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.

A Case of Metastatic Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome-Associated Renal Cell Carcinoma Treated with a Sequence of Axitinib and Nivolumab Following Cytoreductive Nephrectomy

“…In our case, nivolumab sustained stable disease for 11 months after the tumor volume had been significantly reduced by axitinib. Lower MTV on FDG-PET was reported to be associated with more favorable outcomes of ICIs in advanced melanoma ( 25 ) and NSCLC ( 26 ). It remains to be elucidated whether that is the case or not in metastatic RCC.…”

Tumor Burden and Immunotherapy: Impact on Immune Infiltration and Therapeutic Outcomes

“…Despite the immense positive impact of ICB in the clinical setting, many patients do not respond, and tumor burden is one metric that negatively correlates with ICB efficacy. Preclinical data reveals that PD-1 blockade is more effective in mice bearing smaller lung squamous cell tumors ( 22 ). Similarly, mice with advanced ovarian tumors are more resistant to PD-L1 blockade than mice with earlier stage tumors ( 21 , 46 ).…”

“…This negative correlation of tumor size and ICB sensitivity is borne out in patients where total tumor volume is predictive of response to αPD-1 with local or metastatic melanoma ( 47 , 48 ). In patients with NSCLC, metabolic tumor volume was also a prognostic factor for sensitivity to PD-1 blockade in both retrospective and prospective studies ( 22 , 49 ). Furthermore, dual ICB, which targets both PD-1 and CTLA-4 at the same time, has shown greater efficacy than single ICB in patients with metastatic NSCLC and melanoma ( 40 , 43 ), and is more effective in melanoma patients with smaller baseline tumor diameters ( 50 ).…”

“…Tumor resection is the oldest method of treating cancer, and one of the original methods of restoring defective tumor surveillance in mouse models ( 1 ). The use of tumor resection prior to administration of immunotherapy improves control of tumor growth in multiple mouse models ( 3 , 22 , 78 ). This “resetting” of the immune response has been linked to the alleviation of immune suppression by tumor-derived IL-1 and granulocyte colony-stimulating factor (G-CSF) and could be phenocopied by mAb blockade of either cytokine ( 3 ).…”

Initiation of immunotherapy with activated natural killer cells and anti-GD2 antibody dinutuximab prior to resection of primary neuroblastoma prolongs survival in mice

“…In addition to the benefit of resecting the primary tumor cells, there may be other benefits of surgery including the removal of immunosuppressive tumor-associated macrophages and regulatory T cells, as well as creation of fewer tumor cell targets for immunotherapy. 10 11 It is well accepted that immunotherapy is most effective against minimal disease, and removal of bulk tumor disease might therefore increase the efficacy of immunotherapy against metastatic disease by multiple mechanisms.…”