Background Novel efficient therapeutic options for lung carcinoma are needed as the survival at 5 years of metastatic disease treated by the standard of care is near zero.

Methods In this regard, we used a novel preclinical model of lung adenocarcinoma to assess the safety and efficacy of radio-immunotherapy combining local hypofractionated radiotherapy with tumor-stroma targeted FAP-CD40 agonistic bispecific antibody and PD1-IL2v immunocytokine.

Results In this model, combination treatments using hypofractionated RT + anti-FAP-CD40 and/or anti-PD1-IL2v mediate tumor growth retardation and extend mouse survival compared with radiotherapy alone or immunotherapy used as a single agent. Importantly, they were devoid of measurable toxicity. The best anti-tumor activity was obtained with the RT + anti-PD1-IL2v and RT + anti-FAP-CD40 + anti-PD1-IL2v combinations. In these treatment groups, survival of mice was extended more than 30 days (60 days post tumor engraftment) compared to the control cohorts. Immuno pharmacodynamic analysis and immunofluorescence data in these groups show that treatment with radiotherapy and anti-PD1-IL2v + anti-FAP-CD40 associates with increases in the endogenous CD8 T cells and transferred OT-1 infiltrating the lungs. The anti-tumor activity of the anti-PD1-IL2v monotherapy required CD8 T cells as suggested by immune cell depletion experiments. Additionally, the SV2 lung adenocarcinoma cell line has been transduced with a library of barcodes to study clonal dynamics of tumor cells during disease progression and therapy.

Conclusions The results of our preclinical study warrant and inform the translation and clinical testing of these novel immunotherapeutic agents in patients with metastatic lung adenocarcinoma.

Ethics Approval All animal procedures were carried out under the license VD3173.1c which was approved by the Veterinary Authority of the Swiss Canton of Vaud.