Is Low Tumor Mutational Burden Predictive of Response to Oncolytic Polio Virus Therapy in Recurrent Glioblastoma?

低肿瘤突变负荷是否可以预测复发性胶质母细胞瘤对溶瘤脊髓灰质炎病毒治疗的反应？

• 批准号: 9807277
• 负责人: David M. Ashley
• 金额: $ 44.28万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9807277
• 关键词: Agonist; Antiviral Agents; Archives; Award; Biological Markers; Biopsy; Canes; Cell Nucleus; Cells; Clinical; Clinical Trials; DNA Sequence Alteration; Data; Development; Exhibits; Frequencies; Glioblastoma; Glioma; Goals; Human poliovirus; Immune; Immunologic Markers; Immunologics; Immunosuppression; Immunotherapy; Induced Mutation; Journals; Link; Malignant Glioma; Mediating; Medicine; Modality; Molecular; Mutation; Natural Immunity; New England; Oncolytic poliovirus; Oncolytic viruses; Patients; Phase I Clinical Trials; Phase II Clinical Trials; Prognostic Marker; Protocols documentation; Publishing; RNA; RNA analysis; Recombinants; Recurrence; Refractory Disease; Reporting; Resistance; Sampling; Signal Transduction; Somatic Mutation; Survival Rate; T-Lymphocyte; Testing; The Cancer Genome Atlas; Toll-like receptors; Treatment Efficacy; Tumor Immunity; Work; base; cancer immunotherapy; cell type; checkpoint inhibition; checkpoint therapy; chemotherapy; cohort; conventional therapy; effective therapy; exhaust; exhaustion; exome sequencing; experience; immune checkpoint; immunological status; individual patient; mortality; novel; patient population; patient stratification; patient subsets; predicting response; predictive marker; prognostic; receptor; response; response biomarker; success; temozolomide; transcriptome sequencing; tumor

Recurrent WHO grade IV malignant glioma (rGBM) is a uniformly lethal disease refractory to all currently approved therapies. We have developed a recombinant poliovirus, PVSRIPO, that has shown promise in a completed phase I clinical trial for rGBM; with a 21% survival rate 3 years after therapy. However, only a subset of patients experienced such responses, indicating a need for biomarkers that predict therapy success and elucidation of mechanisms of therapy resistance. More broadly, the understanding of the immunological landscape of rGBM and how it may be targeted by cancer immunotherapy strategies remains crude. Tumor mutation burden (TMB) is an emerging biomarker for immune checkpoint immunotherapy (ICI), with higher TMB-carrying tumors being more responsive. Rather than engaging distinct receptors on adaptive immune cells like ICI, PVSRIPO engages innate, antiviral signaling in tumors to prime adaptive anti-tumor immunity and reverse immunosuppression. Whether TMB may hold value as a biomarker for such innate simulating cancer immunotherapy strategies has not been explored. Remarkably, in contrast to observations for ICI, patients responding to PVSRIPO with long-term survival had lower tumor mutation burden. Stratifying patients from the TCGA GBM cohort by TMB did not reveal such a survival benefit for patients with lower TMB; suggesting that low TMB may be a predictive biomarker for response to PVSRIPO rather than a general prognostic marker for GBM. Additionally, prior alkylating chemotherapy exposure [Temozolomide (Temo)] and the associated Temo-mutation signature percentage were also lower in patients that responded to PVSRIPO therapy. Suggesting a link between TMB, Temo-induced mutations, and the immunological status of tumors: cytolytic score, an RNA based marker for immune effector presence and activity, was higher in patients with low TMB. Collectively, these findings suggest that TMB may serve as a predictive biomarker for response to PVSRIPO therapy; and that prior Temo therapy and the associated genetic mutations may preclude PVSRIPO mediated efficacy in rGBM patients. Therefore, we hypothesize that low levels of TMB is an indicator of an immunological state in rGBM required for response to oncolytic poliovirus therapy. Towards this end we will (i) Determine the utility of low TMB as a predictive biomarker for survival benefit from PVSRIPO therapy and (ii) Explore the molecular and cellular link(s) between TMB, Temo related mutations and the tumor immune landscape. These studies will substantiate and advance our novel observation that low TMB is a predictive biomarker for response to PVSRIPO. They will inform clinical administration of PVSRIPO, begin to reveal both tumor intrinsic and immune mechanisms mediating primary resistance to PVSRIPO, and may inform other innate- stimulating caner immunotherapy modalities.

反复发生IV级恶性神经胶质瘤（RGBM）是当前所有人的均匀致命疾病难治性 批准的疗法。我们已经开发了一种重组脊髓灰质炎病毒PVSripo，该脊髓病毒在 完成了RGBM的I期临床试验；治疗后3年生存率为21％。但是，只有一个子集 患者经历了这种反应，表明需要预测治疗成功的生物标志物 阐明治疗耐药性机制。更广泛地，对免疫学的理解 RGBM的景观及其如何被癌症免疫疗法策略瞄准。 肿瘤突变负担（TMB）是免疫检查点免疫疗法（ICI）的新兴生物标志物， 随着较高的TMB携带肿瘤的反应性更高。而不是在适应性上吸引不同的受体 ICI，PVSRIPO等免疫细胞与肿瘤中的先天性，抗病毒信号接合，以促进自适应抗肿瘤 免疫和反向免疫抑制。 TMB是否可以作为这种先天的生物标志物具有价值 尚未探讨模拟癌症免疫疗法策略。 值得注意的是，与ICI的观察相反，对PVSRIPO的患者具有长期生存 肿瘤突变负担较低。通过TMB从TCGA GBM队列中对患者进行分层 TMB患者的生存益处；表明低TMB可能是响应的预测生物标志物 用于PVSripo，而不是GBM的一般预后标记。另外，先前的烷基化化疗 暴露[Temozolomide（Temo）]和相关的Temo-Monnotage标志百分比也较低 对PVSRIPO疗法有反应的患者。提出TMB，TEMO诱导的突变和 肿瘤的免疫学状态：胞溶液评分，一种基于RNA的免疫效应子的标记和 低TMB患者的活性较高。总的来说，这些发现表明TMB可以用作 预测性生物标志物，以应对PVSRIPO疗法；以及先前的Temo疗法和相关的遗传 突变可能排除PVSRIPO介导的RGBM患者的功效。因此，我们假设低水平 TMB的指标是对肺炎病毒疗法反应的RGBM中免疫学状态的指标。 为此，我们将（i）确定低TMB作为生存收益的预测生物标志物的实用性 从PVSRIPO疗法和（ii）探索TMB之间的分子和细胞链接，Temo相关突变 和肿瘤免疫景观。 这些研究将证实并推动我们新颖的观察结果，即低TMB是一种预测性生物标志物 响应PVSripo。他们将告知PVSripo的临床给药，开始揭示这两个肿瘤 介导对PVSRIPO的主要抵抗力的内在和免疫机制，并可能告知其他先天性 刺激罐头免疫疗法方式。