Vaccine and radiation for the therapy of human cancers

放射治疗是癌症治疗的主要手段。放射还可以减少治疗范围外的肿瘤生长，通常被称为非内窥镜效应。这种异常效应的机制和治疗潜力尚未完全阐明。在这里，我们评估了针对肿瘤相关抗原(TAA)的疫苗在诱导和放大辐射诱导的异常效应中的作用。用TAA特异性疫苗方案进行主动免疫治疗，以诱导和增强针对癌胚抗原(CEA)的T细胞反应，并与皮下肿瘤的局部照射相结合。我们研究了以痘病毒为基础的CEA疫苗方案在CEA转基因(TG)小鼠中与外照射或局部肿瘤的近距离放射治疗的潜在协同作用。联合治疗后观察疫苗未编码的多发性TAA特异性CD8+T细胞的诱导情况。在两种肿瘤模型中，疫苗和局部放射诱导的抗原级联反应介导了远端皮下或肺部位抗原阴性转移的消退。在临床上，原发肿瘤的局部控制是必要的，有时可以防止转移，但放射治疗通常无法控制先前存在的转移。这里的研究表明，通过将肿瘤放射与免疫治疗相结合，异常效应可以从坊间观察转变为一种明确的机制，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了解有所提高，人们对将这种类型的治疗与基于免疫的治疗相结合治疗癌症的兴趣也越来越大。治疗性癌症疫苗已被证明启动了宿主免疫系统激活的动态过程，最终导致宿主癌细胞被识别为异物。放射治疗后创造的环境可以被有效的治疗性癌症疫苗利用，以实现进一步、更强大的免疫系统激活。我们现在集中于临床前研究，研究了不同类型的放射治疗后，与免疫刺激分子有关的肿瘤微环境的变化，包括外照射、放射性标记的单抗、寻骨放射性核素和近距离放射治疗。我们还强调了与癌症疫苗的联合治疗如何利用这些变化来实现更好的治疗效果。最后，我们描述了这些实验室发现如何转化为接受联合放射治疗和癌症疫苗接种的患者的临床益处。

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.