Antigen Presenting Cell Mimetic Lipid Nanoparticles for Rapid mRNA CAR T Cell Cancer Immunotherapy

Author:

Metzloff Ann E.1ORCID,Padilla Marshall S.1,Gong Ningqiang1,Billingsley Margaret M.1,Han Xuexiang1,Merolle Maria2,Mai David134,Figueroa‐Espada Christian G.1,Thatte Ajay S.1,Haley Rebecca M.1,Mukalel Alvin J.1,Hamilton Alex G.1,Alameh Mohamad‐Gabriel56,Weissman Drew56,Sheppard Neil C.347,June Carl H.347,Mitchell Michael J.13468ORCID

Affiliation:

1. Department of Bioengineering School of Engineering and Applied Science University of Pennsylvania Philadelphia PA 19104 USA

2. Department of Pathobiology School of Veterinary Medicine University of Pennsylvania Philadelphia PA 19104 USA

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

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

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

6. Penn Institute for RNA Innovation Perelman School of Medicine University of Pennsylvania Philadelphia PA 19104 USA

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

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

Abstract

AbstractChimeric antigen receptor (CAR) T cell therapy has achieved remarkable clinical success in the treatment of hematological malignancies. However, producing these bespoke cancer‐killing cells is a complicated ex vivo process involving leukapheresis, artificial T cell activation, and CAR construct introduction. The activation step requires the engagement of CD3/TCR and CD28 and is vital for T cell transfection and differentiation. Though antigen‐presenting cells (APCs) facilitate activation in vivo, ex vivo activation relies on antibodies against CD3 and CD28 conjugated to magnetic beads. While effective, this artificial activation adds to the complexity of CAR T cell production as the beads must be removed prior to clinical implementation. To overcome this challenge, this work develops activating lipid nanoparticles (aLNPs) that mimic APCs to combine the activation of magnetic beads and the transfection capabilities of LNPs. It is shown that aLNPs enable one‐step activation and transfection of primary human T cells with the resulting mRNA CAR T cells reducing tumor burden in a murine xenograft model, validating aLNPs as a promising platform for the rapid production of mRNA CAR T cells.

Funder

Emerson Collective

Publisher

Wiley

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