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

复发的WHO IV级恶性胶质瘤(RGBM)是一种目前对所有人都难以治愈的致死性疾病 批准的治疗方法。我们已经开发出一种重组脊髓灰质炎病毒PVSRIPO，它在一项 完成rGBM的I期临床试验；治疗3年后存活率为21%。然而，只有子集 的患者经历了这种反应，这表明需要预测治疗成功和 阐明治疗耐药的机制。更广泛地说，对免疫学的理解 RGBM的前景以及它可能如何被癌症免疫治疗策略靶向仍然是粗糙的。 肿瘤突变负荷(TMB)是一种新的免疫检查点免疫治疗(ICI)生物标志物。 携带TMB较高的肿瘤反应更灵敏。而不是让不同的受体参与适应性 免疫细胞如ICI、PVSRIPO在肿瘤中参与天然的抗病毒信号以启动适应性抗肿瘤 免疫和逆转免疫抑制。TMB是否具有作为这种先天生物标志物的价值 模拟癌症免疫治疗策略还没有被探索过。 值得注意的是，与ICI的观察相反，PVSRIPO有效的患者长期存活 有较低的肿瘤突变负担。根据TMB对TCGA GBM队列中的患者进行分层并没有显示出这样的情况 低TMB患者的生存受益；提示低TMB可能是一个预测疗效的生物标志物 PVSRIPO而不是GBM的一般预后标志物。此外，之前的烷化化疗 暴露[替莫唑胺(Temo)]和相关的Temo突变签名百分比也较低 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：细胞溶解分数，一种基于RNA的免疫效应物存在的标志，以及 活性，在低TMB患者中较高。总而言之，这些发现表明，TMB可能是一种 预测PVSRIPO治疗反应生物标志物；以及先前的TEMO治疗和相关的遗传 突变可能会阻碍PVSRIPO介导的rGBM患者的疗效。因此，我们假设低水平的 TMB是对溶瘤脊髓灰质炎病毒治疗反应所需的rGBM免疫状态的指标。 为此，我们将(I)确定低TMB作为生存益处的预测性生物标记物的效用 从PVSRIPO治疗和(II)探索TMB、TEMO相关突变之间的分子和细胞联系(S) 以及肿瘤免疫格局。 这些研究将证实和推进我们的新观察，即低TMB是一个预测性生物标志物 以回应PVSRIPO。他们将通知临床管理部门PVSRIPO，开始揭示这两个肿瘤 介导对PVSRIPO的原发抗性的内在和免疫机制，并可能告知其他先天- 刺激癌症免疫治疗方式。

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.