Revitalizing systemic immune responses in advanced NSCLC using FLT3L and SBRT

Area of Science:

• Oncology
• Immunotherapy
• Radiotherapy

Background:

• Non-small cell lung cancer (NSCLC) remains a leading cause of cancer mortality globally.
• Limited treatment options exist for advanced NSCLC patients with progressive disease post-chemotherapy and immunotherapy.
• Stereotactic body radiotherapy (SBRT) is a localized radiation technique targeting tumor sites.

Purpose of the Study:

• To evaluate the efficacy and immune effects of combining SBRT with CDX-301 (a recombinant human Fms-like tyrosine kinase 3 ligand - FLT3L) in advanced NSCLC patients.
• To identify immune signatures associated with treatment response, including abscopal effects.
• To assess the safety and tolerability of this combined treatment modality.

Main Methods:

• A Phase II clinical trial involving 29 advanced NSCLC patients previously treated with chemotherapy and immunotherapy.
• Patients received SBRT targeting a single disease site concurrently with CDX-301.
• Immune profiling included high-dimensional flow cytometry of peripheral blood and multiplex proteomic analysis of plasma.

Main Results:

• Progression-free survival at four months (PFS4) was achieved in 48% of patients.
• Abscopal responses, observed via FDG-PET, occurred in 31% of patients, with a median overall survival of 31 months for these responders versus 18 months for all participants.
• The combination therapy increased circulating myeloid cells, including dendritic cells (DCs) and myeloid-derived suppressor cells (MDSCs), and was associated with robust T cell activation, particularly CD4 T cells.

Conclusions:

• Combining SBRT with FLT3L (CDX-301) can induce systemic anti-tumor immune responses in advanced NSCLC.
• Abscopal responses are linked to coordinated immune activation, including sustained DC induction and T cell responses.
• This combination strategy represents a potential therapeutic approach for enhancing innate and adaptive anti-tumor immunity in NSCLC.