Table II.
Summary of pre-clinical studies combining ionizing radiation and immune checkpoint blockade in syngeneic mouse models of cancer.
| Title and reference | Authors | Journal | Year | Model | IR | ICB | Results |
|---|---|---|---|---|---|---|---|
| Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody23 | Dewan et al. | Clin Cancer Res. | 2009 | TSA, MC38 | 20Gy × 1, 8Gy × 3, 6Gy × 5 | CTLA-4 mAb | Best tumor control with 8Gyx3+CTLA-4 mAb; abscopal control of distant tumor only observed with 8Gyx3+CTLA-4 mAb |
| Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer | Demaria et al. | Clin Cancer Res. | 2005 | 4T1 | 12Gy × 1 | CTLA-4 mAb | Combo significantly enhanced survival of 4T1 tumor-bearing mice and slowed formation of lung metastases |
| Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice | Deng et al. | J Clin Invest. | 2014 | TUBO, MC38 | 12Gy × 1 | PD-L1 mAb | Combo significantly enhanced survival of TUBO or MC38 tumor-bearing mice; CD8+ cell dependent |
| Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas | Zeng et al. | Int J Radiat Oncol Biol Phys. | 2013 | GL261 | 10Gy × 1 | PD-1 mAb | Combo significantly enhanced survival of GL261 intracranial tumor-bearing mice; cured mice rejected challenge with original cell line indicating immunologic memory |
| Abscopal effects of radiotherapy are enhanced by combined immunostimulatory mAbs and are dependent on CD8 T cells and cross-priming | Rodriguez-Ruiz et al. | Cancer Res. | 2016 | MC38, 4T1, B16-OVA | 8Gyx3 | PD-1 mAb and 41BB mAb | Combo significantly reduced primary tumor growth; combo resulted in abscopal control of distant tumors; abscopal effect was CD8+ cell dependent; abscopal effect dependent on type I IFN signaling and DCs |
| Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade | Dovedi et al. | Cancer Res. | 2014 | CT26, 4434, 4T1 | 2Gy × 5 | PD-1 mAb or PD-L1 mAb | Combo induced rejection in 66–80% of tumor-bearing mice, concurrent treatment needed for result; result CD8+ cells and IFNγ dependent |
| Suppressing T cell motility induced by anti-CTLA-4 monotherapy improves antitumor effects | Ruocco et al. | J Clin Invest. | 2012 | 4T1 | 12Gy × 2 | CTLA-4 mAb | Combo enhanced primary tumor growth control; dependent upon arrest of TIL within tumor in an MHC class I and ICAM dependent fashion |
| Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. | Twyman-Saint Victor, et al. | Nature | 2015 | B16–F10, TSA, PDA.4662 | 20Gyx1, 8Gyx3 | CTLA-4 mAb and PD-1 mAb | The addition of PD-1 mAb to IR plus CTLA-4 significantly enhanced tumor growth control and rates of tumor rejection |
| DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity | Vanpouille-Box, et al. | Nat Commun | 2017 | TSA | 30Gyx1, 8Gyx3 | CTLA4 mAb | 8Gyx3 but not 30Gyx1 synergized with CTLA-4 mAb to control primary and abscopal tumors |