Combination of proton radiations and oncolytic viruses to eradicate cancer

胶质母细胞瘤（GBM）和胰腺导管腺癌（PDAC）都有令人沮丧的预后，迫切需要开发新的和更有效的治疗方法。这两种肿瘤实体的特征都是免疫抑制（“冷”）肿瘤微环境（TME）阻碍免疫介导的癌细胞识别和清除。目前的抗肿瘤免疫疗法包括免疫检查点抑制，尽管在许多肿瘤实体中非常成功，但迄今为止未能在GBM或PDAC中提供治疗效果。这些数据强调迫切需要替代治疗方法，将免疫抑制TME重塑为炎症表型，以便重新建立免疫监视和癌细胞清除。溶瘤病毒（OVs）是一种新兴的抗肿瘤免疫疗法，在临床前和临床研究中对GBM和PDAC显示出良好的效果。除了直接杀伤肿瘤细胞外，这些治疗还通过激活PAMP或damp敏感受体以及从被破坏的恶性细胞中释放肿瘤抗原（TA）来触发免疫原性细胞死亡（ICD）。这些过程对包括T细胞、dc细胞和NK细胞在内的关键免疫细胞群具有强大的刺激作用，有助于建立有效的抗癌免疫。重要的是，OV治疗经常导致抗病毒和免疫刺激细胞因子的产生，如i型干扰素（ifn），这一特征与大多数抗癌免疫疗法的有利疾病结局相关。在这里，我们假设OV （PV、MeV或两者）与质子放射治疗（RT）的结合，是一种能够通过参与cGAS-Sting途径诱导炎症和ifn产生的补充治疗方式，代表了一种独特而有前途的治疗GBM和PDAC的方法。我们的多学科团队由病毒学家，生物学家，物理学家，放射化学家，肿瘤学家和放射治疗师组成，在开发，表征和翻译溶瘤病毒以及基于质子的放射治疗和高分辨率成像技术方面具有长期的专业知识。基于我们的上述假设和近几个月来获得的令人鼓舞的初步数据，我们建议在本研究计划中回答三个主要问题：1。在各种GBM和PDAC模型中，单个病毒（PV和MeV）是否与基于质子的RT协同作用？2. 基于它们诱导和受ifn信号传导影响的不同能力，pv和mev是否在GBM或PDAC肿瘤的序贯治疗方案中协同作用？3. 我们能否将这种双重病毒治疗方法与基于质子的放射治疗相结合，以克服免疫抑制性TME，并诱导强大而持久的抗肿瘤免疫反应？通过这项研究，我们的目标是为GBM和PDAC联合放射病毒治疗的近期临床转化提供基础。

Glioblastoma (GBM) and pancreatic ductal adenocarcinoma (PDAC) both have dismal prognoses and urgently require the development of novel and more efficacious therapies. Both tumor entities are characterized by an immunosuppressive (“cold”) tumor microenvironment (TME) impeding immune-mediated recognition and clearance of cancer cells. Current anti-tumor immunotherapies including immune checkpoint inhibition, albeit highly successful in many tumor entities, have thus far failed to deliver therapeutic benefits in GBM or PDAC. These data underline the urgent need for alternative therapeutic approaches that reshape the immunosuppressive TME towards an inflamed phenotype in order to re-establish immune surveillance and cancer cell clearance.Oncolytic viruses (OVs) are emerging anti-tumor immunotherapies and have shown promising results against GBM and PDAC in pre-clinical and clinical studies. Besides direct tumor cell killing, these treatments trigger an immunogenic cell death (ICD) through the activation of PAMP- or DAMP-sensing receptors as well as the release of tumor antigens (TA) from disrupted malignant cells. These processes represent potent stimuli for critical immune cell populations including T cells, DCs and NK cells, instrumental for mounting an effective anticancer immunity. Importantly, OV treatment frequently leads to the production of antiviral and immunostimulatory cytokines, such as type-I interferons (IFNs), a feature correlated with favorable disease outcome for most anticancer immunotherapies. Here, we hypothesize that the combination of an OV (PV, MeV, or both) with proton-based radiotherapy (RT), a complementary treatment modality able to induce inflammation and IFN-production through engagement of the cGAS-Sting pathway, represents a unique and promising treatment approach for GBM and PDAC. Our multi-disciplinary team consisting of virologists, biologists, physicists, radiochemists, oncologists and radiotherapists has a long-standing expertise in developing, characterizing and translating oncolytic viruses as well as in proton-based radiotherapy and high-resolution imaging techniques. Based upon our hypothesis mentioned above and encouraging preliminary data obtained during the last months, we propose to answer three major question within this research proposal: 1. Do the individual viruses (PV and MeV) synergize with proton-based RT in various models of GBM and PDAC? 2. Based on their different abilities to induce and be affected by IFN-signaling, do PVs and MeVs synergize in a sequential treatment schedule of GBM or PDAC tumors? 3. Can we combine this dual virotherapy approach with proton-based radiotherapy to overcome the immunosuppressive TME and induce a robust and durable anti-tumor immune response?With this study, we aim at providing the basis for a near-term clinical translation of a combination radiovirotherapy for treatment of GBM and PDAC.