Enhancing the abscopal effect in cancer treatment by immune modulation

 描述(申请人提供)：在大多数癌症中，疾病的转移扩散是导致死亡的原因。放射治疗传统上在局部疾病的治疗中有突出的作用，但在远处转移的治疗中仅起到姑息性作用。首次观察到照射野外的异常效应，即肿瘤的消退或消失。 20世纪50年代；然而，在常规临床实践中很少观察到这种情况。随着免疫调节剂的使用，这种效应越来越多地被报道。我们的实验室和其他几个实验室最近发表的研究表明，癌症治疗中的异常效应是由免疫系统介导的。不幸的是，在几乎所有的病例中，由局部放射治疗触发的免疫反应的抗肿瘤作用本身不足以完全根除远处的肿瘤。重要的是，我们最近报道了抗PD-L1和放射治疗可以减少放疗后肿瘤的免疫抑制。假设：我们提出，通过调节抑制免疫功能的因素，可以增强对局部辐射的免疫反应。我们假设，非镜检效应的一个关键决定因素是继发性肿瘤微环境中免疫抑制和T细胞功能障碍的水平。值得注意的是，这一假设是新颖的，不同于传统的非镜下回归理论，后者将APC功能和引流淋巴结中的T细胞启动作为最重要的非镜下事件。具体目的：1)研究控制放射治疗和免疫治疗检查点阻断能力的机制，通过阻断PD-L1抗体将肿瘤微环境转变为“免疫中枢”，从而通过免疫媒介使远处疾病消退，并消除导致晚期复发的微转移。2)利用转移性乳腺癌细胞系4T1，分析局部IR联合T细胞、基质调节剂光和抗PD-L1抗体的治疗作用，以调节肿瘤免疫微环境，进一步增强全身免疫活性。在这里，我们将重点关注改善T细胞功能以及减少免疫抑制。这些实验的结果不仅将产生与调节远端效应有关的数据，这将大大有助于通过优化局部IR的剂量和时机来开发毒性较低的新的转移癌治疗方法，这种局部IR结合免疫疗法(抗PD-L1抗体和LIGH)产生全身效应，更重要的是可能导致放射治疗从存在转移的姑息治疗方式转变为潜在的治愈方式。

 DESCRIPTION (provided by applicant): Metastatic spread of disease is the cause of mortality in most cancers. Radiotherapy has traditionally had a prominent role in the treatment of localized disease but only a palliative role in the treatment of distant metastasis. The abscopal effect, regression or disappearance of tumor outside of the irradiated field, was first observed in the 1950s; however, it is quite rarely observed in routine clinical practice. With the use of immune modifiers, this effect has been increasingly reported. Our laboratory as well as several others have recently published studies that indicate that the abscopal effect in cancer treatment is mediated by the immune system. Unfortunately, in almost all cases, the anti-tumor action of the immune response that is triggered by local radiation treatment is inadequate on its own to fully eradicate distant tumors. Importantly, we have recently reported that anti PD-L1 and radiation decrease immunosuppression in irradiated tumors. Hypothesis: We propose that the immune response to local radiation can be augmented by modulation of factors that inhibit immune function. We hypothesize that a critical determinant of the abscopal effect is the level of immunosuppression and T cell dysfunction in the secondary tumor microenvironment. Notably, this hypothesis is novel and distinct from conventional theories of abscopal regression that cite APC function and T cell priming in the draining lymph node as the most important abscopal events. Specific Aims: 1) Investigate the mechanisms that govern the capacity of radiotherapy and immunotherapeutic checkpoint blockade using blocking antibodies to PD-L1 to transform the tumor microenvironment into an "immunological hub" resulting in immune-mediated regression of distant disease and elimination of micrometastases that contribute to late relapse. Here we will focus on reducing immunosuppression in the irradiated tumor, which can influence T cell function in distant tumors; 2) Utilize the metastatic breast tumor line 4T1 to analyze the effect of local IR in combination with therapeutic delivery of the T cell and stromal modulator LIGHT and anti-PD-L1 antibodies for modulation of the tumor immune microenvironment to further enhance systemic immune activation. Here we will focus on improving T cell function as well as reducing immunosuppression. The results of these experiments will not only produce data pertaining to modulating abscopal effects, which will contribute significantly to the development of new, less toxic therapies for metatstatic cancer through the optimization of dose and timing of local IR that produces systemic effects in combination with immune therapies (anti-PD-L1 antibodies and LIGHT), but more importantly could lead to the transformation of radiotherapy from a palliative modality, in the presence of metastases, to a potentially curative modality.