PO-426 Targeting of VEGFR2-expressing cells by chimeric antigen receptor (CAR) T cells for solid tumour therapy

Abstract

Introduction Metabolic reprogramming is one of the hallmarks of cancer, to support their needs for massive growth and proliferation. One major metabolic reprogramming is from oxidative phosphorylation to aerobic glycolysis, a well-documented phenomenon known as the Warburg effect. A key enzyme in this process is hexokinase 2 (HK2), which catalyses the first step of glucose metabolism and is overexpressed in many cancer types. Unlike HK1, which is ubiquitously expressed in normal cells, HK2 is required for cancer initiation and transformation even though their catalytic activity is highly similar. HK2 in cancer cells is attached to the outer mitochondrial membrane via the VDAC1 channel. VDAC1/HK2 association blocks pro-apoptotic signals, is less sensitive to feedback inhibition by the HK product, glucose-6-phosphate, as well as allows a continuous flux of mitochondrial ATP to HK, leading to apoptosis prevention and a high rate of glycolysis.Temporal high HK2 expression, and binding to VDAC, is also found in a variety of activated immune cells to support their changing metabolic needs. Detachment of HK2 from VDAC1 in activated immune cells leads to a range of responses ranging from glycolysis inhibition, NLRP3-mediated inflammasome activation, and metabolic reprogramming to activate immune pathways. Material and methods A novel small molecule VDAC/HK2 modulator, VDA-1102, is being developed as a bi-functional drug for the treatment of solid tumours -triggering apoptosis in cancer cells while simultaneously enhancing an immunemediated anti-tumour response by regulating immune cell metabolism. Results and discussions In vitro studies established that VDA-1102 selectively detaches HK2, but not HK1, from VDAC1 leading to cancer cell apoptosis, glycolysis inhibition, and prevention of cancer cell proliferation. In vivo efficacy studies demonstrated significant tumour growth delay and prolongation of survival in syngeneic solid tumour models. Analysis of tumor-associated macrophages in vivo indicated a treatmentinduced change in these macrophage phenotype from M2 to M1.

CAR-T Therapy for Solid Tumors: Development of New Strategies

“…Other ECM-targeted approach such as anti-fibulin 3 CAR-T cells was found to efficiently eradicate glioblastoma cells in mouse models evidenced by increased expression of IFN-gamma, IL-2, perforin and granzymes in the site of tumor [47] . While some are targeting ECM-components, some CAR-Ts are modified to target VEGFR (vascular endothelial growth factor receptor) [48] to specifically direct T-cell effect as guide from tumoral activities that hijacks vasculature formation.…”