Translational development and first-in-human compassionate infusion of NK-92 cells expressing a CD5-based chimeric antigen receptor (SRCD5CAR-NK-92) in a patient with multidrug-resistant fusariosis.

INTRODUCTION

Invasive fungal infections (IFI) remain a major therapeutic challenge due to limited antifungal options, emergence of multidrug-resistant (MDR) strains and high mortality rates. This has turned up the development of immune-based therapies to restore and/or enhance anti-fungal immune responses into a clinical priority. This is in line with the recent demonstration that antifungal activity of primary (cord blood-derived) NK cells can be potentiated by endowing them with a CD5-based second-generation chimeric antigen receptor (SRCD5CAR) targeting β-glucans, a constitutive and broadly distributed component of fungal cell walls. Building on this, we aimed at exploring whether the reported constitutive antifungal activity of leukemia-derived NK-92 cells can also be potentiated by engineering them for further potential use as a homogeneous and ready-to-use source of allogeneic cells for adoptive transfer therapy in IFI.

METHODS

NK-92 cells lentivirally transduced and selected for stable and high-level expression of the SRCD5CAR for further testing in in vitro fungal killing assays, as well as in an in vivo model of fungal infection.

RESULTS

SRCD5CAR-NK-92 cells showed superior antifungal activity than untransduced NK-92 cell counterparts. SRCD5CAR-NK-92 cells also exhibited superior activity against a MDR Fusarium petroliphilum isolate from a patient undergoing a hematological malignancy and devoid of alternative therapeutic options. Following compassionate use approval, the patient received escalating intravenous infusions of irradiated SRCD5CAR-NK-92 cells at 2-5 day intervals, without significant local or systemic adverse effects (e.g., cytokine storm or alloreactivity).

DISCUSSION: Despite the patient ultimately succumbed due to progression of the underlying hematological malignancy, this represents first-in-human use of SRCD5CAR-NK-92 cells in the context of a severe MDR IFI. The results highlight its potential as a safe and off-the-shelf therapeutic strategy, while underscoring the need for further investigation on efficacy and long-term outcomes.