Patient-Reported Outcomes in a Phase 2 Study Comparing Atezolizumab Alone or With Bevacizumab Versus Sunitinib in Previously Untreated Metastatic Renal Cell Carcinoma.
在一项 2 期研究中比较 Atezolizumab 单独或与贝伐单抗与舒尼替尼在既往未经治疗的转移性肾细胞癌中的患者报告结局。
- 作者列表："Pal SK","McDermott DF","Atkins MB","Escudier B","Rini BI","Motzer RJ","Fong L","Joseph RW","Oudard S","Ravaud A","Bracarda S","Suarez C","Lam ET","Choueiri TK","Ding B","Quach C","Hashimoto K","Schiff C","Piault-Louis E","Powles T
OBJECTIVE:To evaluate patient-reported outcome (PRO) data from IMmotion150. The phase 2 IMmotion150 study showed improved progression-free survival with atezolizumab plus bevacizumab versus sunitinib in patients with PD-L1+ tumours and suggested activity of atezolizumab monotherapy in previously untreated metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS:Patients with previously untreated mRCC were randomised to atezolizumab 1200 mg intravenously (IV) every 3 weeks (n = 103), the atezolizumab regimen plus bevacizumab 15 mg/kg IV every 3 weeks (n = 101), or sunitinib 50 mg orally daily (4 weeks on, 2 weeks off; n = 101). MD Anderson Symptom Inventory (MDASI) and Brief Fatigue Inventory (BFI) were administered on days 1 and 22 of each 6-week cycle. Time to deterioration (TTD), change from baseline in MDASI core and RCC symptom severity, interference with daily life, and BFI fatigue severity and interference scores were reported for all comers. TTD was the first ≥ 2-point score increase over baseline. Absolute effect size ≥ 0.2 suggested a clinically important difference with checkpoint inhibitor therapy versus sunitinib. RESULTS:Completion rates were > 90% at baseline and ≥ 80% at most visits. Delayed TTD in core and RCC symptoms, symptom interference, fatigue, and fatigue-related interference was observed with atezolizumab (both alone and in combination) versus sunitinib. Improved TTD (HR [95% CI]) was more pronounced with atezolizumab monotherapy: core symptoms, 0.39 (0.22-0.71); RCC symptoms, 0.22 (0.12-0.41); and symptom interference, 0.36 (0.22-0.58). Change from baseline by visit, evaluated by the MDASI, also showed a trend favouring atezolizumab monotherapy versus sunitinib. Small sample sizes may have limited the ability to draw definitive conclusions. CONCLUSION:PROs suggested that atezolizumab alone or with bevacizumab maintained daily function compared with sunitinib. Notably, symptoms were least severe with atezolizumab alone versus sunitinib. (IMmotion150; NCT01984242.).
目的: 评价来自 immotion150 的患者报告结局 (PRO) 数据。2 期 IMmotion150 研究显示，与舒尼替尼相比，atezolizumab 联合贝伐单抗可改善 PD-L1 + 肿瘤患者的无进展生存期，并提示 atezolizumab 单药治疗既往未经治疗的转移性肾细胞癌 (mRCC) 具有活性。 患者和方法: 既往未经治疗的 mRCC 患者随机接受 atezolizumab 1200 mg 静脉 (IV) 每 3 周 (n = 103),atezolizumab 方案加贝伐单抗 15 mg/kg 每 3 周静脉注射 (n = 101)，或舒尼替尼 50 mg 每日口服 (4 周开始，2 周休息; n = 101)。MD Anderson 症状量表 (MDASI) 和简明乏力量表 (BFI) 在每个 6 周周期的第 1 天和第 22 天进行。报告所有来者的恶化时间 (TTD) 、 MDASI 核心和 RCC 症状严重程度较基线的变化、对日常生活的干扰以及 BFI 乏力严重程度和干扰评分。TTD 是首次超过基线 ≥ 2 分的评分增加。绝对效应大小 ≥ 0.2 提示检查点抑制剂治疗与舒尼替尼有临床重要差异。 结果: 基线时完成率> 90%，大多数访视时 ≥ 80%。Atezolizumab (单独和联合) 与舒尼替尼相比，观察到 core 和 RCC 症状、症状干扰、乏力乏力相关干扰延迟。Atezolizumab 单药治疗的 TTD 改善 (HR [95% CI]) 更明显: 核心症状，0.39 (0.22-0.71); RCC 症状，0.22 (0.12-0.41); 症状干扰,0.36 (0.22-0.58)。由 MDASI 评估的按访视基线的变化也显示出有利于 atezolizumab 单药治疗与舒尼替尼治疗的趋势。样本量小可能限制了得出明确结论的能力。 结论: PROs 建议，与舒尼替尼相比，atezolizumab 单独或联合贝伐单抗维持日常功能。值得注意的是，与舒尼替尼相比，单用 atezolizumab 症状最不严重。(IMmotion150; Nct0198242.)。
METHODS::Macrophages (MΦ) play a critical role in tumor growth, immunosuppression and inhibition of adaptive immune responses in cancer. Hence, targeting signaling pathways in MΦs that promote tumor immunosuppression will provide therapeutic benefit. PI3Kγ has been recently established by our group and others as a novel immuno-oncology target. Herein, we report that a macrophage Syk-PI3K axis drives polarization of immunosuppressive MΦs which establish an immunosuppressive tumor microenvironment in in vivo syngeneic tumor models. Genetic or pharmacological inhibition of Syk and/or PI3Kγ in MΦs promotes a pro-inflammatory MΦphenotype, restores CD8+ T cell activity, destabilizes HIF under hypoxia, and stimulates an antitumor immune response. Assay for Transposase-accessible Chromatin using Sequencing (ATAC-seq) analyses on the bone marrow derived macrophages (BMDMs) show that inhibition of Syk kinase promotes activation and binding of NF-κB motif in SykMC-KO BMDMs, thus stimulating immunostimulatory transcriptional programming in MΦs to suppress tumor growth. Finally, we have developed in silico the "first in class" dual Syk/PI3K inhibitor, SRX3207, for the combinatorial inhibition of Syk and PI3K in one small molecule. This chemotype demonstrates efficacy in multiple tumor models and represents a novel combinatorial approach to activate antitumor immunity.
METHODS::Dysfunction of invariant natural killer T (iNKT) cells in tumor microenvironment hinders their anti-tumor efficacy, and the underlying mechanisms remain unclear. Here we report that iNKT cells increase lipid biosynthesis after activation, and that is promoted by PPARγ and PLZF synergically through enhancing transcription of Srebf1. Among those lipids, cholesterol is required for the optimal IFN-γ production from iNKT cells. Lactic acid in tumor microenvironment reduces expression of PPARγ in intratumoral iNKT cells and consequently diminishes their cholesterol synthesis and IFN-γ production. Importantly, PPARγ agonist pioglitazone, a thiazolidinedione drug for type 2 diabetes, successfully restores IFN-γ production in tumor-infiltrating iNKT cells from both human patients and mouse models. Combination of pioglitazone and alpha-galactosylceramide treatments significantly enhances iNKT cell-mediated anti-tumor immune responses and prolongs survival of tumor-bearing mice. Our studies provide a strategy to augment the anti-tumor efficacy of iNKT cell-based immunotherapies via promoting their lipid biosynthesis.
METHODS::Near-infrared photoimmunotherapy (NIR-PIT) is a newly developed and selective cancer treatment that induces necrotic and immunogenic cell death and utilizes a monoclonal antibody conjugated to a photo-absorber dye, IR700DX, activated by NIR light. Although CD44 is surface cancer marker associated with drug resistance, anti-CD44-IR700 NIR-PIT results in inhibited cell growth and prolonged survival in multiple tumor types. Meanwhile, anti-CD25-IR700-targeted NIR-PIT has been reported to achieve selective and local depletion of FOXP3+CD25+CD4+ regulatory T cells (Tregs), which are primary immunosuppressive cells in the tumor microenvironment (TME), resulting in activation of local antitumor immunity. Combined NIR-PIT with CD44- and CD25-targeted agents has the potential to directly eliminate tumor cells and also amplify the immune response by removing FOXP3+CD25+CD4+ Tregs from the TME. We investigated the difference in therapeutic effects of CD44-targeted NIR-PIT alone, CD25-targeted NIR-PIT alone, and the combination of CD44- and CD25-targeted NIR-PIT in several syngeneic tumor models, including MC38-luc, LL/2, and MOC1. The combined NIR-PIT showed significant tumor growth inhibition and prolonged survival compared with CD44-targeted NIR-PIT alone in all tumor models and showed prolonged survival compared with CD25-targeted NIR-PIT alone in MC38-luc and LL/2 tumors. Combined CD44/CD25 NIR-PIT also resulted in some complete remissions, whereas this was not achieved with either type of NIR-PIT alone. Therefore, combined NIR-PIT simultaneously targeting cancer antigens and immunosuppressive cells in the TME may be more effective than either type of NIR-PIT alone and may have potential to induce prolonged immune responses in treated tumors.