Radiation and Immune Checkpoint Blockade: From Bench to Clinic

https://doi.org/10.1016/j.semradonc.2017.03.002Get rights and content

Immune escape of malignant cells is an important hallmark of cancer, necessary for tumor formation and progression. Accordingly, in recent years, therapies that enhance the immune system have had remarkable success in treating a myriad of malignancies. Particularly successful has been immune checkpoint blockade (ICB), which is a therapy that targets T-cell inhibitory receptors, or immune checkpoints. Despite these encouraging clinical results, most patients do not respond to such agents. Therefore, determining methods to better target and enhance the therapeutic efficacy of ICB is of paramount importance. One appealing approach is to use standard anticancer therapies, such as radiation, chemotherapy, and targeted biologics, to favorably modulate the immune system and enhance the anticancer immune response. For example, although radiation therapy has classically been thought of as a local therapy, there is significant potential for combining radiation therapy with ICB to both optimize local control and to treat metastatic disease. This concept is supported by numerous preclinical studies and clinical case reports and has since led to many early and ongoing clinical trials. However, it is still unclear how to optimally combine radiation and ICB to maximize the therapeutic effect. In this review, we highlight relevant preclinical and clinical studies in the field of radiation and ICB and discuss optimal strategies for combination therapies moving forward.

Section snippets

ICB in the Treatment of Cancer

Evasion of the body׳s natural immune system appears to be an important hallmark of cancer that leads to tumor formation and progression.1 An important mechanism of this immune escape is through the activation of immune checkpoints that then dampen the immune response. These checkpoints are important safeguards that are in place to restrain an immune response to prevent immune overactivation or autoimmunity. Upon activation by foreign pathogens or tumor cells, T cells upregulate inhibitory

Immune Stimulatory Effects of Radiation

Radiotherapy is classically thought of as a local therapy killing tumor cells via intrinsic DNA damage in the radiation field. However, there is a well-established phenomenon of an abscopal response to radiation, where tumors outside a radiation field also respond to treatment.19 When these rare abscopal responses occur, it is thought to be immune mediated. This led to early ideas that radiation can have immune stimulatory effects that could be more commonly observed if combined with

Immune-Suppressive Effects of Radiation

With the plethora of data showing how radiation can enhance the immune system, it may seem surprising that the abscopal effect of radiation is such a rare event. However, cancer cells typically develop elaborate ways to evade normal immune defenses long before radiation is typically initiated as a therapy. Furthermore, as with many aspects of the immune system, radiation can have a dichotomous effect on immune function, where it is simultaneously both immunostimulatory and immunosuppressive.

Optimal Fractionation and Dose for Immunostimulatory Effect

Much of radiation clinical and translational research has focused on defining optimal radiation dose and fractionation to maximize cytotoxicity and local control. Indeed, the success of these efforts has been instrumental in setting current standards of care. For example, higher dose per fraction results in improved local control for early-stage larynx cancer,38 and various hypofractionated schedules markedly improve local control in early-stage lung tumors.39 It is thought that dose and

Clinical Experience With Radiation and ICB

In recent years, numerous case reports, institutional reviews, and prospective clinical trials have contributed significant knowledge about both the potential clinical benefits and also potential toxicity of combining radiation with ICB. For the most part, these studies have predominantly involved radiation combined with blockade of the CTLA-4 or PD-1/PD-L1 pathway.

Issues Affecting Implementation of Radiation With Checkpoint Blockade

Based on mounting preclinical evidence demonstrating that the combination of radiotherapy and ICB can enhance tumor response and based on encouraging earlier patient-safety data, many clinical trials have recently opened that combine both fractionated and hypofractioned radiation in both the definitive and metastatic setting. Trials that combine radiation with anti-PD-1/PD-L1 (Table 1), anti-CTLA-4 (Table 2), or combination of anti-PD-1/PD-L1 and anti-CTLA-4 (Table 3) add up to approximately 80

Conclusion

Overall, radiation therapy is no longer viewed solely as a local therapy, as it is becoming clear that radiation can have powerful immunostimulatory effects. Robust preclinical investigation and numerous case reports suggest that radiation may enhance the systemic response to ICB. These have established the foundation for dozens of actively accruing clinical trials combining a variety of checkpoint inhibitors with different radiation dose and fractionation regimens for numerous types of

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