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CAR T cells produced in vivo to treat cardiac injury

Commented by the ESC WG on Cardiovascular Regenerative & Reparative Medicine

Gene Therapy, Cell Therapy

The use of chimeric antigen receptor (CAR) T cells to specifically eliminate activated fibroblasts as a therapy for heart failure has been previously demonstrated. CART cell therapy uses the working horses of the immune system, being the T cells, and led them express receptors on their surface called chimeric antigen receptors (CARs). The special receptors allow the T cells to recognize and attach to specific proteins, thereby recognize certain cells in order to target and destroy them. Eliminating activated fibroblasts via this approach resulted in a significant reduction in fibrosis and improved cardiac function. A drawback of the previous applied technology, used mainly in the oncology clinical setting, is the indefinite persistence of engineered T cells that will target the activated fibroblasts and thereby affect normal wound-healing responses as well. In the latest work, the authors further improved their approach by using a transient antifibrotic CAR T therapeutic via nucleoside-modified mRNA technology. They used an approach that avoids removing T cells from the patient but simply injects modified mRNAs in lipid nanoparticles (LNPs) that target T cells and produce functional CAR T cells in vivo. In their work, CD5-targeted LNPs were used that normally is expressed by T cells. In short, T cell encapsulate these lipid nanoparticles and start to express the provided modified mRNA against the fibroblast activation protein (FAB). By applying this technology in vivo, they were able to effectively remove activated fibroblasts transiently and improve cardiac function after injury by eliminating fibroblasts. Of course, more studies will be needed to understand dosing, need for re-dosing, LNP composition and further improved targeting to reduce any toxicity, but a clear proof-of-concept study is provided with a universal off-the-shelve approach to engineer specific immune interventions in heart failure.


References of Commented Article: 1.- Mathur A, Fernández-Avilés F, Dimmeler S, et al. The consensus of the Task Force of the European Society of Cardiology concerning the clinical investigation of the use of autologous adult stem cells for the treatment of acute myocardial infarction and heart failure: update 2016. Eur Heart J 2017;38:2930–2935.
2.- Mathur A, Arnold R, Assmus B, et al. The effect of intracoronary infusion of bone marrow-derived mononuclear cells on all-cause mortality in acute myocardial infarction: rationale and design of the BAMI trial. Eur J Heart Fail 2017;19:1545–1550.
3.- Assmus B, Leistner DM, Schächinger V, et al. REPAIR-AMI Study Group. Long-term clinical outcome after intracoronary application of bone marrow-derived mononuclear cells for acute myocardial infarction: migratory capacity of administered cells determines event-free survival. Eur Heart J 2014;35:1275–1283.
4.- Schächinger V, Erbs S, Elsässer A, et al. REPAIR-AMI Investigators. Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med 2006;355:1210–1221.
5.- Martin-Rendon E, Brunskill SJ, Hyde CJ, et al. Autologous bone marrow stem cells to treat acute myocardial infarction: a systematic review. Eur Heart J 2008;29:1807–1818.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

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