Background: Targeting of MDSCs is a major clinical challenge in the era of immunotherapy. Antibodies which deplete MDSCs in murine models can reactivate T cell responses. In humans such approaches have not developed due to difficulties in identifying targets amenable to clinical translation. Methods: RNA-sequencing of M-MDSCs and G-MDSCs from cancer patients was undertaken. Flow cytometry and immunohistochemistry of blood and tumours determined MDSC CD33 expression. MDSCs were treated with Gemtuzumab ozogamicin and internalisation kinetics, and cell death mechanisms determined by flow cytometry, confocal microscopy and electron microscopy. Effects on T cell proliferation and CART cell anti-tumour cytotoxicity were identified in the presence of Gemtuzumab ozogamicin. Findings: RNA-sequencing of human M-MDSCs and G-MDSCs identified transcriptomic differences, but that CD33 is a common surface marker. Flow cytometry indicated CD33 expression is higher on M-MDSCs, and CD33+ MDSCs are found in the blood and tumours regardless of cancer subtype. Treatment of human MDSCs leads to Gemtuzumab ozogamicin internalisation, increased p-ATM, and cell death; restoring T cell proliferation. Anti-GD2-/mesothelin-/EGFRvIII-CART cell activity is enhanced in combination with the anti-MDSC effects of Gemtuzumab ozogamicin. Interpretation: The study identifies that M-MDSCs and G-MDSCs are transcriptomically different but CD33 is a therapeutic target on peripheral and infiltrating MDSCs across cancer subtypes. The immunotoxin Gemtuzumab ozogamicin can deplete MDSCs providing a translational approach to reactivate T cell and CART cell responses against multiple cancers. In the rare conditions of HLH/MAS gemtuzumab ozogamicin provides a novel antimyeloid strategy.

BackgroundFibrates are used especially in patients with hypertriglyceridaemia, a feature of the metabolic syndrome. Elevated LFTs are often observed in these patients perhaps related to fatty infiltration.AimWe wished to study changes seen in LFTs (GGT, ALT and ALP) following fibrate therapy and then determine associated factors.MethodsThis was a retrospective observational study in which data was collected from case notes of patients started on fibrates (n = 118, 2002–2008) in the lipid clinic at Good Hope Hospital and pre/post-fibrate lipid and LFT values were obtained. All biochemistry was performed on the Roche P-Unit using supplied reagents. Statistical analyses included t tests and regression analyses (factorised when quartiles were compared).ResultsOf the study population 106 patients were on fenofibrate; the remaining on bezafibrate. Significant lowering of GGT (p < 0.0001), ALT (p = 0.0014) and ALP (p < 0.0001) levels were observed following fibrate treatment. Baseline lipid (cholesterol, triglycerides and HDL) concentrations, alcohol intake, length of treatment, gender, concurrent statin treatment and diabetes did not correlate with these changes in LFT in a multiple regression analysis. Higher pre-fibrate GGT (p < 0.0001), ALT (p < 0.0001) and ALP (p < 0.0001) concentrations were associated with larger decreases in each of these tests respectively with the highest 2 quartiles (GGT > 57 IU/l, ALT > 34 IU/l and ALP > 94 IU/l) significantly different to the lowest quartile. The above associations remained significant even when the regression analyses were corrected for changes in lipid values (which did not show an association).ConclusionsFibrate treatment led to improvements in LFT, the greatest benefit seen in patients with higher baseline LFT values. It appears that baseline and changes in lipid values post fibrate treatment were not associated with change in LFT.

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