Synergy of radiotherapy and PD-1 blockade in Kras-mutant lung cancer

• Published in: JCI insight Vol. 1; no. 9; p. e87415
• Main Authors: Herter-Sprie, Grit S, Koyama, Shohei, Korideck, Houari, Hai, Josephine, Deng, Jiehui, Li, Yvonne Y, Buczkowski, Kevin A, Grant, Aaron K, Ullas, Soumya, Rhee, Kevin, Cavanaugh, Jillian D, Neupane, Neermala Poudel, Christensen, Camilla L, Herter, Jan M, Makrigiorgos, G Mike, Hodi, F Stephen, Freeman, Gordon J, Dranoff, Glenn, Hammerman, Peter S, Kimmelman, Alec C, Wong, Kwok-Kin
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 16.06.2016
• Subjects: Animals; Antibodies, Monoclonal - therapeutic use; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung - radiotherapy; Carcinoma, Non-Small-Cell Lung - therapy; Cell Line, Tumor; Female; Immunotherapy; Lung Neoplasms - radiotherapy; Lung Neoplasms - therapy; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neoplasm Recurrence, Local; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Protein-Serine-Threonine Kinases - genetics; Proto-Oncogene Proteins p21(ras) - genetics
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.87415

Radiation therapy (RT), a critical modality in the treatment of lung cancer, induces direct tumor cell death and augments tumor-specific immunity. However, despite initial tumor control, most patients suffer from locoregional relapse and/or metastatic disease following RT. The use of immunotherapy in non-small-cell lung cancer (NSCLC) could potentially change this outcome by enhancing the effects of RT. Here, we report significant (up to 70% volume reduction of the target lesion) and durable (up to 12 weeks) tumor regressions in conditional -driven genetically engineered mouse models (GEMMs) of NSCLC treated with radiotherapy and a programmed cell death 1 antibody (αPD-1). However, while αPD-1 therapy was beneficial when combined with RT in radiation-naive tumors, αPD-1 therapy had no antineoplastic efficacy in RT-relapsed tumors and further induced T cell inhibitory markers in this setting. Furthermore, there was differential efficacy of αPD-1 plus RT among -driven GEMMs, with additional loss of the tumor suppressor serine/threonine kinase 11/liver kinase B1 ( ) resulting in no synergistic efficacy. Taken together, our data provide evidence for a close interaction among RT, T cells, and the PD-1/PD-L1 axis and underscore the rationale for clinical combinatorial therapy with immune modulators and radiotherapy.