Background
Authors | Years | Tumors | Numbers of cases | Immunotherapy | RT | Sequence of RT and immunotherapy | Occurrence of abscopal effect |
---|---|---|---|---|---|---|---|
Roger et al. [157] | 2018 | Melanoma | 25 | Anti-PD-1 (pembrolizumab, 2 mg/kg/3 weeks or nivolumab, 3 mg/kg/2 weeks) | 26 Gy/3–5 fractions | Concurrent and post-radiation | Observed |
Formenti et al. [135] | 2018 | Metastatic breast cancer | 23 | Anti-TGFβ (fresolimumab,1 mg/kg/3 weeks or 10 mg/kg/3 weeks) | 22.5 Gy/3 fractions | Concurrent | Observed |
Rodríguez-Ruiz et al. [136] | 2018 | Advanced cancer | 15 | DC vaccination and TLR-3 agonist | Stereotactic ablative RT | Concurrent | Observed |
Aboudaram et al. [130] | 2017 | Melanoma | 17 | Anti-PD-1 (pembrolizumab, 2 mg/kg/3 weeks or nivolumab, 3 mg/kg/3 weeks) | 30 Gy/10 fractions | Concurrent | Observed |
Theurich et al. [158] | 2016 | Melanoma | 45 | Anti-CTLA-4 (ipilimumab, 3 mg/kg/3 weeks) | SBRT | Concurrent and post-radiation | Observed |
Koller et al. [119] | 2016 | Melanoma | 70 | Anti-CTLA-4 (ipilimumab, 3 mg/kg/3 weeks) | Conventional external beam radiation and stereotactic radiosurgery | Concurrent | Observed |
Twyman-Saint et al. [145] | 2015 | Melanoma | 22 | Anti-CTLA-4 (ipilimumab) | Lung/bone 8 Gy × 2 or 8 Gy × 3 Liver/subcutaneous 6 Gy × 2 or 6 Gy × 3 | RT before ipilimumab | Observed |
Golden et al. [107] | 2015 | Metastatic solid tumors | 41 | GM-CSF (125 μg/m2/2 weeks) | 35 Gy/10 fractions | Concurrent | Observed |
Grimaldi et al. [118] | 2014 | Melanoma | 21 | Anti-CTLA-4 (ipilimumab, 3 mg/kg/3 weeks) | RT of brain metastasis or extracranial sites | RT after ipilimumab | Observed |
Hwang et al. [159] | 2018 | Metastatic lung cancer | 164 | Anti-PD-1/PD-L1 | Thoracic RT | RT before or after immunotherapy | Non-observed |
Shaverdian et al. [129] | 2017 | NSCLC | 97 | Anti-PD-1 (pembrolizumab, 2 mg/kg/3 weeks, 10 mg/kg/3 weeks, or 10 mg/kg/3 weeks) | Extracranial radiotherapy and thoracic radiotherapy | Ipilimumab after RT | Non-observed |
Kropp et al. [160] | 2016 | Melanoma | 16 | Anti-CTLA-4 (ipilimumab, 3 mg/kg/3 weeks) | SBRT | RT after ipilimumab | Non-observed |
Levy et al. [133] | 2016 | Metastatic tumors | 10 | Anti-PD-L1 (durvalumab, 10 mg/kg/3 weeks) | 28 Gy/5 fractions (median) | Concurrent | Non-observed |
Kwon et al. [121] | 2014 | Castration-resistant prostate cancer | 799 | Anti-CTLA-4 (ipilimumab, 10 mg/kg/3 weeks) | 8 Gy/target bone lesion | Ipilimumab after RT | Non-observed |
Slovin et al. [120] | 2013 | Castration-resistant prostate cancer | 50 | Anti-CTLA-4 (ipilimumab, 10 mg/kg/3 weeks) | 8 Gy/target bone lesion | Concurrent | Non-observed |
RT reprograms the tumor microenvironment
Radiation-induced release of cytokines and chemokines
Radiation-induced infiltration of leukocytes
Radiation-induced increased susceptibility of tumor cells
Effect of RT | Pro-immunogenic | Anti-immunogenic |
---|---|---|
Cytokine secretion | IFN I | TGF-β |
IFN II | CSF-1 | |
IL-1β | IL-6 | |
IL-18 | IL-10 | |
Chemokine secretion | CXCL9 | CXCL12 |
CXCL10 | ||
CXCL16 | ||
Leukocyte infiltration | DCs | MDSCs |
Effector T cells | Treg cells | |
M1 macrophages | M2 macrophages | |
Signal molecule expression | MHC-I | PD-L1 |
STING | Trex 1 | |
Fas |
Anti-tumor immune effects of RT: from local to abscopal
RT generates in situ vaccination
Immunotherapy enhances the systemic anti-tumor response of RT
CTLA-4 and CTLA-4 blockade
PD-1/PD-L1 and PD-1/PD-L1 blockade
Other agents
ClinicalTrials.gov identifier | Phase | Conditions | Drug classification | Interventions | Sponsors |
---|---|---|---|---|---|
NCT01996202 | Phase 1 | Melanoma | CTLA-4 inhibitors | Ipilimumab with radiation therapy | Duke University |
NCT02642809 | Phase 1 | EC | PD-1 inhibitors | Pembrolizumab with brachytherapy (16 Gy in 2 fractions) | Washington University School of Medicine |
NCT02837263 | Phase 1 | Colorectal cancer | PD-1 inhibitors | Pembrolizumab with SBRT (40–60 Gy in 5 fractions) | University of Wisconsin, Madison |
NCT02587455 | Phase 1 | Thoracic tumors | PD-1 inhibitors | Arm I: pembrolizumab with low-dose radiation therapy Arm II: pembrolizumab with high-dose radiation therapy | Royal Marsden NHS Foundation Trust |
NCT03151447 | Phase 1 | TNBC | PD-L1 inhibitors | JS001 with SBRT | Fudan University |
NCT02868632 | Phase 1 | Pancreatic cancer | PD-L1 and CTLA-4 inhibitors | Durvalumab or/and tremelimumab with SBRT (30 Gy in 5 fractions) | New York University School of Medicine |
NCT03275597 | Phase 1 | NSCLC | PD-L1 and CTLA-4 inhibitors | Durvalumab and tremelimumab with SBRT (30–50 Gy in 5 fractions) | University of Wisconsin, Madison |
NCT02239900 | Phase 1/2 | Liver cancer, lung cancer | CTLA-4 inhibitors | Ipilimumab with SBRT | M.D. Anderson Cancer Center |
NCT03050554 | Phase 1/2 | NSCLC | PD-L1 inhibitors | Avelumab with SBRT (48 Gy in 4 fractions or 50 Gy in 5 fractions) | Andrew Sharabi |
NCT02696993 | Phase 1/2 | Brain metastases (NSCLC) | PD-1 and CTLA-4 inhibitors | Arm I: nivolumab with stereotactic radiosurgery Arm II: nivolumab with whole brain radiation therapy Arm III: nivolumab and ipilimumab with stereotactic radiosurgeryArm IV: nivolumab and ipilimumab with whole brain radiation therapy | M.D. Anderson Cancer Center |
NCT01970527 | Phase 2 | Melanoma | CTLA-4 inhibitors | Ipilimumab with SBRT | University of Washington |
NCT02609503 | Phase 2 | Head and neck cancer | PD-1 inhibitors | Pembrolizumab with radiation therapy | UNC Lineberger Comprehensive Cancer Center |
NCT02730130 | Phase 2 | Metastatic breast cancer | PD-1 inhibitors | Pembrolizumab with radiation therapy | Memorial Sloan Kettering Cancer Center |
NCT02992912 | Phase 2 | Metastatic tumors | PD-L1 inhibitors | Atezolizumab with SBRT (45 Gy in 3 fractions) | Gustave Roussy, Cancer Campus, Grand Paris |
NCT03122509 | Phase 2 | Metastatic colorectal cancer | PD-L1 and CTLA-4 inhibitors | Tremelimumab and durvalumab with radiation therapy | Memorial Sloan Kettering Cancer Center |
NCT02888743 | Phase 2 | Colorectal cancer and NSCLC | PD-L1 and CTLA-4 inhibitors | Arm I: tremelimumab and durvalumab Arm II: tremelimumab and durvalumab with high-dose radiation therapy Arm III: tremelimumab and durvalumab with low-dose radiation therapy | National Cancer Institute (NCI) |
NCT02701400 | Phase 2 | Recurrent SCLC | PD-L1 and CTLA-4 inhibitors | Arm I: tremelimumab and durvalumab Arm II: tremelimumab and durvalumab with SBRT | Emory University |
NCT02617589 | Phase 3 | Brain Cancer | PD-1 inhibitors | Arm I: nivolumab with radiation therapy Arm II: temozolomide with radiation therapy | Bristol-Myers Squibb |
NCT02768558 | Phase 3 | NSCLC | PD-1 inhibitors | Cisplatin and etoposide plus radiation followed by nivolumab | RTOG Foundation, Inc. |