- D3.545 - Natural Killer and Dendritic Cells Leverage Synergistic Interactions to Enhance Treatment of Non-Small Cell Lung Cancer

Allergen-induced signaling can trigger complex interactions between Natural Killer (NK) cells and Dendritic Cells (DCs). Under specific conditions, this DC-NK intercellular crosstalk can be harnessed to establish a microenvironment that counteracts tumor immune evasion. Furthermore, the use of allergy-mimetic pathways to reprogram DCs and NK cells—effectively reversing tumor-induced suppression—has emerged as a rapidly maturing domain in cancer immunotherapy. In this study, we evaluate the immune subpopulation dynamics, cytokine profiles, and cytotoxic activity from a Phase I, single-arm clinical trial. This trial investigates a dual-compartment cellular immunotherapy strategy, involving the administration of autologous DCs and NK cells, to assess its safety and immunologic efficacy in patients with advanced non-small cell lung cancer (NSCLC).

In this phase 1, single-arm clinical study, patients with advanced NSCLC received repeated intranodal injections of immature autologous DCs and serial intravenous infusions of autologous NK cells. Primary objectives were feasibility and safety. Secondary and exploratory objectives included longitudinal immune profiling, NK cytotoxic function and immune correlates associated with clinical outcome. Statistical analyses were exploratory and hypothesis-generating.

Ten patients were enrolled. Manufacturing and delivery were highly feasible, with successful administration of 36 of 37 planned DC doses (97.3%) and 89 of 94 planned NK infusions (94.7%). At the prespecified assessment, 20% of patients achieved partial response (n = 2) and 30% had stable disease (n = 3), for a disease control rate of 50%, while 50% experienced disease progression (n = 5). Treatment was well tolerated, with no evidence of uncontrolled systemic immune activation. At the cohort level, major leukocyte populations remained stable over time. Exploratory immune analyses stratified by clinical outcome revealed that non-progression (partial response or stable disease) was associated with enrichment of cytotoxic NK-cell subsets, increased ex vivo NK cytotoxicity, Th1 polarization, and higher proportions of effector CD8⁺ T cells and central memory CD4⁺ T cells. In contrast, progression was associated with naïve T-cell phenotypes, increased PD-1 expression on T-cell subsets, and enrichment of suppressive myeloid populations. Rising IL‑6 and PD‑1 expression may predict progression

Combined intranodal DC administration and autologous NK-cell infusion is feasible and well tolerated in patients with NSCLC and is associated with coordinated immune remodeling linked to non-progression. These findings provide first-in-human evidence supporting DC–NK cooperative immunotherapy and inform the design of biomarker-driven, mechanism-based clinical trials in solid tumors. (NCT07202611).