GeneCentric Therapeutics, Inc., Durham, North Carolina.
Levine Cancer Institute, Atrium Health, Charlotte, North Carolina.
Cancer Res Commun. 2022 Aug 30;2(8):894-903. doi: 10.1158/2767-9764.CRC-21-0153. eCollection 2022 Aug.
Recombinant human high-dose IL2 (HD-IL2; aldesleukin) was one of the first approved immune-oncology agents based upon clinical activity in renal cell carcinoma (RCC) and metastatic melanoma but use was limited due to severe toxicity. Next-generation IL2 agents designed to improve tolerability are in development, increasing the need for future identification of genomic markers of clinical benefit and/or clinical response. In this retrospective study, we report clinical and tumor molecular profiling from patients with metastatic RCC (mRCC) treated with HD-IL2 and compare findings with patients with RCC treated with anti-PD-1 therapy. Genomic characteristics common and unique to IL2 and/or anti-PD-1 therapy response are presented, with insight into rational combination strategies for these agents. Residual pretreatment formalin-fixed paraffin embedded tumor samples from = 36 patients with HD-IL2 mRCC underwent RNA-sequencing and corresponding clinical data were collected. A 40-gene nearest centroid IL2 treatment response classifier and individual gene and/or immune marker signature differences were correlated to clinical response and placed into context with a separate dataset of = 35 patients with anti-PD-1 mRCC. Immune signatures and genes, comprising suppressor and effector cells, were increased in patients with HD-IL2 clinical benefit. The 40-gene response classifier was also highly enriched for immune genes. While several effector immune signatures and genes were common between IL2 and anti-PD-1 treated patients, multiple inflammatory and/or immunosuppressive genes, previously reported to predict poor response to anti-PD-L1 immunotherapy, were only increased in IL2-responsive tumors. These findings suggest that common and distinct immune-related response markers for IL2 and anti-PD-1 therapy may help guide their use, either alone or in combination.
Next-generation IL2 agents, designed for improved tolerability over traditional HD-IL2 (aldesleukin), are in clinical development. Retrospective molecular tumor profiling of patients treated with HD-IL2 or anti-PD-1 therapy provides insights into genomic characteristics of therapy response. This study revealed common and distinct immune-related predictive response markers for IL2 and anti-PD-1 therapy which may play a role in therapy guidance, and rational combination strategies for these agents.
重组人高剂量白细胞介素 2（HD-IL2；aldesleukin）是首批基于肾癌（RCC）和转移性黑色素瘤的临床活性而批准的免疫肿瘤药物之一，但由于严重毒性，其使用受到限制。为了提高耐受性，正在开发下一代白细胞介素 2 药物，这增加了未来确定临床获益和/或临床反应的基因组标志物的需求。在这项回顾性研究中，我们报告了接受 HD-IL2 治疗的转移性肾细胞癌（mRCC）患者的临床和肿瘤分子特征，并将这些发现与接受抗 PD-1 治疗的 RCC 患者进行了比较。报告了白细胞介素 2 和/或抗 PD-1 治疗反应的共同和独特的基因组特征，并深入了解了这些药物的合理联合策略。对 = 36 例接受 HD-IL2 mRCC 治疗的患者的预处理福尔马林固定石蜡包埋肿瘤样本进行了 RNA 测序，并收集了相应的临床数据。将 40 个基因最近的中心点白细胞介素 2 治疗反应分类器以及单个基因和/或免疫标志物特征差异与临床反应相关联，并将其与另一个包含 = 35 例接受抗 PD-1 mRCC 治疗的患者的数据集进行比较。在具有 HD-IL2 临床获益的患者中，免疫特征和基因（包括抑制细胞和效应细胞）增加。反应分类器也富含免疫基因。虽然白细胞介素 2 和抗 PD-1 治疗的患者之间有几个效应免疫特征和基因是共同的，但以前报道的预测抗 PD-L1 免疫治疗反应不良的多个炎症和/或免疫抑制基因仅在白细胞介素 2 反应性肿瘤中增加。这些发现表明，白细胞介素 2 和抗 PD-1 治疗的常见和独特的免疫相关反应标志物可能有助于指导其单独或联合使用。
为了提高传统 HD-IL2（aldesleukin）的耐受性，正在开发下一代白细胞介素 2 药物。对接受 HD-IL2 或抗 PD-1 治疗的患者进行回顾性肿瘤分子特征分析，为治疗反应的基因组特征提供了深入了解。这项研究揭示了白细胞介素 2 和抗 PD-1 治疗的共同和独特的免疫相关预测反应标志物，这些标志物可能在治疗指导和这些药物的合理联合策略中发挥作用。
