Hunter et al. developed LNPs for in vivo i.v. CAR delivery, with reduced liver tropism and superior tolerability in rats and non-human primates (NHP) compared to Pfizer’s COVID vaccine formulation. In humanized mice and NHPs, CD8-targeted LNPs encapsulating optimized anti-CD19 CAR mRNA facilitated preferential CAR expression in CD8+ T cells (peaked around 6h) and rapidly depleted B cells in blood (within hours) and tissues. After dosing, rebounding NHP B cells were skewed towards a naive phenotype. The LNPs also treated Nalm6 xenograft tumors in PBMC-humanized mice, and generated functional CAR T cells from autoimmune patient T cells.
Contributed by Alex Najibi
ABSTRACT: Chimeric antigen receptor (CAR) T cell therapies have transformed treatment of B cell malignancies. However, their broader application is limited by complex manufacturing processes and the necessity for lymphodepleting chemotherapy, restricting patient accessibility. We present an in vivo engineering strategy using targeted lipid nanoparticles (tLNPs) for messenger RNA delivery to specific T cell subsets. These tLNPs reprogrammed CD8(+) T cells in both healthy donor and autoimmune patient samples, and in vivo dosing resulted in tumor control in humanized mice and B cell depletion in cynomolgus monkeys. In cynomolgus monkeys, the reconstituted B cells after depletion were predominantly nave, suggesting an immune system reset. By eliminating the requirements for complex ex vivo manufacturing, this tLNP platform holds the potential to make CAR T cell therapies more accessible and applicable across additional clinical indications.
Author Info: (1) Capstan Therapeutics, San Diego, CA, USA. (2) Capstan Therapeutics, San Diego, CA, USA. (3) Capstan Therapeutics, San Diego, CA, USA. (4) Capstan Therapeutics, San Diego, CA, U
Author Info: (1) Capstan Therapeutics, San Diego, CA, USA. (2) Capstan Therapeutics, San Diego, CA, USA. (3) Capstan Therapeutics, San Diego, CA, USA. (4) Capstan Therapeutics, San Diego, CA, USA. (5) Capstan Therapeutics, San Diego, CA, USA. (6) Capstan Therapeutics, San Diego, CA, USA. (7) Capstan Therapeutics, San Diego, CA, USA. (8) Capstan Therapeutics, San Diego, CA, USA. (9) Capstan Therapeutics, San Diego, CA, USA. (10) Capstan Therapeutics, San Diego, CA, USA. (11) Capstan Therapeutics, San Diego, CA, USA. (12) Capstan Therapeutics, San Diego, CA, USA. (13) Capstan Therapeutics, San Diego, CA, USA. (14) Capstan Therapeutics, San Diego, CA, USA. (15) Capstan Therapeutics, San Diego, CA, USA. (16) Capstan Therapeutics, San Diego, CA, USA. (17) Capstan Therapeutics, San Diego, CA, USA. (18) Capstan Therapeutics, San Diego, CA, USA. (19) Capstan Therapeutics, San Diego, CA, USA. (20) Capstan Therapeutics, San Diego, CA, USA. (21) Capstan Therapeutics, San Diego, CA, USA. (22) Capstan Therapeutics, San Diego, CA, USA. (23) Capstan Therapeutics, San Diego, CA, USA. (24) Capstan Therapeutics, San Diego, CA, USA. (25) Capstan Therapeutics, San Diego, CA, USA. (26) Capstan Therapeutics, San Diego, CA, USA. (27) Capstan Therapeutics, San Diego, CA, USA. (28) Muscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA. (29) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (30) Capstan Therapeutics, San Diego, CA, USA. (31) Capstan Therapeutics, San Diego, CA, USA. (32) Capstan Therapeutics, San Diego, CA, USA. (33) Capstan Therapeutics, San Diego, CA, USA. (34) Capstan Therapeutics, San Diego, CA, USA. (35) Capstan Therapeutics, San Diego, CA, USA. (36) Capstan Therapeutics, San Diego, CA, USA. (37) Capstan Therapeutics, San Diego, CA, USA. (38) Capstan Therapeutics, San Diego, CA, USA. (39) Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Parker Institute for Cancer Immunotherapy at the University of Pennsylvania, Philadelphia, PA, USA. (40) Capstan Therapeutics, San Diego, CA, USA. Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
