CAR T cells produced in vivo to treat cardiac injury
Joel G Rurik, István Tombácz, Amir Yadegari, Pedro O Méndez Fernández, Swapnil V Shewale, Li Li, Toru Kimura, Ousamah Younoss Soliman, Tyler E Papp, Ying K Tam, Barbara L Mui, Steven M Albelda, Ellen Puré, Carl H June, Haig Aghajanian, Drew Weissman, Hamideh Parhiz, Jonathan A Epstein, Joel G Rurik, István Tombácz, Amir Yadegari, Pedro O Méndez Fernández, Swapnil V Shewale, Li Li, Toru Kimura, Ousamah Younoss Soliman, Tyler E Papp, Ying K Tam, Barbara L Mui, Steven M Albelda, Ellen Puré, Carl H June, Haig Aghajanian, Drew Weissman, Hamideh Parhiz, Jonathan A Epstein
Abstract
Fibrosis affects millions of people with cardiac disease. We developed a therapeutic approach to generate transient antifibrotic chimeric antigen receptor (CAR) T cells in vivo by delivering modified messenger RNA (mRNA) in T cell–targeted lipid nanoparticles (LNPs). The efficacy of these in vivo–reprogrammed CAR T cells was evaluated by injecting CD5-targeted LNPs into a mouse model of heart failure. Efficient delivery of modified mRNA encoding the CAR to T lymphocytes was observed, which produced transient, effective CAR T cells in vivo. Antifibrotic CAR T cells exhibited trogocytosis and retained the target antigen as they accumulated in the spleen. Treatment with modified mRNA-targeted LNPs reduced fibrosis and restored cardiac function after injury. In vivo generation of CAR T cells may hold promise as a therapeutic platform to treat various diseases.
Conflict of interest statement
Competing Interests: S.M.A., E.P., C.H.J., H.A., D.W., H.P., and J.A.E. are scientific founders and hold equity in Capstan Therapeutics. Y.K.T. and B.L.M. are employees and hold equity in Acuitas Therapeutics. S.M.A. is on the scientific advisory boards of Verismo and Bioardis. C.H.J. is a scientific founder and has equity in Tmunity Therapeutics and DeCART Therapeutics and reports grants from Tmunity Therapeutics and is on the scientific advisory boards of BluesphereBio, Cabaletta, Carisma, Cellares, Celldex, ImmuneSensor, Poseida, Verismo, Viracta Therapeutics, WIRB Copernicus Group and Ziopharm Oncology. D.W. receives research support from BioNTech. S.M.A., E.P., and C.H.J. are inventors (University of Pennsylvania, Wistar Institute) on a patent for a FAP CAR (US Utility Patent 9,365,641 issued 14 June 2016, WIPO Patent Application PCT/US2013/062717). S.M.A., E.P., H.A., and J.A.E. are inventors (University of Pennsylvania) on a patent for the use of CAR T therapy in heart disease (US Provisional Patent Application 62/563,323 filed 26 September 2017, WIPO Patent Application PCT/US2018/052605). J.G.R., I.T., H.A., D.W., H.P., and J.A.E. are inventors (University of Pennsylvania) on a patent for the use of CD5/LNP-FAPCAR as an anti-fibrotic therapy (US Provisional Patent Application 63/090,998 filed 13 September 2020, WIPO Patent Application PCT/ US21/54764 filed 13 October 2021). I.T., D.W., and H.P. are inventors (University of Pennsylvania) on a patent for the in vivo targeting of T cells for mRNA therapeutics (US Provisional Patent Application 63/090,985 filed 13 October 2020, WIPO Patent Application PCT/US21/54769 filed 13 October 2021). I.T., D.W., and H.P. are inventors (University of Pennsylvania) on a patent for the in vivo targeting of CD4+ T cells for mRNA therapeutics (US Provisional Patent Application 63/091,010 filed 13 October 2020, WIPO Patent Application PCT/US21/54775). In accordance with the University of Pennsylvania policies and procedures and our ethical obligations as researchers, D.W. is named on additional patents that describe the use of nucleoside-modified mRNA and targeted lipid nanoparticles as platforms to deliver therapeutic proteins and vaccines. C.H.J. is named on additional patents that describe the creation and therapeutic use of chimeric antigen receptors. These interests have been fully disclosed to the University of Pennsylvania, and approved plans are in place for managing any potential conflicts arising from licensing these patents.
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Source: PubMed