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reversing
immune
evasion tumour
s grow and escape the immune system either by taking advantage of cells known to suppress the immune system or recruiting healthy cells for growth. they do so by employing characteristic changes in lipid metabolism. rgenix?s lead programme, rgx-104 is a small molecule that targets a specific type of cell receptor known as lxr (liver x receptor). lxr is a master regulator of lipid metabolism and has been shown to play a role in tumour progression. through selective activation of lxr, rgx-104 targets a key immune cell type in the tumour micro-environment, reversing immune evasion and generating robust anti-tumour immune activity. rgx-104 has obtained fda orphan drug designation in several solid tumour types of high unmet need, and enters clinical trials in the second half of 2016. arcellx ? engineering specificity and function arcellx is a pre-clinical company developing therapies using a proprietary binding domain directed against key tumour antigen
s. chimeric antigen receptors (cars) (fig. 4) are emerging as powerful tools for reprogramming t-cell specificity and function. these cells combine the antigen specificity of an antibody with the biologic properties of t-cells. car-t therapy is a form of adoptive cell therapy (fig. 3) in which t-cells from a patient are genetically modified to express synthetic receptors targeting tumour-specific surface antigens (sparing healthy tissue). due to their potentially long-lived nature, car-t cells can persist in the patient and provide long-term immune surveillance. cars are composed of a binding domain (fig. 4) ? typically a small fragment of an antibody that selectively targets a known tumour antigen. however, there are several challenges using the current methods. for example: ? targeting of a single antigen doesn?t always eliminate the cancer entirely, as tumours will escape by eliminating the targeted antigen; and ? the inability to turn the cars on and off has certain safety consequences. arcellx aims to address these issues by pursuing an alternative binding domain technology (d-domain) developed in collaboration with the national cancer institute (nci). the d-domain?s small size allows for engineering cars that bind and kill tumour through one or more target antigens, which should reduce recurrences due to antigen escape. in addition, d-domains can act as integrated functional switches, modulating the activity of cars to help overcome safety issues. b-cell t-cell } tumour-specific antibody from b-cells tumour antigen scfv cd3 ? or fc ? ri ? cd8 v h v l tumour cell fig. 4 cars are composed of a single-chain anti- body variable fragment (scfv) comprised of an extracellular domain linked through hinge and transmembrane domains to a cytoplasmic signaling region. arcellx is developing a modified car that addresses current challenges in the field. source: kershaw, et al. nature reviews cancer. 2013. 35 novo ventures
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