In vitro-transcribed antigen receptor mRNA nanocarriers for transient expression in circulating T cells in vivo

N N Parayath,S B Stephan,P S Nelson,A L Koehne,M T Stephan

doi:10.1038/s41467-020-19486-2

Abstract

Engineering chimeric antigen receptors (CAR) or T cell receptors (TCR) helps create disease-specific T cells for targeted therapy, but the cost and rigor associated with manufacturing engineered T cells ex vivo can be prohibitive, so programing T cells in vivo may be a viable alternative. Here we report an injectable nanocarrier that delivers in vitro-transcribed (IVT) CAR or TCR mRNA for transiently reprograming of circulating T cells to recognize disease-relevant antigens. In mouse models of human leukemia, prostate cancer and hepatitis B-induced hepatocellular carcinoma, repeated infusions of these polymer nanocarriers induce sufficient host T cells expressing tumor-specific CARs or virus-specific TCRs to cause disease regression at levels similar to bolus infusions of ex vivo engineered lymphocytes. Given their ease of manufacturing, distribution and administration, these nanocarriers, and the associated platforms, could become a therapeutic for a wide range of diseases.

Highlights

Engineering chimeric antigen receptors (CAR) or T cell receptors (TCR) helps create diseasespecific T cells for targeted therapy, but the cost and rigor associated with manufacturing engineered T cells ex vivo can be prohibitive, so programing T cells in vivo may be a viable alternative
Using orthotopic xenograft mouse models of lymphoma, prostate cancer, and hepatitis B virus (HBV)-induced hepatocellular carcinoma, we demonstrate that, when administered periodically, CAR-encoding or TCR-encoding mRNA particles can genetically reprogram circulating T cells to induce antitumor responses with similar efficacies compared to conventional adoptively transferred T cells that have been virally transduced ex vivo
The particles were made cell-targeting by coupling an anti-CD8 antibody to polyglutamic acid (PGA), forming a conjugate that was electrostatically adsorbed to the particles

Summary

Introduction

Engineering chimeric antigen receptors (CAR) or T cell receptors (TCR) helps create diseasespecific T cells for targeted therapy, but the cost and rigor associated with manufacturing engineered T cells ex vivo can be prohibitive, so programing T cells in vivo may be a viable alternative. In mouse models of human leukemia, prostate cancer and hepatitis Binduced hepatocellular carcinoma, repeated infusions of these polymer nanocarriers induce sufficient host T cells expressing tumor-specific CARs or virus-specific TCRs to cause disease regression at levels similar to bolus infusions of ex vivo engineered lymphocytes. Given their ease of manufacturing, distribution and administration, these nanocarriers, and the associated platforms, could become a therapeutic for a wide range of diseases. Should engineered T cell therapy reach its promise of extending to diverse populations across a variety of cancer types, the challenges of economics and manufacturing will likely grow

Methods

Results

Conclusion