Abstract Introduction Disseminated Coccidioides immitis infection remains difficult to treat, particularly in immunocompromised hosts where antifungal therapy often fails. Delayed antifungal initiation and host immune dysfunction worsen outcomes. We report emergency use of a novel combination immunotherapy using the interleukin-15 superagonist N-803 and allogeneic invariant natural killer T (iNKT) cells (agenT-797) in a patient with unresolving fungal pneumonia and multi-organ failure. Case A 70-year-old man with chronic obstructive pulmonary disease presented with recurrent severe acute respiratory distress syndrome (ARDS) unresponsive to antibiotics, corticosteroids, and standard antifungal therapy. Bronchoalveolar lavage (BAL) confirmed C. immitis infection with secondary Pseudomonas aeruginosa. Under emergency authorization, he received 600 µg subcutaneous N-803 followed 48 hours later by 1 × 109 agenT-797 cells. Within seven days, both pathogens cleared from respiratory samples, with marked improvement in oxygenation and hemodynamic stability. No infusion-related adverse events occurred. Immune Response Plasma and BAL cytokine profiling demonstrated a structured, biphasic immune response. N-803 monotherapy induced a TH1-skewed cytokine surge (IFN-γ, IL-8, VEGF-D) consistent with IL-15-mediated activation of T, NK, and iNKT cells. Following agenT-797 infusion, a balanced TH1/TH2 cytokine pattern emerged, characterized by increased IL-10, IL-1RA, and IL-4, and downregulation of pro-inflammatory mediators (IL-6, TNF-α, IL-1β, IL-18, MCP-1, IP-10). This transition coincided with pathogen clearance, declining inflammatory markers, and clinical stabilization. Discussion Sequential administration of N-803 and agenT-797 was feasible, well-tolerated, and associated with restoration of immune competence and resolution of treatment-refractory fungal and bacterial infections. The temporal cytokine dynamics suggest that IL-15-driven priming followed by iNKT-mediated modulation can rebalance hyperinflammation and support pathogen clearance in critically ill patients. These findings highlight the therapeutic potential of cytokine-based immune restoration in severe infectious and inflammatory diseases, warranting further clinical investigation. This abstract is funded by: MiNK Therapeutics Inc
Hammond et al. (Fri,) studied this question.