Ionizable Lipid Nanoparticles with Integrated Immune Checkpoint Inhibition for mRNA CAR T Cell Engineering

Author:

Hamilton Alex G.1,Swingle Kelsey L.1,Joseph Ryann A.1,Mai David123,Gong Ningqiang1,Billingsley Margaret M.1,Alameh Mohamad‐Gabriel45,Weissman Drew45,Sheppard Neil C.236,June Carl H.236,Mitchell Michael J.12578ORCID

Affiliation:

1. Department of Bioengineering University of Pennsylvania Philadelphia PA 19104 USA

2. Abramson Cancer Center, Perelman School of Medicine University of Pennsylvania Philadelphia PA 19104 USA

3. Center for Cellular Immunotherapies, Perelman School of Medicine University of Pennsylvania Philadelphia PA 19104 USA

4. Department of Medicine University of Pennsylvania Philadelphia PA 19104 USA

5. Institute for RNA Innovation University of Pennsylvania Philadelphia PA 19104 USA

6. Department of Pathology and Laboratory Medicine Perelman School of Medicine University of Pennsylvania Philadelphia PA 19104 USA

7. Institute for Immunology, Perelman School of Medicine University of Pennsylvania Philadelphia PA 19104 USA

8. Cardiovascular Institute, Perelman School of Medicine University of Pennsylvania Philadelphia PA 19104 USA

Abstract

AbstractThe programmed cell death protein 1 (PD‐1) signaling pathway is a major source of dampened T cell activity in the tumor microenvironment. While clinical approaches to inhibiting the PD‐1 pathway using antibody blockade have been broadly successful, these approaches lead to widespread PD‐1 suppression, increasing the risk of autoimmune reactions. This study reports the development of an ionizable lipid nanoparticle (LNP) platform for simultaneous therapeutic gene expression and RNA interference (RNAi)‐mediated transient gene knockdown in T cells. In developing this platform, interesting interactions are observed between the two RNA cargoes when co‐encapsulated, leading to improved expression and knockdown characteristics compared to delivering either cargo alone. This messenger RNA (mRNA)/small interfering RNA (siRNA) co‐delivery platform is adopted to deliver chimeric antigen receptor (CAR) mRNA and siRNA targeting PD‐1 to primary human T cells ex vivo and strong CAR expression and PD‐1 knockdown are observed without apparent changes to overall T cell activation state. This delivery platform shows great promise for transient immune gene modulation for a number of immunoengineering applications, including the development of improved cancer immunotherapies.

Funder

National Institutes of Health

National Center for Advancing Translational Sciences

Publisher

Wiley

Subject

Pharmaceutical Science,Biomedical Engineering,Biomaterials

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