a non-genotoxic manner by targeting its primary repressor, the MDM2 protein. Clinical trials involving MDM2 inhibitors are currently being conducted in a growing body of investigation, reflecting of the interest in incorporating these treatments into cancer treatment strategies. Early-phase clinical trials have demonstrated the promise of idasanutlin (RG7388), one of the developed compounds. It is a second-generation MDM2-p53 binding antagonist with enhanced potency, selectivity, and bioavailability. The aim of this study is to evaluate the efficacy of RG7388 as a therapeutic strategy for ALL and to investigate its potential impact on improving treatment outcomes for high-risk patients. RG7388 potently decreased the viability in five out of six ALL cell lines with diverse TP53 mutation profiles, whereas only one cell line exhibited high resistance. RG7388 induced a pro-apoptotic gene expression signature with upregulation of p53-target genes involved in the intrinsic and extrinsic pathways of apoptosis. Consequently, RG7388 led to a concentration-dependent increase in caspase-3/7 activity and cleaved poly (ADP-ribose) polymerase. In this research, RG7388 was investigated with pre-clinical methods in ALL cells as a novel treatment strategy. This study suggests further functional research and in-vivo evaluation, and it highlights the prospect of treating p53-functional ALL with MDM2 inhibitors.
{"title":"Targeting MDM2-mediated suppression of p53 with idasanutlin: a promising therapeutic approach for acute lymphoblastic leukemia.","authors":"Seyda Gungordu, Erhan Aptullahoglu","doi":"10.1007/s10637-024-01473-9","DOIUrl":"10.1007/s10637-024-01473-9","url":null,"abstract":"<p><p>Despite available treatments for acute lymphoblastic leukemia (ALL), the disease's high clinical variability necessitates new therapeutic strategies, particularly for patients with high-risk features. The tumor suppressor protein p53, encoded by the TP53 gene and known as the guardian of the genome, plays a crucial role in preventing tumor development. Over 90% of ALL cases initially harbor wild-type TP53. Reactivation of p53, which is encoded from the wild type TP53 but lost its function for several reasons, is an attractive therapeutic approach in cancer treatment. p53 can be activated in a non-genotoxic manner by targeting its primary repressor, the MDM2 protein. Clinical trials involving MDM2 inhibitors are currently being conducted in a growing body of investigation, reflecting of the interest in incorporating these treatments into cancer treatment strategies. Early-phase clinical trials have demonstrated the promise of idasanutlin (RG7388), one of the developed compounds. It is a second-generation MDM2-p53 binding antagonist with enhanced potency, selectivity, and bioavailability. The aim of this study is to evaluate the efficacy of RG7388 as a therapeutic strategy for ALL and to investigate its potential impact on improving treatment outcomes for high-risk patients. RG7388 potently decreased the viability in five out of six ALL cell lines with diverse TP53 mutation profiles, whereas only one cell line exhibited high resistance. RG7388 induced a pro-apoptotic gene expression signature with upregulation of p53-target genes involved in the intrinsic and extrinsic pathways of apoptosis. Consequently, RG7388 led to a concentration-dependent increase in caspase-3/7 activity and cleaved poly (ADP-ribose) polymerase. In this research, RG7388 was investigated with pre-clinical methods in ALL cells as a novel treatment strategy. This study suggests further functional research and in-vivo evaluation, and it highlights the prospect of treating p53-functional ALL with MDM2 inhibitors.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"603-611"},"PeriodicalIF":3.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142287373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-01Epub Date: 2024-10-21DOI: 10.1007/s10637-024-01479-3
Salma Begum, Scheldon D Irvin, Carol K Cox, Zhouyang Huang, Justin J Wilson, Jerry D Monroe, Yann Gibert
Ovarian cancer is the fifth leading cause of cancer related death in the United States. Cisplatin is a platinum-based anti-cancer drug used against ovarian cancer that enters malignant cells and then damages DNA causing cell death. Typically, ovarian cancer cells become resistant to cisplatin making it necessary to increase subsequent dosage, which usually leads to side-effects including irreversible damage to kidney and auditory system tissue. Ovarian cancer resistance is often associated with upregulation of histone deacetylase (HDAC) enzymes that cause DNA to adopt a closed configuration which reduces the ability of cisplatin to target and damage DNA. Compound B, a platinum(IV) complex with two axial phenylbutyrate (PBA) HDAC inhibitor ligands attached to a cisplatin core, can simultaneously inhibit HDAC activity and damage DNA causing decreased cancer cell viability in cisplatin-sensitive (A2780) and -resistant (A2780cis) ovarian cancer cell lines. However, compound B was not previously evaluated in vivo. As simultaneously inhibiting HDAC-mediated resistance with cisplatin treatment could potentiate the platinum drug's effect, we first confirmed the anti-cancer effect of compound B in the A2780 and A2780cis cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide spectrophotometric assay. Then, we used zebrafish embryo and transgenic animal models to comparatively analyze the effect of cisplatin, compound B, and controls on general organismal, auditory, and renal system toxicity, and cancer metastasis. We found that lower dosages of compound B (0.3 or 0.6 µM) than of cisplatin (2.0 µM) could cause similar or decreased levels of general, auditory, and renal tissue toxicity, and at 0.6 µM, compound B reduces cancer metastasis more than 2.0 µM cisplatin.
卵巢癌是美国癌症致死的第五大原因。顺铂是一种以铂为基础的抗癌药物,用于治疗卵巢癌,它能进入恶性细胞,然后破坏 DNA,导致细胞死亡。通常情况下,卵巢癌细胞会对顺铂产生耐药性,因此必须增加后续剂量,这通常会导致副作用,包括对肾脏和听觉系统组织造成不可逆的损害。卵巢癌的耐药性通常与组蛋白去乙酰化酶(HDAC)的上调有关,HDAC 可使 DNA 采用封闭构型,从而降低顺铂靶向和损伤 DNA 的能力。化合物 B 是一种铂(IV)复合物,带有两个轴向苯丁酸(PBA)HDAC 抑制剂配体,连接在顺铂核心上,可以同时抑制 HDAC 活性和损伤 DNA,从而降低顺铂敏感(A2780)和抗性(A2780cis)卵巢癌细胞系的癌细胞活力。不过,化合物 B 以前未在体内进行过评估。由于在顺铂治疗的同时抑制 HDAC 介导的抗药性可增强铂类药物的效果,我们首先使用 3-(4,5-二甲基噻唑-2-基)-2,5-二苯基溴化四氮唑分光光度法证实了化合物 B 在 A2780 和 A2780cis 细胞系中的抗癌效果。然后,我们利用斑马鱼胚胎和转基因动物模型比较分析了顺铂、化合物 B 和对照组对一般机体、听觉和肾脏系统毒性以及癌症转移的影响。我们发现,与顺铂(2.0 µM)相比,较低剂量的化合物 B(0.3 或 0.6 µM)可引起相似或更低程度的全身、听觉和肾组织毒性,而在 0.6 µM时,化合物 B 比 2.0 µM的顺铂更能减少癌症转移。
{"title":"Anti-ovarian cancer migration and toxicity characteristics of a platinum(IV) pro-drug with axial HDAC inhibitor ligands in zebrafish models.","authors":"Salma Begum, Scheldon D Irvin, Carol K Cox, Zhouyang Huang, Justin J Wilson, Jerry D Monroe, Yann Gibert","doi":"10.1007/s10637-024-01479-3","DOIUrl":"10.1007/s10637-024-01479-3","url":null,"abstract":"<p><p>Ovarian cancer is the fifth leading cause of cancer related death in the United States. Cisplatin is a platinum-based anti-cancer drug used against ovarian cancer that enters malignant cells and then damages DNA causing cell death. Typically, ovarian cancer cells become resistant to cisplatin making it necessary to increase subsequent dosage, which usually leads to side-effects including irreversible damage to kidney and auditory system tissue. Ovarian cancer resistance is often associated with upregulation of histone deacetylase (HDAC) enzymes that cause DNA to adopt a closed configuration which reduces the ability of cisplatin to target and damage DNA. Compound B, a platinum(IV) complex with two axial phenylbutyrate (PBA) HDAC inhibitor ligands attached to a cisplatin core, can simultaneously inhibit HDAC activity and damage DNA causing decreased cancer cell viability in cisplatin-sensitive (A2780) and -resistant (A2780cis) ovarian cancer cell lines. However, compound B was not previously evaluated in vivo. As simultaneously inhibiting HDAC-mediated resistance with cisplatin treatment could potentiate the platinum drug's effect, we first confirmed the anti-cancer effect of compound B in the A2780 and A2780cis cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide spectrophotometric assay. Then, we used zebrafish embryo and transgenic animal models to comparatively analyze the effect of cisplatin, compound B, and controls on general organismal, auditory, and renal system toxicity, and cancer metastasis. We found that lower dosages of compound B (0.3 or 0.6 µM) than of cisplatin (2.0 µM) could cause similar or decreased levels of general, auditory, and renal tissue toxicity, and at 0.6 µM, compound B reduces cancer metastasis more than 2.0 µM cisplatin.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"644-654"},"PeriodicalIF":3.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11625067/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142465561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-01Epub Date: 2024-12-02DOI: 10.1007/s10637-024-01483-7
Manyi Xu, Yanhua Wang, Ke Wang, Yue Hao, Chunwei Xu, Lei Shi, Zhengbo Song
Background: The efficacy of immune rechallenge in patients with advanced non-small cell lung cancer (NSCLC) who responded well to initial immune checkpoint inhibitor (ICI) treatment is becoming a research hotspot. This study was aimed at describing the survival and clinical characteristics after immune rechallenge in initial immunotherapy responders.
Patients and methods: We retrospectively identified 104 patients with advanced NSCLC who responded well in the first ICI and were rechallenged with immunotherapy to treat progression between January 2018 and June 2023 at Zhejiang Cancer Hospital. Progression-free survival (PFS) 2 and overall survival (OS) were defined as the time from the first day of the second ICI to the date of progression, death, or last follow-up.
Results: Of 104 enrolled patients, 33 received immune monotherapy, and 71 were rechallenged with combination therapy (34 combined with anti-angiogenesis therapy). Patients with an initial immunotherapy duration exceeding 12 months, compared with a duration within 12 months, achieved a significantly prolonged mPFS2 and mOS (PFS2: 9.2 vs. 3.4 months, P < 0.001; OS: 25.5 vs. 10.7 months, P = 0.006). Patients rechallenged with combination therapy had significantly longer PFS2 than those receiving monotherapy (5.8 vs. 2.5 months, P = 0.040), and showed a favorable OS trend (15.9 vs. 10.1 months, P = 0.301). A significant difference in PFS2, particularly for patients receiving combined treatment with anti-angiogenesis therapy (8.7 vs. 4.6 months, P = 0.011), and a tendency toward longer OS (25.3 vs. 13.7 months, P = 0.090), were observed. Multivariate analysis identified long-term treatment duration (P = 0.005) and combined treatment with anti-angiogenesis therapy (P = 0.030) as independent positive factors associated with PFS after rechallenge.
Conclusion: Immune rechallenge is recommend for responders with a prolonged initial immunotherapy duration. Combination therapy, particularly that including anti-angiogenic therapy, is an alternative effective approach to immune rechallenge.
{"title":"Efficacy of immune checkpoint inhibitor rechallenge in initial immunotherapy responders with advanced non-small cell lung cancer: A single-center retrospective study.","authors":"Manyi Xu, Yanhua Wang, Ke Wang, Yue Hao, Chunwei Xu, Lei Shi, Zhengbo Song","doi":"10.1007/s10637-024-01483-7","DOIUrl":"10.1007/s10637-024-01483-7","url":null,"abstract":"<p><strong>Background: </strong>The efficacy of immune rechallenge in patients with advanced non-small cell lung cancer (NSCLC) who responded well to initial immune checkpoint inhibitor (ICI) treatment is becoming a research hotspot. This study was aimed at describing the survival and clinical characteristics after immune rechallenge in initial immunotherapy responders.</p><p><strong>Patients and methods: </strong>We retrospectively identified 104 patients with advanced NSCLC who responded well in the first ICI and were rechallenged with immunotherapy to treat progression between January 2018 and June 2023 at Zhejiang Cancer Hospital. Progression-free survival (PFS) 2 and overall survival (OS) were defined as the time from the first day of the second ICI to the date of progression, death, or last follow-up.</p><p><strong>Results: </strong>Of 104 enrolled patients, 33 received immune monotherapy, and 71 were rechallenged with combination therapy (34 combined with anti-angiogenesis therapy). Patients with an initial immunotherapy duration exceeding 12 months, compared with a duration within 12 months, achieved a significantly prolonged mPFS2 and mOS (PFS2: 9.2 vs. 3.4 months, P < 0.001; OS: 25.5 vs. 10.7 months, P = 0.006). Patients rechallenged with combination therapy had significantly longer PFS2 than those receiving monotherapy (5.8 vs. 2.5 months, P = 0.040), and showed a favorable OS trend (15.9 vs. 10.1 months, P = 0.301). A significant difference in PFS2, particularly for patients receiving combined treatment with anti-angiogenesis therapy (8.7 vs. 4.6 months, P = 0.011), and a tendency toward longer OS (25.3 vs. 13.7 months, P = 0.090), were observed. Multivariate analysis identified long-term treatment duration (P = 0.005) and combined treatment with anti-angiogenesis therapy (P = 0.030) as independent positive factors associated with PFS after rechallenge.</p><p><strong>Conclusion: </strong>Immune rechallenge is recommend for responders with a prolonged initial immunotherapy duration. Combination therapy, particularly that including anti-angiogenic therapy, is an alternative effective approach to immune rechallenge.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"703-715"},"PeriodicalIF":3.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142768880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}