Reprogramming CD22 CAR-T cells in vivo using CD8-targeted mRNA-LNPs to treat hematological malignancies

  • Mol Ther. 2026 May 6;34(5):2621-2636. doi: 10.1016/j.ymthe.2026.02.020.
Viktor T Lemgart  1 ,  Andrew J Sawyer  2 ,  William Kuhlman  1 ,  Aaron P Griset  1 ,  Mir M Ali  1 ,  Allison Caron  1 ,  Dharini Shah  2 ,  Tiffany Le  3 ,  Laura Strauss  4 ,  Jing Jiao  4 ,  Francis J Descamps  5 ,  Sampa Maiti  1 ,  Michael T Monte  2 ,  Ralston Augspurg  1 ,  Eyoung Shin  2 ,  Ernesto Luna  6 ,  Pankaj Agrawal  6 ,  Jan Pype  5 ,  Olga Lihoradova  1 ,  James Cao  7 ,  Brandon Quido  4 ,  Laura Powers  4 ,  Fazila Nasimi  3 ,  Jacob Scantland  3 ,  Kavana Girish  3 ,  Rasika D Kunden  3 ,  Jennifer Richards  2 ,  Samantha Stewart  3 ,  Seunghee Lee  3 ,  Garry Cuneo  8 ,  Janina Schwarte  9 ,  Christian Mueller  3 ,  Christopher M Borges  3 ,  Austin W Boesch  2 ,  Valeria R Fantin  2 ,  Ulrik B Nielsen  2 ,  Donald R Shaffer  10 ,  Daryl C Drummond  1
Affiliations
  • 1. Oncology Research, Sanofi, Cambridge, MA 02141, USA; Genomic Medicine Unit, Sanofi, Waltham, MA, USA.
  • 2. Oncology Research, Sanofi, Cambridge, MA 02141, USA.
  • 3. Genomic Medicine Unit, Sanofi, Waltham, MA, USA.
  • 4. Oncology Pharmacology, Sanofi, Cambridge, MA 02141, USA.
  • 5. LMR, Sanofi, 1831 Ghent, Belgium.
  • 6. VaxDesign, Sanofi, Orlando, FL 32826, USA.
  • 7. Global Discovery Pathology and Multimodal Imaging, Sanofi, Cambridge, MA 02141, USA.
  • 8. Cytek Biosciences, Fremont, CA 94538, USA.
  • 9. PMCB, Sanofi, Cambridge, MA 02141, USA.
  • 10. Oncology Research, Sanofi, Cambridge, MA 02141, USA. Electronic address: [email protected].
PMID: 41691371 DOI: 10.1016/j.ymthe.2026.02.020
Abstract

Ex vivo chimeric antigen receptor (CAR) T cell therapy has proven successful in patients with B cell hematologic malignancies. However, current approaches are limited by the requirement for personal manufacturing processes and by barriers such as limited efficacy against solid Tumors, treatment-associated toxicities, insufficient CAR-T cell trafficking to the tumor microenvironment, on-target off-tumor effects, and tumor antigen escape. Here, we describe a novel delivery platform that overcomes many of these barriers by employing targeted Lipid Nanoparticles (LNPs) to reprogram circulating human T cells in vivo. Using a NANOBODYVHH (variable heavy domain of heavy chain)-based targeting moiety, we deliver mRNA encoding a novel CD22 CAR specifically to CD8+ cells, enabling transient functional CAR expression in vitro and in vivo. Our targeted LNP formulation allows for repeated dosing and minimizes mRNA expression in off-target cells. Furthermore, in a humanized Nalm6 tumor mouse model, non-stimulated T cells reprogrammed in vivo inhibit tumor cell growth. Our platform is a flexible and broadly applicable CAR-T treatment for hematologic malignancies, which promises to be adaptable to Other Diseases.

Keywords
CAR-T; CD22; CD8(+) T cells; LNP; in vivo reprogramming; lipid nanoparticle; mRNA.
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