Abstract
Simple SummaryAlthough immune checkpoint blockade has yielded unprecedented and durable responses in cancer patients, the efficacy of this treatment remains limited. Radiation therapy can induce immunogenic cell death that contributes to the local efficacy of irradiation. However, radiation-induced systemic responses are scarce. Studies combining radiation with checkpoint inhibitors suggest a synergistic potential of this strategy. In this review, we focused on parameters that can be optimized to enhance the anti-tumor immune response that results from this association, in order to achieve data on dose, fractionation, target volume, lymph nodes sparing, radiation particles, and other immunomodulatory agents. These factors should be considered in future trials for better clinical outcomes. To this end, we discussed the main preclinical and clinical data available to optimize the efficacy of the treatment combination.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.
Highlights
Programmed Cell Death Protein 1 (PD-1) and its ligand Programmed Cell Death Ligand 1 (PD-L1) play a central role in inhibiting immune responses to tumor cells by reducing the activation, the proliferation, and the cytotoxic activity of T-cells [1]
Lan et al reported the development of bintrafusp alfa, a bifunctional fusion protein composed of the extracellular domain of the TGFβ RII receptor to trap TGFβ, fused to a human immunoglobulin G1 antibody blocking PD-L1 [52]
The interest in combinations based on Radiation therapy (RT) and anti-PD-(L)1 drugs is well accepted by the scientific and medical community
Summary
Programmed Cell Death Protein 1 (PD-1) and its ligand Programmed Cell Death Ligand 1 (PD-L1) play a central role in inhibiting immune responses to tumor cells by reducing the activation, the proliferation, and the cytotoxic activity of T-cells [1]. In melanoma and breast cancer models, the combination of hypo-fractionated regimen of 3 × 9.18 Gy in 3 or 5 days, and 5 × 6.43 Gy in 10 days with an anti-PD-1 antibody, resulted in growth inhibition of both irradiated primary and non-irradiated tumors [12]. In breast (TUBO) and colon (MC38) cancer models, 1 × 12 Gy or 1 × 20 Gy increased the level of PD-L1 expression, and the combination of those regimens with an anti-PD-L1 antibody resulted in an efficient tumor control on both irradiated and non-irradiated lesions [15]. A new RT paradigm is being evaluated, consisting of a limited number of high-dose fractions separated in time by weeks or months instead of the classic daily fractions This new scheme, known as personalized ultra-fractionated stereotactic adaptive radiation therapy (PULSAR), was tested with an anti-PD-L1 in a MC38 colon cancer model [17]. The optimal time-course, if it exists at all, is still to be defined
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