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B-cell maturation antigen (BCMA) is a promising target in Multiple Myeloma (MM) and is the current chosen target for numerous MM-directed CAR T-cells, as well as therapeutic monoclonal antibodies – see MM Hub article. However, expression can vary between patients and several studies suggest it has a low target density which further decreases at relapse, thereby potentially escaping therapies and minimizing clinical efficacy.
To address this issue, Lydia Lee and colleagues from the Department of Haematology, UCL Cancer Institute, London, UK, in collaboration with Autolus Ltd, have developed a third generation CAR T-cell construct using the truncated form of a proliferation-inducing ligand (APRIL), the natural ligand for both BCMA and TACI (transmembrane activator and CAML interactor). The resultant construct has been termed ACAR and was tested both in-vitro and in-vivo (with a mouse model). The study was published in Blood in December 2017.
In summary, this study provides a strong rationale for the further clinical investigation of a dual targeting CAR. ACAR displayed target cytolysis at low E: T ratios in vitro and rapid tumor regression in an intramedullary murine myeloma model (48 hours post-ACAR T-cell injection). Additionally, no normal tissue toxicity was observed in vivo and no obvious off-target effects. A-CAR could prove to be especially beneficial for patients with low levels of tumor BCMA, as well as heavily pre-treated patients that may experience antigen down-regulation.
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