Vaccine and radiation for the therapy of human cancers

放射是癌症治疗的主要方式。放射治疗也可以减少肿瘤 在治疗区域外生长，通常称为远位效应。的机制 远位效应的治疗潜力尚未完全阐明。这里我们 评估了针对肿瘤相关抗原（TAA）的疫苗接种在 诱导和放大辐射诱导的远位效应。活性特异性 使用TAA特异性疫苗方案的免疫疗法来诱导和增强T细胞活化。 对癌胚抗原（CEA）的反应与局部辐射的组合 皮下肿瘤我们研究了基于痘病毒的CEA疫苗方案的潜在协同作用， 在CEA转基因（Tg）小鼠中， 局部肿瘤的近距离放射治疗。诱导对多种TAA具有特异性的CD 8 + T细胞并不 在联合治疗后观察到疫苗编码的病毒。在两种肿瘤模型中， 疫苗和局部辐射诱导的抗原级联反应介导了 远端皮下或肺部部位的抗原阴性转移。临床上，当地 控制原发肿瘤是必要的，有时可以防止转移，放射治疗， 通常无法控制已存在的转移。研究表明， 将肿瘤放射与免疫治疗相结合，远距离效应可以超越传闻， 观察到一个明确的机制，可用于治疗系统性 疾病随着我们对辐射的免疫调节作用的理解的提高， 有兴趣将这种类型的治疗与基于免疫的治疗相结合，用于治疗 癌症已经长大了。治疗性癌症疫苗已被证明可以启动这一动态过程 宿主免疫系统激活，最终识别宿主癌细胞为 外国的放射治疗后创造的环境可以被积极的治疗方法所利用。 癌症疫苗，以实现进一步的，更强大的免疫系统激活。我们现在已经 集中的临床前研究已经检查了肿瘤微环境的改变， 关于不同类型放射治疗后的免疫刺激分子， 包括外部射线照射、放射性标记的单克隆抗体、骨导向 放射性核素和近距离放射治疗。我们还强调联合治疗癌症 疫苗可以利用这些变化来实现改善的治疗益处。最后，我们描述 这些实验室发现如何转化为患者的临床益处， 联合放疗和癌症疫苗接种。

Radiation is a primary modality in cancer treatment. Radiation can also reduce tumor growth outside the treatment field, often referred to as the abscopal effect. The mechanisms and therapeutic potential of the abscopal effect have not been fully elucidated. Here, we evaluated the role of vaccination directed against a tumor-associated antigen (TAA) in the induction and amplification of radiation induced abscopal effects. Active-specific immunotherapy with a TAA- specific vaccine regimen was used to induce and potentiate T-cell responses against carcinoembryonic antigen (CEA) in combination with local radiation of subcutaneous tumors. We examined the potential synergy of a poxvirus-based CEA vaccine regimen in CEA-transgenic (Tg) mice in combination with either external beam radiation or brachytherapy of local tumors. The induction of CD8+ T-cells specific for multiple TAAs not encoded by the vaccine were observed after the combination therapy. In two tumor models, the antigen cascade responses induced by vaccine and local radiation mediated the regression of antigen negative metastases at distal subcutaneous or pulmonary sites. Clinically, local control of the primary tumor is necessary and can sometimes prevent metastases, radiation generally fails to control pre-existing metastases. By The studies here suggest that by coupling tumor radiation with immunotherapy, the abscopal effect can transcend from anecdotal observation to a defined mechanism that can be exploited for the treatment of systemic disease. As our understanding of the immunomodulatory effects of radiation has improved, interest in combining this type of therapy with immune-based therapies for the treatment of cancer has grown. Therapeutic cancer vaccines have been shown to initiate the dynamic process of host immune system activation, culminating in the recognition of host cancer cells as foreign. The environment created after radiotherapy can be exploited by active therapeutic cancer vaccines in order to achieve further, more robust immune system activation. We have now focused preclinical studies that have examined the alteration of the tumor microenvironment with regard to immunostimulatory molecules following different types of radiotherapy, including external beam radiation, radiolabeled monoclonal antibodies, bone-seeking radionuclides, and brachytherapy. We also emphasize how combination therapy with a cancer vaccine can exploit these changes to achieve improved therapeutic benefit. Lastly, we describe how these laboratory findings are translating into clinical benefit for patients undergoing combined radiotherapy and cancer vaccination.