Combination of Immune Checkpoint Therapy with Radiotherapy
Radiotherapy (RT), utilizing ionizing radiation beams including high-energy X-ray and γ-ray to induce DNA damage and kill cancer cells, has been widely applied in the clinic to treat solid tumors at different stages. Elucidating the pathways for radiation-induced immune stimulation provides a mechanism for the observed synergy between radiation and immunotherapy. The combination of RT and immune checkpoint blockade (ICB) has been an important and effective approach to improving cancer immunotherapy.
Importantly, RT is emerging as an optimal partner because of its ability to induce a response in otherwise non-responsive patients. RT has the potential to convert immunologically 'cold' tumors into 'hot' tumors by a combination of distinct mechanisms, including:
Increasing tumor immunogenicity via the upregulation of antigenic expression, antigen processing, major histocompatibility molecules, and costimulatory signals.
Overcoming an immunosuppressive tumor microenvironment by shifting the cytokine balance in favor of immunostimulation (e.g., by increasing the production of immunostimulatory cytokines).
Recruiting antigen-presenting and immune effector cells to the tumor microenvironment.
These findings provide a strong rationale for the evaluation of localized tumor ablation with systemic immune checkpoint blockade.
Fig.1 Radiation priming of a tumor-specific immune response and opportunities for combination approaches with ICB immunotherapy. (Ko, 2018)
Preclinical and Clinical Studies Combining ICB and RT
Combination of CTLA-4 blockade with RT
Combination therapy with anti-CTLA-4 antibody and local radiation has been shown to cause tumor regression at both irradiated and non-irradiated sites-the latter known as the abscopal effect. Indeed, the radiotherapy combined with anti-CTLA-4 improved control of irradiated tumors and reduced non-irradiated lung metastases in preclinical models. A number of clinical case studies showed that concurrent treatment with radiotherapy and CTLA-4 blockade promoted an abscopal effect in metastatic melanoma as well as in NSCLC.
Combination of PD-1 blockade with RT
Combing PD-1/PD-L1 inhibitors and RT could (1) reduce the numbers of MDSCs in the tumor microenvironment; (2) increase CD8+ to Treg ratio; (3) enhance CD8+ infiltration and thus, augment anti-tumor response. Substantial data have proposed a positive role of combing PD-1/PD-L1 inhibitors and RT in different types of tumors, including NSCLC. The results of these preclinical studies indicate that RT can work synergistically with PD-1/PD-L1 inhibitors.
A phase I trial was underway testing the combined use of anti-PD-1 antibody and RT in GBM. A phase II study was also ongoing to evaluate the combination of anti-PD-1 antibody and radiosurgery in cancer patients, including renal cell carcinoma and NSCLC, with brain metastases. The anticipated validation of these trials will provide a new perspective for the treatment of cancer patients.
Services at Creative Biolabs
Combining state-of-the-art technology with personal service and attention, Creative Biolabs offers a series of custom services for immune checkpoints, including but not limited to: