Development and validation of a prognostic model for patients with advanced lung cancer treated with the immune checkpoint inhibitor atezolizumab.
免疫检查点抑制剂 atezolizumab 治疗晚期肺癌患者预后模型的开发和验证。
- 作者列表："Hopkins AM","Kichenadasse G","Garrett-Mayer E","Karapetis CS","Rowland A","Sorich MJ
PURPOSE:Immune checkpoint inhibitors (ICI) are a significant advance to the treatment of advanced non-small cell lung cancer (NSCLC), however, their initiation is associated with heterogeneity in outcomes. This study aimed to develop and validate a prognostic tool of survival in advanced NSCLC patients treated with ICIs. EXPERIMENTAL DESIGN:A pre-treatment prognostic model was developed and validated using clinicopathological data. Development data consisted of advanced NSCLC patients treated with atezolizumab from the randomised trials OAK and POPLAR (n=751). Data from the single-arm atezolizumab trials BIRCH and FIR (n=797) were used for external validation. Prognostic scores were categorised into low, intermediate-low, intermediate, intermediate-high and high-risk prognostic groups. The primary outcome was overall survival (OS), with progression-free survival (PFS) secondary. RESULTS:Pre-treatment C-reactive protein (CRP) was the most predictive variable for OS. The prognostic tool was optimally defined by CRP, lactate dehydrogenase, derived neutrophil-to-lymphocyte ratio, albumin, PD-L1 expression, performance status, time since metastatic diagnosis, and metastatic sites count. Prognostic groups had significantly different OS (c-statistic=0.72), with median OS ranging from >24 to 3 months for the low to high-risk groups. Performance was maintained on validation (c=0.76). Findings were similar for PFS, with median PFS ranging from 5 to 1 month for the low to high-risk groups. Benefit of atezolizumab (versus docetaxel) was greatest in the low-risk group (>3 months median OS improvement), with little benefit apparent for the highest-risk group. CONCLUSIONS:A prognostic tool was developed and validated to identify patient groups with distinctly different survival following atezolizumab initiation for advanced NSCLC.
目的: 免疫检查点抑制剂 (ICI) 是晚期非小细胞肺癌 (NSCLC) 治疗的一个重大进展，然而，它们的启动与结局的异质性相关。本研究旨在开发和验证接受 ICIs 治疗的晚期 NSCLC 患者的生存预后工具。 实验设计: 开发了治疗前预后模型，并使用临床病理数据进行了验证。发展数据包括来自随机试验 OAK 和 pomber (n = 751) 的接受 atezolizumab 治疗的晚期 NSCLC 患者。来自单组 atezolizumab 试验 (BIRCH 和 FIR，n = 797) 的数据用于外部验证。预后评分分为低、中-低、中、中高和高危预后组。主要结局为总生存期 (OS)，无进展生存期 (PFS) 为次要。 结果: 治疗前 C 反应蛋白 (CRP) 是 OS 的最预测变量。通过 CRP 、乳酸脱氢酶、中性粒细胞与淋巴细胞比值、白蛋白、 PD-L1 表达、性能状态、转移诊断时间和转移部位计数来确定预后工具。预后组有显著不同的 OS (c-statistics = 0.72)，低至高风险组的中位 OS 范围为> 24 至 3 个月。验证时保持性能 (c = 0.76)。PFS 的结果相似，低至高危组的中位 PFS 为 5 ~ 1 个月。在低风险组中，atezolizumab (与多西他赛相比) 的获益最大 (> 3 个月中位 OS 改善)，而在高风险组中几乎没有明显的获益。 结论: 开发并验证了一个预后工具，以确定在晚期 NSCLC 开始使用 atezolizumab 后具有明显不同生存期的患者组。
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.