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.

复发性WHO IV级恶性胶质瘤（rGBM）是一种目前对所有人都难治的一致致死性疾病。 批准的疗法。我们已经开发了一种重组脊髓灰质炎病毒PVSRIPO， 完成rGBM的I期临床试验;治疗后3年生存率为21%。然而，只有一个子集 的患者经历了这样的反应，表明需要预测治疗成功的生物标志物， 阐明治疗抗性的机制。更广泛地说，对免疫学的理解 rGBM的前景以及它如何被癌症免疫治疗策略靶向仍然很粗糙。 肿瘤突变负荷（TMB）是免疫检查点免疫治疗（ICI）的新兴生物标志物， 携带更多TMB的肿瘤更敏感。而不是在适应性上吸引不同的受体 免疫细胞如ICI、PVSRIPO在肿瘤中参与先天性抗病毒信号传导，以引发适应性抗肿瘤 免疫和反向免疫抑制。TMB是否可以作为这种先天性 模拟癌症免疫治疗策略尚未被探索。 值得注意的是，与ICI的观察结果相反，PVSRIPO应答的长期生存患者 肿瘤突变负荷较低。根据TMB对TCGA GBM队列的患者进行分层， TMB较低患者的生存益处;表明TMB较低可能是反应的预测性生物标志物 而不是GBM的一般预后标志物。此外，既往烷化剂化疗 暴露[替莫唑胺（Temo）]和相关的Temo突变特征百分比也低于 对PVSRIPO治疗有反应的患者。提示TMB、Temo诱导的突变和 肿瘤的免疫状态：细胞溶解评分，一种基于RNA的免疫效应物存在的标志物， 活动，在低TMB的患者中更高。总的来说，这些研究结果表明，TMB可能作为一种 对PVSRIPO治疗反应的预测性生物标志物;以及先前的Temo治疗和相关的遗传 突变可能妨碍PVSRIPO介导的在rGBM患者中的功效。因此，我们假设低水平的 是对溶瘤脊髓灰质炎病毒治疗应答所需的rGBM中免疫状态的指标。 为此，我们将（i）确定低TMB作为生存获益的预测生物标志物的效用 和（ii）探索TMB、Temo相关突变之间的分子和细胞联系 和肿瘤免疫格局。 这些研究将证实和推进我们的新观察，即低TMB是一种预测性生物标志物 回应PVSRIPO。他们将告知PVSRIPO的临床给药，开始揭示两种肿瘤 内在和免疫机制介导对PVSRIPO的原发性抗性，并可能告知其他先天性- 刺激癌症免疫治疗模式。