Investigational New Drugs最新文献

{"title":"Stage-specific efficacy of osimertinib in treatment-naïve EGFR-mutant non-small cell lung cancer according to baseline genetic alterations in circulating tumor DNA.","authors":"Yoshihiko Taniguchi, Akihiro Tamiya, Mitsuo Osuga, Shun-Ichi Isa, Keiichi Nakamura, Yasuyuki Mizumori, Tsutomu Shinohara, Hidetoshi Yanai, Katsumi Nakatomi, Masahide Oki, Masahide Mori, Tomohito Kuwako, Koji Yamazaki, Masahiro Shimada, Masahiko Ando, Yasuhiro Koh","doi":"10.1007/s10637-024-01500-9","DOIUrl":"10.1007/s10637-024-01500-9","url":null,"abstract":"<p><p>The impact of clinical stage on the effectiveness of osimertinib for epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) remains unexamined. We investigated osimertinib therapeutic efficacy variation between stage IVA or lower and stage IVB EGFR mutation-positive lung cancers, focusing on differences in pretreatment co-occurring genetic alterations in circulating tumor DNA. This was a secondary analysis of the ELUCIDATOR study, a multicenter prospective observational study in Japan that assessed the mechanisms underlying resistance to osimertinib as a first-line treatment for advanced NSCLC with EGFR mutations. We compared the progression-free survival (PFS), overall survival (OS), and pretreatment co-occurring genetic alterations detected in plasma between patients with stages IVA (n = 83) and IVB disease (n = 84). Multivariate analysis of PFS and OS revealed that stage IVB was associated with a poor prognosis (hazard ratio [HR]: 2.03, 95% confidence interval [CI]: 1.36-3.04, p < 0.001, HR: 2.35, 95% CI: 1.45-3.90, p < 0.001, respectively). Pre-osimertinib treatment, significantly more TP53- (52.4% vs. 27.7%, p = 0.002), EGFR amplification- (58.3% vs. 23.2%, p < 0.001), and MET amplification-positive cases (22.6% vs. 7.2%, p = 0.008) were found among stage IVB than among stage IVA or lower cases. Patients with EGFR-positive NSCLC in stage IVB exhibited significantly shorter PFS and OS than those in earlier stages when treated with first-line osimertinib. The prevalence of baseline TP53 mutations, EGFR amplification, and MET amplification in plasma were significantly higher in stage IVB cases, implicating them in the worse outcomes of this group.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"101-107"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142949026","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}

{"title":"Synergistic antitumor effect of MK-1775 and CUDC-907 against prostate cancer.","authors":"Saisai Ma, Yichen Xu, Minmin Liu, Shuaida Wu, Ye Zhang, Hongyan Xia, Ji Lu, Yang Zhan","doi":"10.1007/s10637-024-01490-8","DOIUrl":"10.1007/s10637-024-01490-8","url":null,"abstract":"<p><p>Due to the emergence of drug resistance, androgen receptor (AR)-targeted drugs still pose great challenges in the treatment of prostate cancer, and it is urgent to explore an innovative therapeutic strategy. MK-1775, a highly selective WEE1 inhibitor, is shown to have favorable therapeutic benefits in several solid tumor models. Recent evidence suggests that the combination of MK-1775 with DNA-damaging agents could lead to enhanced antitumor efficacy. Here, our results demonstrate that MK-1775 alone could indeed inhibit proliferation and induce apoptosis in prostate cancer. Moreover, the combination of MK-1775 and a dual PI3K and HDAC inhibitor, CUDC-907, can synergistically inhibit cell proliferation and dramatically induces apoptosis in prostate cancer cells. This effect is partially mediated by DNA damage, resulting from the downregulation of DNA damage response (DDR) proteins such as CDK, CHK, and RRM1/2. Notably, the combination of MK-1775 and CUDC-907 leads to significant antitumor effects in vivo. Our findings provide a strong basis for a promising combination strategy against prostate cancer.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"157-166"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143046482","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}

{"title":"A Phase 1b study of the OxPhos inhibitor ME-344 with bevacizumab in refractory metastatic colorectal cancer.","authors":"Patrick M Boland, Heinz-Josef Lenz, Kristen K Ciombor, Vaia Florou, Michael J Pishvaian, Michael Cusnir, Deirdre Cohen, Jessie Y Guo, Min Tang, Prabhu Rajagopalan, Sandra E Wiley, Richard G Ghalie, Howard S Hochster","doi":"10.1007/s10637-024-01489-1","DOIUrl":"10.1007/s10637-024-01489-1","url":null,"abstract":"<p><p>Antiangiogenic drugs may cause vascular normalization and correct hypoxia in tumors, shifting cells to mitochondrial respiration as the primary source of energy. In turn, the addition of an inhibitor of mitochondrial respiration to antiangiogenic therapy holds potential to induce synthetic lethality. This study evaluated the mitochondrial inhibitor ME-344 in combination with bevacizumab in patients with refractory metastatic colorectal cancer (mCRC). Patients were eligible if they had disease progression after standard therapies, adequate hematologic, hepatic and renal function, and no contraindications to bevacizumab. ME-344 was administered intravenously on days 1, 8 and 15 and bevacizumab on days 1 and 15 of 28-day cycles until disease progression or intolerance. The primary efficacy endpoint was progression-free survival (PFS) at week 16. In the 23 patients enrolled, the median age was 58 years, median number of prior lines of therapy was 4, and median interval from last therapy was 3 months. The most common adverse events (all grades/grade ≥ 3) were fatigue (48%/13%), abdominal pain (35%/4%), diarrhea (30%/4%) and constipation (30%/0%). No patient had an objective response; 9 patients (39%) achieved stable disease. The 16-week PFS was 30.6% (95% confidence interval [CI]: 12.2-51.3), the median PFS was 1.9 months (95% CI: 1.6-4.7), and the median overall survival was 6.7 months (95% CI: 3.4-not reached). ME-344 plus bevacizumab was well tolerated. Disease control was limited in this heavily pretreated patient population. Additional investigations in earlier lines are indicated, and extended-release ME-344 formulations may provide longer drug exposure to maximize benefit. (Trial registration number ClinicalTrials.gov NCT05824559. Registration date 22 March 2022).</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"60-68"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11868331/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142894701","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}

{"title":"Dual PTCH2 mutation [Ser391*, Leu104Pro]: unveiling a potential new genetic susceptibility factor for glioma development.","authors":"Xiang Li, Yingting Wu, Tiantian Han, Ran Ding, Rongrong Kong, Siqi Chen, Ningning Luo, Mingji Jin, Dongsheng Chen, Ping Zhang","doi":"10.1007/s10637-024-01491-7","DOIUrl":"10.1007/s10637-024-01491-7","url":null,"abstract":"<p><p>Gliomas are a heterogeneous type of central nervous system tumor. The etiology of glioma formation remains elusive, with approximately 5% of gliomas being familial, underscoring the significance of understanding genetic susceptibility in glioma development. In this study, a dual germline PTCH2 mutation [Ser391*, Leu104Pro] was identified in a family with a history of glioma, and sequencing data from WES/SimcereDx Neuro-Onco 360 including 910 Chinese patients with glioma and 1666 patients with solid tumors were analyzed. A potential link between PTCH2 mutations and glioma development was observed in the Chinese population. Comprehensive analysis revealed that gliomas harboring dual PTCH2 mutations were segregated into two distinct clinical subtypes, indicating that the presence of PTCH2 is a novel genetic risk factor for glioma. These findings expand the genetic risk profile of glioma and offer promising avenues for the development of targeted diagnostic and therapeutic strategies. The results of this study emphasize the necessity for a comprehensive investigation into the genetic predisposition to gliomas, particularly in Asian populations, to achieve a better understanding of and management strategy for this complex disease.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"126-134"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970843","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}

{"title":"Efficacy and safety of the combination of envafolimab and lenvatinib in unresectable hepatocellular carcinoma: a single-arm, multicentre, exploratory phase II clinical study.","authors":"Yi Jiang, Ke Su, Han Li, Chenjie Wang, Zhenying Wu, Jiali Chen, Zhiyao Zhang, Kun He, Yunwei Han","doi":"10.1007/s10637-024-01468-6","DOIUrl":"10.1007/s10637-024-01468-6","url":null,"abstract":"<p><p>Currently, therapeutic combinations of immune checkpoint inhibitors (ICIs) with anti-angiogenic agents have shown promising outcomes and have the potential to establish a new standard of care. The efficacy and safety of the first-line combination of envafolimab (an ICI) and lenvatinib (an anti-tumor angiogenesis drug) for the treatment of patients with inoperable hepatocellular carcinoma (HCC) have not been demonstrated. Unresectable HCC patients with an Eastern Cooperative Oncology Group (ECOG) physical status score ≤ 1 and a Child-Pugh score ≤ 7 who had not received systemic therapy were included in this single-arm, exploratory, multicentre phase II clinical study. All patients were required to meet the criteria of being at least 18 years of age, having no history of other malignancies, and existing at least one measurable lesion. The patients were treated with envafolimab (150 mg, QW, subcutaneous) in combination with lenvatinib (12 mg for patients weighing over 60 kg, 8 mg for patients weighing under 60 kg). The co-primary endpoint of the study was overall survival (OS), while surrogate endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety. Between March 2022 and April 2023, 36 patients were enrolled, 30 of whom were treated with envafolimab plus lenvatinib. At data cutoff, the median follow-up duration was 20 months (95% CI 18.9-21.1). Among the 30 assessable patients (patients treated according to the trial protocol), the median overall survival (mOS) and median progression-free survival (mPFS) for the therapy comprising envafolimab alongside lenvatinib were 18.5 months (95% CI 13.2-23.8) and 9.4 months (95% CI 1.6-15.6), respectively. The ORR and the DCR (evaluated according to mRECIST criteria) reached 40% and 80%, respectively. In terms of safety, 23 patients (76.7%) experienced at least one treatment-related adverse event (TRAE), of which the most common was elevated aspartate aminotransferase (AST, 23.3%). Furthermore, grade 3 and higher TRAEs occurred in 30%. This study demonstrates that envafolimab in combination with lenvatinib exhibits favourable anti-cancer activity and a manageable safety profile for the first-line treatment of patients with unresectable HCC.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"18-29"},"PeriodicalIF":3.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11868376/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142846507","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}

{"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}

{"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}

{"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}

{"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}

{"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 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.</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}