Huang, Theelen, and Belcaid et al. report the immunomodulatory effects of stereotactic body radiation therapy (SBRT) followed by pembrolizumab in patients with metastatic NSCLC based on a phase 2 trial. Multiomic analysis of serial tissue and blood biospecimens revealed upregulation of adaptive immunity programs, and longer PFS in immunologically cold tumors harboring features of immunotherapy resistance (TMB-low, PD-L1-null or Wnt-mutated) in the SBRT arm. Radioimmunotherapy upregulated interferon signaling, antigen presentation, and T cell infiltration in abscopal tumor sites, and induced systemic neoantigen-reactive T cell responses.
Contributed by Shishir Pant
ABSTRACT: The abscopal effects of radiation may sensitize immunologically cold tumors to immune checkpoint inhibition. We investigated the immunostimulatory effects of radiotherapy leveraging multiomic analyses of serial tissue and blood biospecimens (n = 293) from a phase 2 clinical trial of stereotactic body radiation therapy (SBRT) followed by pembrolizumab in metastatic non-small cell lung cancer ( NCT02492568 ). Participants with immunologically cold tumors (low tumor mutation burden, null programmed death ligand 1 expression or Wnt pathway mutations) had significantly longer progression-free survival in the SBRT arm. Induction of interferon-γ, interferon-α and antigen processing and presentation gene sets was significantly enriched after SBRT in nonirradiated tumor sites. Significant on-therapy expansions of new and pre-existing T cell clones in both the tumor (abscopal) and the blood (systemic) compartments were noted alongside clonal neoantigen-reactive autologous T cell responses in participants with long-term survival after radioimmunotherapy. These findings support the systemic immunomodulatory and antitumor effects of radioimmunotherapy and may open a therapeutic window of opportunity to overcome immunotherapy resistance.
Author Info: (1) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (2) Netherlands Cancer Institute, Amsterdam, The Netherlands. (3
Author Info: (1) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (2) Netherlands Cancer Institute, Amsterdam, The Netherlands. (3) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (4) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (5) Netherlands Cancer Institute, Amsterdam, The Netherlands. (6) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (7) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (8) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (9) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (10) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (11) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD, USA. (12) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (13) Department of Pulmonary Diseases, Radboud University Medical Center, Nijmegen, The Netherlands. (14) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (15) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (16) Netherlands Cancer Institute, Amsterdam, The Netherlands. (17) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. vanagno1@jhmi.edu. The Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. vanagno1@jhmi.edu.
