B95-10 A First-in-human Study of Pulmonary Macrophage Transplantation Therapy of Hereditary Pulmonary Alveolar Proteinosis

Background

CSF2RA mutations cause hereditary alveolar proteinosis (hPAP), a surfactant accumulation disorder, by disrupting GM-CSF signaling to alveolar macrophages (AMs), which require GM-CSF to maintain normal surfactant clearance and other functions and regulation of AM population size (in mice). Pulmonary macrophage transplantation (PMT) is a promising therapeutic approach for hPAP based on genetically restoring GM-CSF signaling to AMs. Preclinical mouse studies demonstrated PMT was safe and that efficacy was proportional to cell dose and time allowed for treatment development. Objectives: This study evaluated the feasibility, tolerability, safety, and efficacy of CSF2RA gene/PMT therapy in a 22-year-old woman with hPAP caused by biallelic CSF2RA mutations (G174R, gene deletion).

Methods

Autologous, gene-corrected macrophages (cells) were prepared from bone marrow progenitors by transduction with a self-inactivating, 3rd generation lentiviral vector expressing a CSF2RA transgene, followed by ex vivo cell expansion, differentiation into macrophages, and cryopreservation until administration. The cell dose (11 million cells/kg ideal body weight) was based on mouse toxicology results and was equivalent in size to 16% of the adult human AM population. Cells were thawed, formulated in saline, tested, and instilled bronchoscopically into individual lung segments in two doses. The first was a split-dose delivered into 1, 4, then 14 segments sequentially at 2-month intervals. The second dose involved delivery into all 19 segments 16 months later. The rationale for this administration scheme was our focus on safety and because the achievable gene-correction rate had been 100% in mouse cells but only ∼50% in human cells.

Results

Two separate cell lots comprised 131% and 104% of the targeted production amount and met all lot-release criteria. Administration was nominal and not accompanied by bronchospasm, serious adverse events, or antibody responses to either the vector or transgene product. Evidence of biological efficacy included detection of vector DNA and transgene product in AMs, reduced bronchoalveolar lavage turbidity, and detection of morphologically normal AMs. Evidence of clinical efficacy included improvement in body mass index, DLCO%, exercise capacity, minor improvement in computed tomography, and reduction in surfactant burden (total pulmonary surfactant level) as demonstrated by time-dependent reduction in the ‘barrier signal’ from hyperpolarized 129Xe magnetic resonance imaging (MRI) (Figure).

Conclusions

Results show PMT therapy of hPAP was feasible, tolerable, safe, and efficacious. Clinical efficacy was proportional to cell dose and treatment duration and developed over 26 months of follow-up. Interestingly, hyperpolarized 129Xe MRI imaging was more sensitive in measuring surfactant burden than computed tomography.

This abstract is funded by: NIH R33 HL156888