Combining Radiation with Immunotherapy: The University of Pennsylvania Experience.

Immune checkpoint inhibitors have shown remarkable clinical benefit across a variety of cancer types. However, the majority of patients do not respond or develop relapse after therapy. Radiation can favorably modulate the immune system and enhance tumor antigen recognition and rejection. Thus, the combination of radiation and immune checkpoint blockade (ICB) has been recognized as a promising strategy to improve tumor response and broaden the clinical utility of immunotherapy. In this review, we highlight the preclinical and clinical experience at our institution aimed at understanding and promoting the immunostimulatory effect of radiation. We discuss the rationale, design, results, and lessons from our clinical trials in combining radiation with anti-CTLA4 and/or anti-PD-1 therapy. In parallel, our studies to understand the resistance mechanism to radiation and ICB have converged on interferon (IFN) signaling as a key regulatory pathway. Persistent IFN-γ signaling impairs anti-tumor immune responses which can be reversed by using JAK inhibitor to disrupt the IFN signaling. Lastly we discuss remaining challenges, ongoing studies, and future directions in combining radiation with immunotherapy.

Radiation and Immune Checkpoint Blockade: From Bench to Clinic.

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.