A rationale for surgical debulking to improve anti-PD1 therapy outcome in non small cell lung cancer

Sci Rep. 2019 Nov 15;9(1):16902. doi: 10.1038/s41598-019-52913-z.

Abstract

Anti-PD1 immunotherapy has emerged as a gold-standard treatment for first- or second-line treatment of stage IV NSCLC, with response rates ranging from 10 to 60%. Strategies to improve the disease control rate are needed. Several reports suggested that debulking surgery enhances anti-tumor immunity. We aimed at examining tumor burden as a predictive factor of anti-PD1 tretment efficacy and to evaluate the role of cytoreductive surgery in anti-PD1 treated NSCLC. Immunocompetent DBA/2 mice engrafted with various amount of allogeneic lung squamous cancer KLN-205 cells were treated with anti-PD1 monoclonal antibody. Mice engrafted with two tumors also underwent a debulking surgery or a sham procedure. Tumor volume was monitored to assess treatment efficacy. Tumor infiltrating lymphocytes were assessed by flow cytometry. In a retrospective study of 48 stage IV NSCLC patients treated with Nivolumab who underwent a 18-FDG PETscan before treatment onset, the prognostic role of metabolic tumor volume was analysed. Anti-PD1 treatment effect was greater in mice bearing smaller tumors. Treatment with higher doses of anti-PD1 antibody did not improve the outcome, independently of the size of the tumor. In mice bearing 2 tumors, excision of 1 tumor improved the anti-PD1 treatment effect on the remaining tumor. In 48 NSCLC patients receiving anti-PD1 treatment, high metabolic tumor volume was associated with poor overall survival and the absence of clinical benefit. Treg infiltration, but not effector T cells, was positively correlated to tumor volume. Taken together, our results suggest that tumor volume is a predictive factor of anti-PD1 efficacy in NSCLC. Additionally, an experimental murine model suggests that tumor debulking may improve control of residual tumor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Immunological / therapeutic use
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / mortality
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Carcinoma, Non-Small-Cell Lung / surgery*
  • Cell Line, Tumor
  • Chemotherapy, Adjuvant
  • Combined Modality Therapy
  • Cytoreduction Surgical Procedures / methods*
  • Female
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / mortality
  • Lung Neoplasms / pathology
  • Lung Neoplasms / surgery*
  • Male
  • Mice
  • Mice, Inbred DBA
  • Neoplasm, Residual
  • Nivolumab / therapeutic use*
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor / immunology
  • Retrospective Studies
  • Treatment Outcome
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents, Immunological
  • Programmed Cell Death 1 Receptor
  • Nivolumab