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Mireștean, C.C.;  Iancu, R.I.;  Iancu, D.T. Immunotherapy and Radiotherapy. Encyclopedia. Available online: (accessed on 11 December 2023).
Mireștean CC,  Iancu RI,  Iancu DT. Immunotherapy and Radiotherapy. Encyclopedia. Available at: Accessed December 11, 2023.
Mireștean, Camil Ciprian, Roxana Irina Iancu, Dragoș Teodor Iancu. "Immunotherapy and Radiotherapy" Encyclopedia, (accessed December 11, 2023).
Mireștean, C.C.,  Iancu, R.I., & Iancu, D.T.(2022, November 18). Immunotherapy and Radiotherapy. In Encyclopedia.
Mireștean, Camil Ciprian, et al. "Immunotherapy and Radiotherapy." Encyclopedia. Web. 18 November, 2022.
Immunotherapy and Radiotherapy

Immunotherapy, the modern oncological treatment with immune checkpoint inhibitors (ICIs), has been part of the clinical practice for malignant melanoma for more than a decade. Anti-cytotoxic T-lymphocyte antigen 4 (CTLA4), anti-programmed cell death Protein 1 (PD-1), or anti programmed death-ligand 1 (PD-L1) agents are currently part of the therapeutic arsenal of metastatic or relapsed disease in numerous cancers; more recently, they have also been evaluated and validated as consolidation therapy in the advanced local stage. The combination with radiotherapy, a treatment historically considered loco-regional, changes the paradigm, offering—via synergistic effects—the potential to increase immune-mediated tumor destruction.

radiotherapy immunotherapy abscopal synergy

1. The Effect of Radiotherapy on the Antitumor Immune Response

Historically, radiotherapy was considered to induce cell death by producing double-stranded DNA damage, the mechanisms involved being multiple (apoptosis, mitotic catastrophe, and senescence). Following the destruction of malignant cells by irradiation, a series of products result that trigger reactions of the immune system with both stimulatory and suppressive effects. The presentation of the tumor antigen mediated by irradiation has the effect of activating dendritic cells (DCs), increasing the degree of lymphocyte infiltration of the tumor, but also control cell signaling [1][2][3]. Irradiation also has the effect of cross-presentation of the antigen to T cells via DCs and the secretion of inflammatory cytokines. Irradiation has the ability to modulate the expression of interferon 1 (IFN-I), resulting in the activation of CD8+ lymphocytes. Chemokines (C-X-C motif) ligand 10 (CXCL10) and CXCL16 and vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule (ICAM), vascular adhesion molecules, are also modulated by irradiation and participate in the process of tumor detachment from the substrate, invasion, and metastasis. By upregulating the FAS pathway by irradiation and by the induction of sub-lethal DNA lesions the tumoricidal action of CD8 improves, mediating apoptosis by caspases (3, 6, and 7). Thus, the signaling mechanisms are also involved in the tumor response to irradiation. The upregulation of FAS ligand (FAS-L) on endothelial cells could have the final effect of T-lymphocyte death and could promote tumor growth and immunosuppression, blocking cytotoxic T-lymphocyte activation and maturation. The induction of an immunosuppressive microenvironment by irradiation is also potentiated by the recruitment of regulatory T cells (Tregs), tumor associated macrophages (TAMs), and myeloid derived suppressor cells (MDSCs). The recruitment of MDSCs is mediated by neo-angiogenesis via Hypoxia-Inducible Factor-1 (HIF-1). Thus, irradiation should be seen as a treatment with a double effect: potentiation of the immune antitumoral effect and immunosuppression. Identifying the best strategies that will exploit the antitumor effect and limit tumor growth is the goal of present and future research [4][5]. The extracellular matrix (ECM) is more rigid in tumor cells; stiffness and density are associated with unfavorable prognosis, tumor aggressiveness, unfavorable response to treatment, and especially to irradiation. Radiotherapy also has the property of altering the mechanical properties of the ECM [4][5].

2. Immunotherapy–Radiotherapy: Treatment Sequence

Data from the phase III PACIFIC trial, a study in which immunotherapy with durvalumab was administered as maintenance after chemoradiotherapy for patients with unresectable stage III lung cancer, showed impressive results in survival. The initiation of durvalumab within the first 14 days after completion of radiotherapy was associated with a greater survival benefit than the initiation of immunotherapy between 14 and 42 days after irradiation [6]. A subsequent exploratory analysis of the PACIFIC trial data demonstrated a durable response with OS and PFS rates of 49.6% and 35.3% at 4 days of treatment for patients randomized to the durvalumab booster chemoradiotherapy and immunotherapy arm [6][7]. Data from the KEYNOTE-01 trial demonstrate a long-term interaction between radiotherapy and immunotherapy after an initial interaction on days 2–7. An updated analysis of the KEYNOTE-001 clinical trial data proposed by Shaverdian et al. mentions clearly superior treatment results for patients who previously received radiotherapy. A superior PFS and OS (6.3 months and 11.6 months) was obtained for the cases that had a history of irradiation, compared to a PFS of 2 months and an OS of 5.3 months for the cases without previous radiotherapy. A massive abscopal effect with release of non-antigens and tumor exposure to the immune response was the possible explanation proposed by Liu and collaborators [8][9][10].
Data regarding stereotactic radiosurgery (SRT) in a preclinical model did not show benefit in the case of using a single dose of 10Gy before the start of immunotherapy. Vascular permeability has been used as a surrogate marker for tumor immune activation in preclinical models. An increase in this biomarker was recorded after the first 24 hours after irradiation, and after 3-10 days a reduction to the baseline level was observed [11]. A study that combined immunotherapy with CTLA-4 inhibitors in malignant melanoma with brain metastases showed better results in OS if single-fraction stereotactic radiosurgery (SRS) was performed before ipilimumab administration or concomitantly, relative to the situation in which immunotherapy was initiated before irradiation. The study also highlights a slight tendency towards a benefit of the concurrent administration of radiosurgery and immunotherapy [12][13][14].
The concept of synergy of chemotherapy and immunotherapy plus concurrent radiotherapy is exploited in a study (NIRVANA-Lung) ( identifier, NCT03774732). The trial is based on the results of two randomized Phase II studies that demonstrate the concept that concurrent irradiation with pembrolizumab significantly improves the therapeutic benefit in terms of survival compared to immunotherapy alone. The study includes both squamous and non-squamous advanced NSCLC cancers. The NIRVANA-Lung randomized trial is considered the first phase III trial of concurrent RT and pembrolizumab associated with chemotherapy [15]. RTOG 3505, another randomized phase III study, evaluated the combination of concurrent chemoradiation followed by immunotherapy in cases of locally advanced NSCLC. The proposed chemotherapy protocol includes cisplatin and etoposide and radiotherapy in a total dose of 60Gy, and the group that will receive active treatment with nivolumab 240 mg I.V. every 2 weeks for up to 1 year. The aim of the study is to evaluate OS and PFS, but also the quality of life and the toxicity profile in relation to the PD-L1 status, considering the 1% value as the cutoff. The study aims to randomize a total number of 550 patients [16].
The NICOLAS study coordinated by Peters et al. was the first completed phase II study to evaluate the safety and then the efficacy of the addition of pembrolizumab to platinum-based chemotherapy and concurrent radiotherapy for a total dose of 66 Gy in 33 fractions. The study included 74 patients with stage III NSCLC. The median OS rate at 2 years was a median OS of 63.7%, with stage IIIA associated with an OS of 81% and stage IIIB with an OS of 56%. A PFS value of at least 45% in one demonstrates the efficacy of the regimen, even if the final OS and PFS data are higher for other studies involving the same stages of the disease [17].
For advanced NSCLC cases (stage II–III unresectable or inoperable) with PD-L1 expression > 50%, the NRG-LU004 trial proposed replacing chemotherapy with immunotherapy (1500 mg durvalumab) concurrently with radiotherapy. Immunotherapy was administered once a month for 1 year and accelerated fractionated radiotherapy (ACRT) at 60 Gy in 15 fractions and 60 Gy in 30 fractions followed by a safety hold of 90 and 60 days, respectively. All 13 cycles of immunotherapy were completed by 24% of patients and grade III toxicities were identified in both groups. The deaths in each arm were not related to therapy. A regimen that replaces chemotherapy with concurrent immunotherapy with durvalumab for cases with high PD-L1 values is feasible, as it is necessary to validate the regimen in phase II and III trials [18].


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  16. Gerber, D.E.; Urbanic, J.J.; Langer, C.; Hu, C.; Chang, I.F.; Lu, B.; Movsas, B.; Jeraj, R.; Curran, W.J.; Bradley, J.D. Treatment Design and Rationale for a Randomized Trial of Cisplatin and Etoposide Plus Thoracic Radiotherapy Followed by Nivolumab or Placebo for Locally Advanced Non-Small-Cell Lung Cancer (RTOG 3505). Clin. Lung Cancer 2017, 18, 333–339.
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Subjects: Oncology
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