Abscopal Effect Of Radiation Therapy Research Articles

Antiangiogenic Treatment Facilitates the Abscopal Effect of Radiation Therapy Combined With Anti-PD-1 in Hepatocellular Carcinoma

IntroductionMetastasis is one of the most important factors contributing to poor prognosis in hepatocellular carcinoma (HCC). Radiotherapy (RT), along with its induced abscopal effect, is a promising treatment for metastatic patients. However, the incidence of abscopal effect in clinical practice is rare, even when RT is combined with immune checkpoint inhibitors (ICIs). In this study, we aim to investigate the role of antiangiogenic treatment on the abscopal effect induced by RT + ICIs. MethodsBilateral subcutaneous and orthotopic Hepa1-6 and Hep53.4 models were established and treated with different combination treatments. We evaluated changes in the immune microenvironment and vascular normalization by flow cytometry, TCR sequencing, chemotactic gene array, ELISA, and immunofluorescence. ResultsOur studies showed that antiangiogenic treatment with RT + ICIs increased the antitumor response of the unirradiated lesions. Mechanistically, blockade of vascular endothelial receptor 2 (Anti-VEGFR2) increased the activation and maturation of DCs and promoted the production CD8+ T cells in irradiated tumors. These CD8+ T cells were attracted by anti-VEGFR2-induced CCL5 secretion from M1 macrophages in unirradiated tumors. Besides that, Anti-VEGFR2 enhanced the function of CD8+ T cells by reducing myeloid-derived suppressor cells and regulatory T cells. ConclusionThis study demonstrated that the combination of antiangiogenic treatment with RT and ICIs enhanced the abscopal effects. The application of triple therapy and its induced abscopal effect may offer a novel therapeutic approach for HCC, particularly for cases with multiple metastatic lesions.

Macrophage Mediated Abscopal Effects of Radiation Therapy

Radiation therapy (RT) can activate both innate and adaptive immune responses, and the combination of RT and immunotherapy is thought to be a promising strategy. We found that the "don't-eat-me" molecule CD47 is highly expressed on the surface of small cell lung cancer (SCLC) cells, a highly metastatic form of lung cancer, and that blockade of CD47 can enhance the phagocytosis of SCLC cells by macrophages. In this study, we investigated whether combining CD47 blockade and RT could synergize to inhibit the tumor growth of SCLC as well as other cancers in preclinical models. We evaluated efficacy and immune responses by RT and CD47 blockade in SCLC preclinical models as well as in colon cancer and lymphoma preclinical models. We engrafted cancer cells into both flanks of recipient mice and irradiated only one side of tumors with or without CD47 antibodies to investigate local and systemic effects of RT and CD47 blockade. We also used liver metastases models and endogenous lung tumor models to investigate anti-tumor effects and immune responses in their tumor microenvironments. In human patients, we investigated immune responses after RT using CIBERSORTx. We found CD47 blockade potently enhances the local antitumor effects of RT in all the pre-clinical models of SCLC we tested. Strikingly, CD47 blockade also stimulates systemic "abscopal" effects inhibiting non-irradiated SCLC tumors in mice receiving RT. These effects are observed in liver metastases models and endogenous lung tumor models as well as subcutaneous tumor models. Surprisingly, these abscopal effects are independent of T cells but require macrophages that migrate into non-irradiated tumor sites in response to inflammatory signals produced by RT and are locally activated by CD47 blockade to phagocytose cancer cells. Similar abscopal antitumor effects were observed in other cancer models treated with RT and CD47 blockade. We also found that RT increases tumor infiltrating macrophages in human cancer patients. Interestingly, these abscopal antitumor effects are enhanced by PD-1 blockade in some models. Our data clearly demonstrate macrophage-mediated abscopal responses of RT when combined with CD47 blockade in a range of cancer models. The systemic activation of antitumor macrophages following radiation and CD47 blockade may be particularly important in cancer patients who suffer from metastatic disease. RT is a part of standard-of-care and CD47-blocking strategies are in clinical trials, therefore our observations may be rapidly translatable to cancer patients.

Radiotherapy, photodynamic therapy, and cryoablation-induced abscopal effect: Challenges and future prospects.

Local therapy modalities such as radiation therapy, photodynamic therapy, photothermal therapy, and cryoablation have been used to treat localized tumors for decades. The discovery of the abscopal effect causes a paradigm shift where local therapy also causes systemic effects and leads to the remission of nonirradiated tumors. The abscopal effect of radiation therapy, alone or in combination with other treatments, has been extensively studied over the last six decades. However, the results are unsatisfactory in producing robust, reproducible, and long-lasting systemic effects. Although immunotherapy and radiation therapy are promising in producing the abscopal effect, the abscopal effect's mechanism is still unclear, owing to various factors such as irradiation type and dose and cancer type. This article reviews the research progress, clinical and preclinical evidence of the abscopal effect by various local therapies alone and in combination with chemotherapy and immunotherapy, case reports, and the current challenges in producing the abscopal effect by various local therapies, focusing on radiotherapy, photodynamic therapy, cryoablation, and the prospects for obtaining a robust, reproducible, and long-lasting abscopal effect.

The Abscopal Effect of Radiation Therapy

Radiation therapy (RT) in some cases results in a systemic anticancer response known as the abscopal effect. Multiple hypotheses support the role of immune activation initiated by RT-induced DNA damage. Optimal radiation dose is necessary to promote the cGAS-STING pathway in response to radiation and initiate an IFN-1 signaling cascade that promotes the maturation and migration of dendritic cells to facilitate antigen presentation and stimulation of cytotoxic T cells. T cells then exert a targeted response throughout the body at areas not subjected to RT. These effects are further augmented through the use of immunotherapeutic drugs resulting in increased T-cell activity. Tumor-infiltrating lymphocyte presence and TREX1, KPNA2 and p53 signal expression are being explored as prognostic biomarkers.

Toxicity of L19-Interleukin 2 Combined with Stereotactic Body Radiation Therapy: A Phase 1 Study

The immunocytokine L19-IL2 delivers interleukin-2 to the tumor by exploiting the selective L19-dependent binding of extradomain B of fibronectin on tumor blood vessels. In preclinical models, L19-IL2 has been shown to enhance the local and abscopal effects of radiation therapy. The clinical safety of L19-IL2 monotherapy has been established previously. In this study, the safety and tolerability of L19-IL2 after stereotactic body radiation therapy (SBRT) was assessed. Patients with oligometastatic solid tumors received radical SBRT to all visible metastases. Within 1 week after SBRT, intravenous L19-IL2 using a 3 + 3 dose escalation design was administered. Safety and tolerability were analyzed as the primary endpoint using the Common Terminology Criteria for Adverse Events 4.03 scoring system, with progression-free and overall survival as secondary endpoints. A total of 6 patients in 2 L19-IL2 dose levels were included. The 15 million International Units (Mio IU) dose level was well tolerated with no dose-limiting toxicity. The most frequently reported adverse events were chills, noninfectious fever, fatigue, edema, erythema, pruritus, nausea/vomiting, and cough and dyspnea. Blood analysis revealed abnormalities in liver function tests, anemia, hypoalbuminemia, and hypokalemia. At the second dose level (ie, 22.5 Mio IU), which is the recommended dose for L19-IL2 monotherapy, all 3 included patients experienced dose-limiting toxicity but recovered without sequelae. We documented 2 long-term progression-free responders, both having non-small cell lung cancer as primary tumor. Based on the results of this phase 1 clinical trial, the recommended phase 2 dose for SBRT combined with L19-IL2 is 15 Mio IU. The therapeutic efficacy of this combination is currently being evaluated in the multicentric EU-funded phase 2 clinical trial, ImmunoSABR.

Abstract 2258: CD73 targeting therapy enhances the anti-tumor effect of radiation therapy in rectal cancer

Abstract [Background and Purpose]Extracellular adenosine exerts strong immunosuppressive activity and is considered as an important metabolic immune-checkpoint molecule. CD73 (ecto-5'-nucleotidase) is the rate-limiting enzyme to produce adenosine, and high CD73 expression in tumor tissue is linked to poor prognosis. However, the role of CD73/adenosine signaling in the response against radiation therapy (RT) is less understood. Here, we examined the anti-tumor effects of the combination of CD73 blockade and RT. [Method]LuM1, a highly metastatic subtype of colon26 (murine colon cancer cell) were subcutaneously (sc) inoculated in Balb/c mouse. At day 12,14 and16, 4Gy RT was locally applied selectively to sc tumor with lead shielding of other body. Blocking CD73 mAb (200μg/body) was intraperitoneally administrated at day 12,14,16,19,22 and 25. The mice were sacrificed at day 28 and the growth of irradiated tumor and non-irradiated lung metastasis was evaluated. For evaluating immune function, tumor and spleen were excised at day 18. In addition, expression of CD73 in 64 human rectal cancer after chemoradiotherapy (CRT) was examined with immunohistochemistry and evaluated for the impact on patient outcome. [Result]Flowcytometric analysis showed that LuM1 positively expressed CD73 which was significantly enhanced by 10Gy RT in vitro. Local RT (4Gy x 2) also enhanced the expression of CD73 in LuM1 of sc tumor (MFI: Median=177, 120-234 vs 65.5, 24.3-72.3, n= 5, p=0.0079). Local RT caused significant delay in growth of sc tumor. However, the addition of anti-CD73 mAb further reduced the tumor weight as compared with isotype control (Μ=0.15g, 0.004-0.29g vs 0.34g, 0.1-0.73g, n=8, p=0.0379). Interestingly, the number of metastases in non-irradiated lung was also significantly decreased by anti-CD73mAb (Μ=1, 0-30 vs 12, 1-70, n=8, p=0.040).The percentage of IFNγ (+)/CD4 (+) cells and IFNγ (+)/CD8a (+) cells of splenocytes were increased in RT +Anti-CD73 groups compared to RT +Anti-Isotype group. (Μ=9.95%, 7.71-16.6% vs 3.64%, 1.01-11.7%, n=6, p=0.0022 and Μ=15.5%, 11.9-24.1% vs 5.98%, 1.51-16.6%, n=6, p=0.041).In addition, the percentage of IFNγ (+)/CD4 (+) cells of tumor infiltrating lymphocytes was increased in RT +Anti-CD73 groups compared to RT +Anti-Isotype group. (Μ=12.2%, 9.77-18.2% vs 7.09%, 1.55-9.41%, n=6, p=0.0022).Among the patients who received CRT, 13 patients with high expression level of CD73 both in remnant tumor cells and stroma showed significantly worse recurrence free survival and overall survival than other 51 patients (p=0.0059 and p=0.0077). [Conclusion]RT enhances the tissue expression of CD73, which can provide large amounts of adenosine in irradiated tumor tissue and may seriously suppress the local immune response and impair the response against RT. Our results suggest that functional blockade of CD73 can enhance not only direct but also abscopal effects of RT possibly through T cell activations, which may improve the outcome of the patients with advanced rectal cancer. Citation Format: Hidenori Tsukui, Hisanaga Horie, Akira Saito, Koji Koinuma, Hideyuki Ohsawa, Hironori Yamaguchi, Yasunaru Sakuma, Yoshinori Hosoya, Kotaro Yoshimura, Alan Lefor, Naohiro Sata, Joji Kitayama. CD73 targeting therapy enhances the anti-tumor effect of radiation therapy in rectal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2258.

Research Progress and Existing Problems for Abscopal Effect.

Radiation therapy plays a vital role in the treatment of tumours. In particular, the occurrence of the “abscopal effect” brings about a favourable turn for the treatment of patients with advanced metastatic malignant tumours. Because of the abscopal effect, non-irradiated areas are also treated. However, the abscopal effect occurs by chance, not through seeking. Although the abscopal effect has been studied enthusiastically, the desired result does not appear to be achieved. Moreover, its combination with immunotherapy appears to be overwhelming. There is an opinion that abscopal effect is difficult to achieve by irradiation of a single tumour, and irradiation of multiple or total lesions is advocated to increase the possibility of obtaining clinically meaningful outcomes. Obviously, there are still questions about the mechanism, condition and possibility underlying the occurrence of the abscopal effect. Can the abscopal effect truly change the future treatment strategy as the researchers expect? What are the current problems? This article reviewed the research in recent years to explore the progress and controversy surrounding the abscopal effect of radiation therapy.

Amplifying an abscopal effect of radiation therapy with a novel immunotherapeutic agent

Abstract Radiation therapy (RT) is one of the primary treatment modalities for head and neck squamous cell carcinoma (HNSCC). At the time of diagnosis two-thirds of HNSCC patients have local-advanced disease and 50–60% of these patients will experience a local-regional or metastatic relapse within three years. Improving the immunogenic response of RT may help address this clinical problem. However, current RT regiments have failed to reliably generate robust antitumor immunity as evidenced by the rarity of clinical abscopal responses. Recently we engineered a chimeric fusion molecule called Flagrp170, a novel immunostimulatory agent highly capable of promoting antigen presentation and T-cell activation. We hypothesize that the combination of RT and Flagrp170 provides superior immunogenic signals producing effective and durable antitumor immunity against HNSCC. We report that administration of Flagrp170 to the tumor sites upon RT using a small animal radiation research platform (SARPP) results in potent activation of antigen-presenting cells, increased functionality of tumor-infiltrating T-cells, and systemic immune augmentation, when compared to either monotherapy. Additionally, the combination treatment is able to reduce the dose of RT required for tumor control and protects previously cured animals from subsequent tumor re-challenge. Finally, the combination treatment can successfully control the contralateral untreated tumors, supporting the superior activity of Flagrp170 in potentiating abscopal responses of RT. Our data suggest that the Flagrp170 may be used to enhance immunogenic cancer cell death in RT and resultant protective antitumor immunity can potentially help reduce post-RT recurrence of HNSCC.

Pure abscopal effect of radiotherapy in a salivary gland carcinoma: Case report, literature review, and a search for new approaches

We report the case of an 84-year-old woman with poorly differentiated non-small cell carcinoma of the right parotid who presented with headache, was found to have a primary right parotid gland cancer as well as metastatic disease, and underwent palliative radiotherapy to the primary site. The patient received no chemotherapy or immunotherapy, but both the primary site and several non-irradiated foci in the lungs regressed or completely resolved. The patient remained free of disease for about one year before progression. The case is a rare instance of abscopal regression of metastatic disease in the absence of pharmacologic immunomodulation. A literature review surveys the history of the abscopal effect of radiation therapy, attempts to understand the mechanisms of its successes and failures, and points to new approaches that can inform and improve the outcomes of radioimmunotherapy.

Abscopal effect of radiation therapy in monotherapy in a patient with malignant melanoma

Abscopal effect of radiation therapy in monotherapy in a patient with malignant melanoma

The systemic immunostimulatory effects of radiation therapy producing overall tumor control through the abscopal effect

Emerging studies show that radiation therapy produces an important out of field (distant) effect known as the ‘‘abscopal effect” in nonirradiated tumor sites. The objective of this study was to provide an overview of the current state of knowledge and clinical experience of radiation therapy producing abscopal effects in the management of different types of malignant diseases. Peer-reviewed published clinical evidence on the abscopal effect of radiation therapy was collected using electronic databases such as Medline via PubMed and Google Scholar. The reference lists were searched in the publications that we obtained in an attempt to find additional relevant publications. Non-indexed peer-reviewed journals were manually searched and relevant information was extracted. The search was restricted to English language articles. The clinical data on the abscopal effect of radiation therapy were reviewed and the outcomes have been summarized. Currently, only clinical case reports and anecdotes have slowly converted into solid clinical data and interest is building in the field of radiation therapy, specifically on how local radiation can produce the abscopal effects for the management of different types of malignant tumors. Extensive clinical evidence suggests that the radiation therapy induced abscopal antitumor effects are mediated by immune cells such as the T-lymphocytes. This forms a basis for using radiation therapy in combination with immunotherapy to augment the abscopal response rates in cancer patients. Current evidence demonstrates that radiation therapy induces abscopal responses across many tumor types. Together, the clinical outcomes from published reports suggest that localized radiation therapy is capable of inducing abscopal effects in a wide variety of malignant tumors. With the advent of novel immunotherapies, the potential for immune activation by radiation defines a novel role for radiation therapy in the treatment of systemic disease. A clinical consideration of the abscopal effects produced by radiation therapy could lead to a revolutionary change in the current management of patients including radiation treatment strategies and immunotherapies for various malignant tumors.

Abscopal effect of radiation on lymph node metastasis in esophageal carcinoma: A case report and literature review.

The Abscopal effect is a rare phenomenon observed in the treatment of metastatic cancer, where localized irradiation causes a response in non-irradiated tumor sites. Due to the recent success of immunotherapies, the Abscopal effect of radiation therapy has received renewed clinical interest. However, there is limited knowledge regarding the Abscopal effect and radiotherapy treatment of patients with esophageal carcinoma. The present study reports the case of a 65-year-old male patient, who presented with esophageal carcinoma and lymph node metastasis. A transthoracic esophagectomy with left cervical, mediastinal and abdominal lymphadenectomies was performed. A total of 4 cycles of chemotherapy and maintenance therapy with Pembrolizumab was performed until September 2016. Metastases in the left retroperitoneal lymph node in addition to extensive metastases to the pelvic lymph node were observed. The patient received Cyberknife radiotherapy with a dose of 42 Gy in 6 daily fractions targeted at the left retroperitoneal lymph node. Two months after radiation therapy, a positron emission tomography-computed tomography scan revealed complete regression of all lymph node metastases. There is increasing clinical evidence supporting the efficacy of the Abscopal effect, which may be initiated by high-dose radiation. Further research is required to make the Abscopal effect clinically relevant, however it may have potential as a treatment option.

Combinatorial strategies of radiotherapy and immunotherapy in nasopharyngeal carcinoma.

Immunotherapy and radiation therapy (RT) have each demonstrated clinical success in the treatment of nasopharyngeal carcinoma (NPC) when utilized independently. Several characteristics of NPC make it particularly well suited for immunotherapeutic strategies, such as the association with viral infections like EBV and human papilloma virus (HPV), upregulation of PD-L1 expression, and the high number of tumor infiltrating lymphocytes. Immune checkpoint blockade is one such immunotherapeutic strategy that is gaining popularity rapidly. However, clinical benefit of immunotherapy using immune checkpoint inhibitors has been limited to only a small subset of patients with existing T cell responses. Additionally, they are frequently associated with dose-limiting immune-related toxicities. On the other hand, RT is a conventional strategy for NPC treatment, which has demonstrated high efficacy in local tumor control and has also been reported to exhibit immune modulatory effects. However, the abscopal effect of RT alone, i.e., the regression of distant metastases outside of the irradiation field, remains a rare phenomenon. Furthermore, RT treatment efficacy is also limited by radioresistance and radiation-related toxicities. Hence, the combination of RT and immunotherapy has the potential to improve treatment efficacy over either individual therapies alone. Here, we reviewed the clinical problem in locally advanced and recurrent/metastatic NPC, and discussed how combinatorial RT and immunotherapeutic strategies can be relevant to NPC treatment in each clinical scenario by examining the underlying mechanisms involved in the different strategies.

Implications of the Bystander and Abscopal Effects of Radiation Therapy.

Siva and colleagues have demonstrated that localized thoracic radiation resulted in DNA damage at out-of-field sites. Although these interesting findings require validation, we discuss the important clinical implications of these data, especially in the era of immune therapies. Clin Cancer Res; 22(19); 4763-5. ©2016 AACRSee related article by Siva et al., p. 4817.

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.

Abstract 3938: Localized synchrotron radiation affects serum cytokine levels and modulates gene expression in irradiated mouse skin and in skin distant from the irradiated site

Abstract Synchrotron radiation has great potential to improve cancer radiotherapy, a major cancer treatment received by about 50% cancer patients annually. A new synchrotron-based modality, microbeam radiotherapy (MRT), has shown promise for cancer treatment. MRT utilizes high intensity X-rays collimated to planar microbeams 25 μm-wide and with 200 μm period. MRT effectively ablates tumours but causes less damage to normal tissues compared to conventional broadbeam (BB) radiotherapy techniques. Little is known about the mechanisms underlying this remarkable result. We initiated a study of systemic (“abscopal”, “distant bystander”) effects1,2 of MRT and BB irradiation in C57BL/6J mice. Skin areas (2x2 and 8x8 mm) were irradiated with 10 or 40 Gy, and blood and skin samples were collected at 24 and 96 hours post-irradiation. Serum levels of pro-inflammatory cytokines known to be induced by radiation or to mediate the bystander effect, were measured. In parallel, gene expression was measured in irradiated and non-irradiated skin using real time PCR. Statistically significant changes were identified for known radiation responsive genes in both targeted and non-targeted dermal tissue after both BB and MRT treatments. Down-regulation of some genes in distant skin that were up-regulated at the site of irradiation were identified in an apparent contrasting response between these two sets of tissues. Also, the expression for some genes showed differences between MRT and BB-treated mice. MRT-specific bystander responses were also observed in distant tissue, including gene expression of TP53 for which the protein product has a fundamental role in cell fate. Levels of various cytokines in the serum were also altered in response to both BB and MRT. In some cases, the cytokine response was different for MRT compared to BB-treated samples which could potentially explain the benefits of MRT. These results advance the understanding of the biological responses to synchrotron-generated radiation and provide a potential mechanism for MRT.

Abscopal effect of radiation therapy: Interplay between radiation dose and p53 status

Purpose: This study investigates whether the abscopal effect induced by radiation-therapy (RT) is able to sterilize non-irradiated tumour cells through bystander signals.Material and methods: Wild-type (wt)-p53 or p53-null HCT116 human colon cancer cells were xenografted into both flanks of athymic female nude mice. When tumours reached a volume of 0.2 cm3, irradiation was performed, under strict dose monitoring, with a dedicated mobile accelerator designed for intra-Operative-RT (IORT). A dose of 10 or 20 Gy (IR groups), delivered by a 10 MeV electron beam, was delivered to a tumour established in one side flank, leaving the other non-irradiated (NIR groups). A subset of mice were sacrificed early on to carry out short-term molecular analyses.Results: All directly-irradiated tumours, showed a dose-dependent delayed and reduced regrowth, independent of the p53 status. Importantly, a significant effect on tumour-growth inhibition was also demonstrated in NIR wt-p53 tumours in the 20 Gy-irradiation group, with a moderate effect also evident after 10 Gy-irradiation. In contrast, no significant difference was observed in the NIR p53-null tumours, independent of the dose delivered. Molecular analyses indicate that p53-dependent signals might be responsible for the abscopal effect in our model system, via a pro-apoptotic pathway.Conclusions: We suggest that the interplay between delivered dose and p53 status might help to sterilize out-of-field tumour cells.

Abscopal effects of radiation therapy: A clinical review for the radiobiologist

An “abscopal” effect occurs when localized irradiation perturbs the organism as a whole, with consequences that can be either beneficial or detrimental. Mechanistic explanations of this effect are challenging. From the oncologist’s perspective, the term refers to distant tumor regression after localized irradiation. On the other hand, from a biologist’s point of view, abscopal effects include induction of genomic instability, cell death, and oncogenic transformation in normal tissues. This conceptual dichotomy is explored in this review, with a focus on clinically documented cases of anti-tumor abscopal effects and abscopal effects in normal tissues. This review also outlines several suggested mechanisms for abscopal effects.

Abscopal Effect of Radiation Therapy and Signal Transduction

Abscopal Effect of Radiation Therapy and Signal Transduction