Enhancing the abscopal effect in cancer treatment by immune modulation

 描述（由申请人提供）：疾病的转移性扩散是大多数癌症死亡的原因。传统上，放射疗法在治疗局部疾病中具有突出的作用，但在治疗远处转移中仅起姑息作用。远位效应，即照射野外肿瘤的消退或消失，首次在 20世纪50年代;然而，在常规临床实践中很少观察到。随着免疫调节剂的使用，这种效果越来越多地被报道。我们的实验室以及其他几个实验室最近发表的研究表明，癌症治疗中的远位效应是由免疫系统介导的。不幸的是，在几乎所有情况下，局部放射治疗引发的免疫反应的抗肿瘤作用本身不足以完全根除远处肿瘤。重要的是，我们最近报道了抗PD-L1和放射治疗降低了放射肿瘤的免疫抑制。假设：我们提出，局部辐射的免疫反应可以通过调节抑制免疫功能的因素来增强。我们假设，远位效应的一个关键决定因素是继发性肿瘤微环境中的免疫抑制和T细胞功能障碍的水平。值得注意的是，这一假设是新颖的，不同于传统的理论，远位回归，引用APC功能和T细胞引发的引流淋巴结作为最重要的远位事件。具体目标：1）研究控制放射治疗和免疫检查点阻断能力的机制，使用PD-L1阻断抗体将肿瘤微环境转化为“免疫枢纽”，导致免疫介导的远处疾病消退和消除导致晚期复发的微转移。在此，我们将重点关注减少照射肿瘤中的免疫抑制，其可以影响远处肿瘤中的T细胞功能; 2）利用转移性乳腺肿瘤系4 T1来分析局部IR与T细胞和基质调节剂LIGHT和抗PD-L1抗体的治疗性递送组合的作用，以调节肿瘤免疫微环境，从而进一步增强全身免疫活化。在这里，我们将专注于改善T细胞功能以及减少免疫抑制。这些实验的结果将不仅产生与调节远位效应有关的数据，这将通过优化局部IR的剂量和时间来显著有助于开发用于转移性癌症的新的、毒性较小的疗法，所述局部IR与免疫疗法组合产生全身效应（抗PD-L1抗体和LIGHT），但更重要的是，可以导致放射治疗从姑息疗法（在存在转移的情况下）转变为潜在的治愈疗法。

 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.