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

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.

Figure 1

Anti-PD1-induced delay in tumor growth is enhanced in small tumors, independently of treatment schedule. (A) Experimental design. DBA/2 mice bearing allogenic KLN-205 squamous lung cancer tumor allografts originated from injection of 10⁴ to 10⁷ cells were treated with intra-peritoneal anti-PD1 (100 µg per week or 200 µg twice a week from day 14 after allograft). Tumor size was measured twice a week with caliper. Control mice were treated with isotype control. Six animals were used in each group (i.e. mice receiving the same number of cells and the same treatment). Error bars represent the standard error for mean. (B) Absolute tumor volume during treatment with anti-PD1. (C) Tumor volume relatively to the volume at treatment initiation. (D) Legend for (B,C) graphes.

Figure 2

Cytoreductive surgery enhances anti-PD1 treatment effect. (A) Experimental design. DBA/2 mice bearing allogenic KLN-205 squamous lung cancer tumor allografts originated from injection of 10⁴ or 10⁷ cells in the right flank, and 10⁴ cells in the left flank, were treated with intra-peritoneal anti-PD1 (100 µg per week from day 14 after allograft) or isotype control. At day 14 from allograft, they underwent surgical removal of the right tumor or a sham procedure. Tumor size was measured twice a week. Twelve animals were used in each group (6 received 10⁴ cells in the right flank, 6 received 10⁷ cells). Error bars represent the standard error for mean. (B) Absolute tumor volume during treatment with anti-PD1. (C) Tumor volume relatively to the volume at treatment initiation. (D) Legend for (B,C) graphes.

Figure 3

Cytometric analysis of tumors according to their volume.