放疗与免疫治疗联合应用的相关机制及研究进展

放疗主要通过对放射野内肿瘤细胞的杀伤来提高肿瘤的局部控制、降低远处播散并能够激活机体抗肿瘤免疫应答,在免疫治疗的辅助下发挥全身抗肿瘤的作用。放疗联合免疫治疗作为一种新的治疗方式在部分转移性癌症患者中取得了显著疗效。在放射线杀伤局部肿瘤细胞的过程中,肿瘤相关抗原释放表达增加、肿瘤免疫抑制微环境得到改善、激活特异性T细胞免疫应答促使肿瘤细胞形成原位疫苗,合适的放疗剂量与分割模式在最佳时机联合相应的免疫治疗可杀伤放疗野外的远处转移病灶。本文对放疗促进抗肿瘤免疫反应的具体机制以及两者联合应用的广阔前景和面临的挑战进行综述。      

放疗联合免疫治疗的相关机制及研究进展

近年来,恶性肿瘤的发病率越来越高,而肿瘤的各种治疗技术也在不断提高,治疗方案不断完善。放疗主要是通过放射线对局部肿瘤细胞的杀伤来达到治疗效果,而在放疗过程中,可以诱导或提高抗肿瘤免疫反应。合适的放疗剂量、分割模式联合一定的免疫治疗在肿瘤的治疗中越来越起到重要的作用。本文综述了放疗增强抗肿瘤免疫反应的相关机制及放疗联合免疫治疗研究现状和发展前景。     

放疗联合免疫治疗癌症的研究进展

放疗不仅是肿瘤局部治疗的重要手段,同时也对免疫功能有重要的调节作用。放疗可通过产生新抗原、调节细胞因子释放、提高肿瘤对免疫细胞杀伤作用敏感性等方式调节机体抗肿瘤免疫应答。近年来部分研究和临床实践发现,放疗联合免疫治疗在部分病例中出现“远位效应”,照射野范围外的转移性病灶有部分或完全缓解,显示放疗联合免疫治疗的良好前景;但相关机制以及放疗剂量、分割方式等因素对免疫的影响仍有待进一步研究。本文综述了放疗影响免疫的机制以及放疗联合免疫治疗的研究进展。     

放疗与肿瘤免疫

肿瘤微环境中的免疫细胞和细胞因子在抗肿瘤免疫中具有不同功能。放疗可通过放射生物效应杀伤肿瘤细胞,同时还能间接改变肿瘤免疫微环境,协同产生局部或远处抗肿瘤免疫效应。放疗联合免疫治疗的动物和临床试验证实其良好的应用前景,联合治疗时具体的放射治疗模式尚需进一步研究。     

放疗与免疫治疗协同作用的研究进展

放疗是治疗肿瘤的主要手段之一。既往观点认为,传统放疗杀伤免疫细胞,具有免疫抑制作用。但目前越来越多的研究表明,放疗能够改变肿瘤微环境。激发或者增强抗肿瘤免疫反应。许多基础研究及临床研究已经证实了,放疗联合免疫治疗能够增强抗肿瘤的疗效。     

免疫检查点抑制剂与放疗联合治疗局部晚期不可切除非小细胞肺癌的介入时机的研究进展

局晚期非小细胞肺癌（NSCLC）患者治疗多采用放化疗联合的综合治疗模式，免疫检查点抑制剂（ICI）的加入显著改善了其疗效。放疗可通过诱导肿瘤细胞免疫原性死亡、刺激肿瘤细胞自身抗原释放、增加抗原提呈等机制，与免疫治疗产生协同抗肿瘤作用。基于放疗和免疫治疗的协同作用机制，以及PACIFIC 研究的成功，一系列关于放疗联合ICI 的临床研究在NSCLC中相继展开，研究组合形式各异，对于最佳组合方案仍无定论。对于放疗与免疫治疗联合的作用机制、介入时机和联合模式相关的最新临床研究进展的了解具有重要的临床意义。     

肿瘤放疗联合免疫治疗的发展现状和前景

近几年来肿瘤免疫治疗的进展,给晚期肿瘤患者提供了新的治疗选择.放射治疗协同免疫治疗有可能进一步改善患者的免疫系统从而更利于免疫系统杀死肿瘤细胞,达到治疗目的.同时放疗导致的远位效应也可能是机体抗肿瘤免疫应答产生的必要起始条件.今后,放射治疗与免疫治疗的联合应用会有更为广阔的空间,大剂量放疗(SBRT)通过免疫应答刺激产生的远隔效应也会有更深入的理解.本文综述了放射治疗与免疫治疗的应用,以及今后可能的临床应用.     

SBRT联合免疫治疗的机制及研究进展

近年来,大量临床前和临床研究表明,SBRT除直接杀伤肿瘤细胞外,还能导致肿瘤细胞免疫原性死亡,释放大量肿瘤相关抗原(TAA)及危险相关模式分子(DAMPs)形成肿瘤原位疫苗。通过激活的抗原提呈细胞交叉致敏引流淋巴结内的CD8(+) T细胞。SBRT能介导肿瘤局部和全身系统性的抗肿瘤免疫反应,与免疫治疗结合,还可以引发远位效应。SBRT同时能改善肿瘤免疫抑制微环境,增加肿瘤对免疫治疗的敏感性。本文对SBRT联合肿瘤免疫治疗的协同作用机制的研究进展进行综述。     

立体定向放疗联合免疫治疗晚期恶性肿瘤进展

晚期肺转移癌或黑素瘤中放疗联合免疫检测点抑制剂,封闭免疫抑制通路,增强抗肿瘤免疫应答,在临床上明显改善生存。体部立体定向放疗大剂量精准照射到肿瘤靶区,最大程度避免周围正常组织损伤,同时还诱导相关细胞因子和免疫分子表达,较常规放疗更能诱导强烈的免疫反应及远隔效应,更适合与免疫联合。已有研究表明总剂量和分割模式是调节放疗免疫反应的重要参数;放疗与免疫序贯时机显著影响疗效,肿瘤浸润淋巴细胞、PD-L1表达水平和MMR缺陷可能是预测放疗免疫治疗的重要指标。采用合理的放疗剂量和分割模式,选择最佳序贯时机和有效的预测标记物,SBRT联合免疫可以最大程度激活全身免疫反应,发挥远隔效应协同作用晚期恶性肿瘤。     

调节性T细胞在肿瘤放疗联合免疫治疗中的研究进展

调节性T细胞(Treg)是一类具有免疫负向功能的T细胞,不仅能抑制其对自身和非自身抗原的异常/过度免疫反应,维持免疫稳态,还可通过各种方式阻止机体启动抗肿瘤的免疫效应,参与肿瘤的发生发展.放疗目前被广泛应用于临床,在抗肿瘤中的作用越来越突出,绝大多数恶性肿瘤患者均要采取放疗.近年来免疫治疗也得到应用,放疗与免疫治疗的联合应用已成为当前的研究热点,本文以Treg的免疫学特性入手,主要就Treg对肿瘤的发生、发展以及对放疗、免疫治疗疗效的影响作一综述.     

Systematic review of case reports on the abscopal effect

Radiation therapy is a highly effective local treatment for cancer. However, sporadic events of tumor regression in unirradiated fields, known as abscopal effect, have been observed for decades. This abscopal effect has more recently been postulated to be a result of antitumor immune response induced by radiation therapy. With the advent of modern immunotherapy, the potential for immune activation by radiation therapy defines a novel role for radiation therapy in systemic disease. In this context, we have searched documented cases abscopal effect of radiation therapy in literature. A total of 46 reported cases have been identified from 1969 to 2014 with median radiation dose of 31 Gy, median follow-up of 17.5 months, and median documented time to notice the abscopal effect was 2 months. This review systematically summarizes all clinical case reports of abscopal effect to gain insight into this uncommon but important phenomenon.     

The Abscopal Effect of Radiation Therapy: What Is It and How Can We Use It in Breast Cancer?

The abscopal effect refers to the ability of localized radiation to trigger systemic antitumor effects. Over the past 50 years, reports on the abscopal effect arising from conventional radiation have been relatively rare. However, with the continued development and use of immunotherapy strategies incorporating radiotherapy with targeted immunomodulators and immune checkpoint blockade, the abscopal effect is becoming increasingly relevant in less immunogenic tumors such as breast cancer. Here, we review the mechanism of the abscopal effect, the current preclinical and clinical data, and the application of the abscopal effect in designing clinical trials of immunotherapy combined with radiotherapy in breast cancer.     

The Abscopal Effect of Stereotactic Radiotherapy and Immunotherapy: Fool's Gold or El Dorado?

An ‘abscopal’ effect if often used to refer to distant tumour regression after localised irradiation. Since the first report of the abscopal effect in the 1950s, well-documented cases with radiotherapy alone are very rare. It is widely accepted that the immune response plays an important role in the abscopal effect, although the mechanism is still unclear. With the recent success of cancer immunotherapy, there is growing interest in combining immunotherapy with radiotherapy to boost abscopal response rates. Compared with conventional radiotherapy, stereotactic ablative radiotherapy (SABR) not only delivers ablative dose to the tumour, but may also induce robust immune responses. In this review we examine studies that combine SABR and immunotherapy. We review the preclinical rationale for SABR and immunotherapy combinations, the case for and against abscopal effects, and the current landscape of clinical trials.     

肿瘤治疗中的异位效应

异位效应在肿瘤治疗和控制转移方面具有重要作用,将其用于临床肿瘤治疗有重要意义.其生物学机制尚小完全清楚,发现其与免疫应答有关.异位效应可能通过抗原释放和提呈、T细胞和自然杀伤细胞活化、细胞因子作用以及炎症反应和凋亡等环节激活体内抗肿瘤免疫效应.     

Immunothérapie et radiothérapie

Radiotherapy, primarily known for its cytotoxic effect on the tumor cells, via the induction of DNA damages, has the ability to induce a systemic antitumoral response. By an immunologic cell death, tumor cells exposed to radiation release a large amount of neoantigenes and pro-inflammatory mediators, acting as an in situ vaccine, resulting in an tumor regression within the primary irradiated site, but also in the distant “out of field” secondary tumors. However, this phenomenon is extremly rare with radiotherapy alone, suggesting that the radiation-induced antitumor immunity is not sufficient for overcoming the tumor's and its microenvironnement immunosuppressing effect. Over the last years, many scientific data and preclinical studies have demonstrated that the combination of local irradiation with immune therapy has a synergistic action in inducing an antitumoral immunity, thus enhancing an abscopal effect. In this article, we summarize the main mechanisms cancer harnesses to evade the control of the immune system and how ionising radiations can induce an antitumor immunity. A focus reports then on recent preclinical and clinical research built on this background of combined radiation and immune therapy, which bear the great potential to further improve anticancer therapies.     

Optimizing cancer treatments to induce an acute immune response: radiation Abscopal effects, PAMPs, and DAMPs

Clinical results indicate improved survival in poorly differentiated prostate cancer patients following a treatment schedule that maximizes hormone therapy prior to radiation. This may be because of a systemic immune response, called an abscopal effect. A literature review showed an association between acute infection and abscopal cancer remission. This led to the theory that, in the presence of endogenous cancer-specific antigens exposed by cancer necrosis, an innate immune response can adapt to respond to those antigens via a cross-talk mechanism. This theory was validated in an animal model. An acute innate immune T-cell response was stimulated using cluster vaccination with Poly(I:C). In the presence of exogenous cancer-specific antigens, this immune response became adaptive, creating an abscopal effect that resulted in cancer resolution. These concepts may be of clinical value, improving outcomes by inducing systemic abscopal effects.     

A rapid and systemic complete response to stereotactic body radiation therapy and pembrolizumab in a patient with metastatic renal cell carcinoma

Stereotactic body radiation therapy (SBRT) of local tumor would induce an abscopal effect that has been observed in several kinds of human cancers; one important mechanism may involve the improved activation of the host immune system. The immune checkpoint inhibitor can overcome immune tolerance and enhance the activation of antitumor T cells. The combined treatment of SBRT and checkpoint inhibitor may represent a new promising therapeutic approach. Herein, we reported a patient with metastatic renal cell carcinoma (RCC) treated with concurrent SBRT and anti-PD-1 antibody, pembrolizumab, by which the patient achieved an amazingly systemic complete response in only 2.2 months after starting treatment. This case report indicates that the advanced RCC may benefit from the combining treatment of local SBRT and PD-1 inhibitor and provide a useful paradigm worthy of establishing a clinical trial for patients with advanced renal cell carcinoma.     

Targeting the inhibitory receptor CTLA-4 on T cells increased abscopal effects in murine mesothelioma model

We previously demonstrated that blockade of immune suppressive CTLA-4 resulted in tumor growth delay when combined with chemotherapy in murine mesothelioma. Tumor-infiltrating T cells (TIT) after local radiotherapy (LRT) play critical roles in abscopal effect against cancer. We attempt to improve the local and abscopal effect by modulating T cell immunity with systemic blockade of CTLA-4 signal. The growth of primary tumors was significantly inhibited by LRT while CTLA-4 antibody enhanced the antitumor effect. Growth delay of the second tumors was achieved when the primary tumor was radiated. LRT resulted in more T cell infiltration into both tumors, including Treg and cytotoxic T cells. Interestingly, the proportion of Treg over effector T cells in both tumors was reversed after CTLA-4 blockade, while CD8 T cells were further activated. The expression of the immune-related genes was upregulated and cytokine production was significantly increased. LRT resulted in an increase of TIT, while CTLA-4 blockade led to significant reduction of Tregs and increase of cytotoxic T cells in both tumors. The abscopal effect is enhanced by targeting the immune checkpoints through modulation of T cell immune response in murine mesothelioma.