Vaccine and radiation for the therapy of human cancers

放射治疗是癌症治疗的主要方式。放射也可以减少肿瘤在治疗区域外的生长，这通常被称为体外效应。体外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）的疫苗接种在诱导和放大辐射诱导的体外效应中的作用。采用TAA特异性疫苗方案的主动特异性免疫疗法，结合皮下肿瘤局部放疗，诱导和增强针对癌胚抗原（CEA）的t细胞应答。我们研究了基于痘病毒的CEA疫苗方案在CEA转基因（Tg）小鼠中与外部束辐射或局部肿瘤近距离治疗联合使用的潜在协同作用。在联合治疗后，观察到CD8+ t细胞对多种未被疫苗编码的taa的特异性诱导。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位抗原阴性转移灶的消退。临床上，局部控制原发肿瘤是必要的，有时可以防止转移，放疗通常不能控制已经存在的转移。本研究表明，通过肿瘤放射与免疫治疗的结合，体外效应可以超越道听途说的观察，成为一种明确的机制，可以用于全身性疾病的治疗。随着我们对放射的免疫调节作用的理解的提高，将这种疗法与基于免疫的疗法结合起来治疗癌症的兴趣也在增加。治疗性癌症疫苗已被证明可以启动宿主免疫系统激活的动态过程，最终将宿主癌细胞识别为外来细胞。放射治疗后产生的环境可以被活性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。我们现在的重点是临床前研究，研究了不同类型放疗后肿瘤微环境与免疫刺激分子的改变，包括外部放射束辐射、放射性标记单克隆抗体、寻骨放射性核素和近距离放疗。我们还强调如何联合治疗与癌症疫苗可以利用这些变化，以实现更好的治疗效益。最后，我们描述了这些实验室发现如何转化为接受联合放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.