Anti-PD-1/Anti-PD-L1 Drugs and Radiation Therapy: Combinations and Optimization Strategies

Abstract

Immune checkpoint inhibitors have been associated with long-term complete responses leading to improved overall survival in several cancer types. However, these novel immunotherapies are only effective in a small proportion of patients, and therapeutic resistance represents a major limitation in clinical practice. As with chemotherapy, there is substantial evidence that radiation therapy promotes anti-tumor immune responses that can enhance systemic responses to immune checkpoint inhibitors. In this review, we discuss the main preclinical and clinical evidence on strategies that can lead to an enhanced response to PD-1/PD-L1 blockade in combination with radiation therapy. We focused on central issues in optimizing radiation therapy, such as the optimal dose and fractionation for improving the therapeutic ratio, as well as the impact on immune and clinical responses of dose rate, target volume, lymph nodes irradiation, and type of radiation particle. We explored the addition of a third immunomodulatory agent to the combination such as other checkpoint inhibitors, chemotherapy, and treatment targeting the tumor microenvironment components. The strategies described in this review provide a lead for future clinical trials.

Efficacy and safety of combined treatment with pembrolizumab in patients with locally advanced or metastatic esophageal squamous cell carcinoma in the real world

“…Recently, the abscopal effect induced by radiotherapy has drawn increased attention. Studies have shown that radiotherapy could exert immunomodulatory effects that may result in antitumor responses, especially when combined with checkpoint inhibitors (19)(20)(21). Li and colleagues found that the expression of PD-1 was increased in patients receiving radiation, indicating the potential combination of PD-1 inhibitors and radiation (22).…”

Efficacy and safety of PD-1/PD-L1 inhibitors in the treatment of recurrent and refractory ovarian cancer: A systematic review and a meta-analysis

“…Targeted drugs against cytotoxic T-lymphocyte associated protein 4 (CTLA4) and programmed cell death receptor 1 (PDCD1, also known as PD-1)/programmed cell death receptor ligand 1 (PDCD1LG1, also known as PD-L1) play an anti-tumor effect by relieving tumor cells’ inhibition of T cell function ( O'Donnell et al, 2017 ). In recent years, immune checkpoint inhibitors (ICI), as the most common immunotherapy, have brought hope for treating malignant tumors ( Boustani et al, 2021 ).…”

On target methods to induce abscopal phenomenon for Off‐Target effects: From happenstance to happenings

“… 26 A similar technique known as Lattice radiation also administers ablative variable doses of RT to large tumors and helps with preserving surrounding organs at risk. 27 SBRT‐PATHY (stereotactic body radiation therapy‐based partial tumor irradiation targeting hypoxic segment of bulky tumors) is another technique that was developed by Tubin et al to harness hypoxia in bulky tumors where stereotactic body radiation therapy is administered to partial tumor mass irradiation technique. 19 , 27 FLASH‐RT (FLASH Radiotherapy_ which utilizes novel radiotherapy technology with single ultra‐high dose‐rate (≥40 Gy/s) radiotherapy and microbeam radiation therapy are lesser known techniques that are being investigated for abscopal response as well).…”

“… 27 SBRT‐PATHY (stereotactic body radiation therapy‐based partial tumor irradiation targeting hypoxic segment of bulky tumors) is another technique that was developed by Tubin et al to harness hypoxia in bulky tumors where stereotactic body radiation therapy is administered to partial tumor mass irradiation technique. 19 , 27 FLASH‐RT (FLASH Radiotherapy_ which utilizes novel radiotherapy technology with single ultra‐high dose‐rate (≥40 Gy/s) radiotherapy and microbeam radiation therapy are lesser known techniques that are being investigated for abscopal response as well). 19 , 28 Out of these techniques, the SBRT‐PATHY has shined to hold relevant promise in inducing abscopal response as it takes into account radiation‐induced bystander effect, manipulating tumor hypoxia, protecting the peritumoral environment and partial irradiation.…”

“…GRID (Spatially fractionated radiation therapy) block technique using high dose variable radiation spatially was established to administer radiation via Multi Leaf Collimator (MLC) in bulky lesions 26 . A similar technique known as Lattice radiation also administers ablative variable doses of RT to large tumors and helps with preserving surrounding organs at risk 27 . SBRT‐PATHY (stereotactic body radiation therapy‐based partial tumor irradiation targeting hypoxic segment of bulky tumors) is another technique that was developed by Tubin et al to harness hypoxia in bulky tumors where stereotactic body radiation therapy is administered to partial tumor mass irradiation technique 19,27 .…”