Abstract
Immune checkpoint inhibition (ICI) targeting the programmed death receptor 1 (PD-1) has shown promising results in the fight against cancer. Systemic anti-tumor reactions due to radiation therapy (RT) can lead to regression of non-irradiated lesions (NiLs), termed “abscopal effect” (AbE). Combination of both treatments can enhance this effect. The aim of this study was to evaluate AbEs during anti-PD-1 therapy and irradiation. We screened 168 patients receiving pembrolizumab or nivolumab at our center. Inclusion criteria were start of RT within 1 month after the first or last application of pembrolizumab (2 mg/kg every 3 weeks) or nivolumab (3 mg/kg every 2 weeks) and at least one metastasis outside the irradiation field. We estimated the total dose during ICI for each patient using the linear quadratic (LQ) model expressed as 2 Gy equivalent dose (EQD2) using α/β of 10 Gy. Radiological images were required showing progression or no change in NiLs before and regression after completion of RT(s). Images must have been acquired at least 4 weeks after the onset of ICI or RT. The surface areas of the longest diameters of the short- and long-axes of NiLs were measured. One hundred twenty-six out of 168 (75%) patients received ICI and RT. Fifty-three percent (67/126) were treated simultaneously, and 24 of these (36%) were eligible for lesion analysis. AbE was observed in 29% (7/24). One to six lesions (mean = 3 ± 2) in each AbE patient were analyzed. Patients were diagnosed with malignant melanoma (MM) (n = 3), non-small cell lung cancer (NSCLC) (n = 3), and renal cell carcinoma (RCC) (n = 1). They were irradiated once (n = 1), twice (n = 2), or three times (n = 4) with an average total EQD2 of 120.0 ± 37.7 Gy. Eighty-two percent of RTs of AbE patients were applied with high single doses. MM patients received pembrolizumab, NSCLC, and RCC patients received nivolumab for an average duration of 45 ± 35 weeks. We demonstrate that 29% of the analyzed patients showed AbE. Strict inclusion criteria were applied to distinguish the effects of AbE from the systemic effect of ICI. Our data suggest the clinical existence of systemic effects of irradiation under ICI and could contribute to the development of a broader range of cancer treatments.
Highlights
In addition to radiation therapy (RT), chemotherapy (CTX), and surgery, immunotherapy (IT) has been established as a fourth pillar of cancer treatment
Fifty-four percent were diagnosed with malignant melanoma, 29% with non-small cell lung cancer, and 13 and 4% with renal cell carcinoma (RCC) and head and neck cancer (H&N), respectively
Local RT is considered to induce immunogenic cell death (ICD) associated with antigen release, cytokine production, and complement activation, leading to immune responses, and to a tumor vaccination (Formenti and Demaria, 2012; Frey et al, 2014; Barker et al, 2015). Mechanisms such as increasing the expression of the major histocompatibility complex (MHC) class I, activating dendritic cells, enhancing the presentation of tumor antigens and the migration of immune cells into the tumor micromilieu, which leads to an increase of tumorinfiltrating lymphocyte density with a broader T-cell receptor repertoire, improved effector T cell activity, and modulation of TReg cells and immune checkpoint molecule expression may contribute to improved systemic immune response after local radiotherapy (Demaria and Formenti, 2009; Formenti and Demaria, 2012)
Summary
In addition to radiation therapy (RT), chemotherapy (CTX), and surgery, immunotherapy (IT) has been established as a fourth pillar of cancer treatment. More than 50% of all patients with solid tumors are treated with RT only or in a combined treatment setting. In metastatic malignant melanoma (MM), anti-PD1 therapy has been proven as superior treatment to chemotherapy as first-line therapy and after ipilimumab (anti-CTLA-4 antibody) failure (Ribas et al, 2015; Weber et al, 2015) and in non-small cell lung cancer (NSCLC) patients after progression to first-line chemotherapy (Vokes et al, 2018). Not all patients benefit from treatment with ICIs, and different systemic therapies are less effective if the tumor does not contain a mutation that can be targeted. Looking for further treatment strategies, the combination of local irradiation, and ICIs led to promising results even beyond local tumor control (Kang et al, 2016; Salama et al, 2016). The socalled abscopal effect (AbE) describes the regression of lesions or tumor or metastatic regions outside the radiation field induced by radiation
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