Background-Hyperhomocysteinemia is an independent risk factor for coronary heart disease (CHD). Dietary supplementation with B vitamins lowers plasma homocysteine by up to 30%. However, little is known about the potential beneficial effects of homocysteine lowering on vascular function in patients with CHD. Methods and Results-We investigated 89 men with CHD (aged 56 [range 39 to 67] years). Brachial artery flow-mediated dilatation (endothelium dependent) and nitroglycerin-induced dilatation (endothelium independent) were measured before and 8 weeks after treatment with either (1) folic acid (5 mg) and vitamin B 12 (1 mg) daily (nϭ59) or (2) 001).In regression analysis, improved flow-mediated dilatation correlated closely with the reduction in free plasma homocysteine (rϭϪ0.26, Pϭ0.001), independent of changes in protein-bound homocysteine, folate, and vitamin B 12 . Nitroglycerin-induced dilatation was unchanged after both B vitamins and placebo. Conclusions-Folic acid and vitamin B 12 supplementation improves vascular endothelial function in patients with CHD, and this effect is likely to be mediated through reduced concentrations of free plasma homocysteine concentrations. Our data support the view that lowering homocysteine, through B vitamin supplementation, may reduce cardiovascular risk.

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INTRODUCTION: Recent progress in the field of cancer immunotherapy have made it possible to translate several emerging immunostimulatory strategies, e.g. anti-CTLA-4, and anti-PD-1 into the clinic resulting in promising clinical benefits. In addition, a number of treatment strategies such as radiotherapy (RT) oncolytic viruses and certain chemotherapeutic agents e.g. Doxorubicin, Bortezomib and Mitoxantrone have been highlighted as potential inducers of immunogenic cell death through a mechanism resulting in the increased presentation of cell-associated antigens to CD4+ and CD8+ T lymphocytes by dendritic cells. Thus combination strategies of ICD inducers with immunotherapy (IT) could provide opportunities to harness the immune system to extend survival, even among metastatic and heavily pre-treated cancer patients, and may increase the efficacy of immunotherapy in those cancer types to be of a low immunogenic status. Here we compare the efficacy of immune checkpoint inhibitors in combination with documented ICD inducers to demonstrate an additive combination outcome in preclinical syngeneic models. EXPERIMENTAL PROCEDURES: Bioluminescent CT26 mouse colon cells, 4T1 mammary carcinoma cells or H22 hepatoma cells were implanted subcutaneously or orthotopically into BALB/c mice. Subcutaneous tumour growth was monitored by calliper measurement and bioluminescent imaging (BLI) was carried out to confirm orthotopic and/or metastatic growth. Established tumours were treated with immunotherapy in combination with chemotherapy, or hypofractionated image-guided micro-irradiation (IGMI) using the small animal research platform (SARRP; Xstrahl Ltd; body weight and clinical condition of mice were monitored daily. At termination the tumours were collected and assessed for immune cell infiltration and/or ICD markers by FACS and IHC. RESULTS: Response to treatment was evaluated by tumour growth inhibition or BLI following treatment of monotherapy or combinations of immunotherapy and ICD inducers (Oxaliplatin, Doxorubicin, and IGMI). Monotherapy with anti-CTLA4 exerted no statistically significant effect on primary or metastatic (4T1) tumour growth whereas ICD such as IR resulted in a modest tumour growth inhibition (TGI); When combined significant additive effect was observed (60% increase in TGI) on the primary tumour and reduction in tumour burden in the lungs indicating an abscopal effect. Details of modulation of immune cell infiltration and ICD markers observed in all models will be reported and correlated to response. CONCLUSIONS: Combination of immune checkpoint immunotherapy with a known ICD inducer (IGMI) resulted in an additive TGI in both CT26 and 4T1 models and effectively demonstrates their applicability for further exploring combination strategies involving immunotherapy. Citation Format: Andrew Mckenzie, Rajendra Kumari, Qian Shi, Nektaria Papadopoulou, Yinfei Yin, Simon Jiang, Jane Wrigley, Jason King, Neil Williams, Russell Garland. Immune competent syngeneic models demonstrate additive effects of combination strategies using checkpoint immunotherapy and inducers of immunogenic cell death (ICD). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3994.