Abscopal Effects in Radio-Immunotherapy—Response Analysis of Metastatic Cancer Patients With Progressive Disease Under Anti-PD-1 Immune Checkpoint Inhibition

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.

Immune checkpoint pathways in immunotherapy for head and neck squamous cell carcinoma

“…It is estimated that more than 50% of patients with solid tumours receive radiotherapy (RT), which has an advantage over chemotherapy in that it limits systemic toxicity. 85 In combination with immune checkpoint inhibitors, RT normalizes the tumour vascular system, enhances the expression of leukocyte adhesion molecules on endothelial cells, and results in secretion of CD8 + T-attracting chemokines. RT triggers immunogenic cell death by inducing cell surface exposure of calreticulin (CALR) and ATP secretion via autophagy and IFN-I-induced upregulation of MHC-I, HSP70 exposure, TLR3 signal, high-mobility group box 1 (HMGB1) release and IL-1β release.…”

Boosting the Immune Response with the Combination of Electrochemotherapy and Immunotherapy: A New Weapon for Squamous Cell Carcinoma of the Head and Neck?

“…In addition to the capability of maximizing the volume reduction of symptomatic lesions, local treatments can also boost the immunogenicity of the tumor, by increasing the release of TAA, and thus stimulating a systemic response against distant nodules. This phenomenon, known as the “abscopal” effect, was described for the first time in association with radiation therapy [ 56 ], but the same mechanism is valid also for ECT. In fact, both radiotherapy and ECT are able to induce ICD and thus to boost the immune response against cancer.…”

Editorial Comment from Dr Yuasa to Possible abscopal effect after discontinuation of nivolumab in metastatic renal cell carcinoma

“…1 Although the precise mechanism of the abscopal effect remains unclear, an increasing number of reports in the current immune checkpoint inhibitor era support the hypothesis that activation of the immune system as well as modulation of the tumor microenvironment by radiation and immune checkpoint inhibitor therapies definitely play important roles in the abscopal effect. 2 In this issue of IJU Case Reports, Nakajima et al reported a possible abscopal effect of radiation therapy after discontinuation of nivolumab in mRCC. 3 In this report, a patient with mRCC of International mRCC Database Consortium intermediate risk underwent targeted therapy using pazopanib, axitinib, and everolimus.…”