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

Area of Science:

• Immunology
• Biotechnology
• Oncology

Background:

• Ex vivo chimeric antigen receptor (CAR) T cell therapy is effective for B cell hematologic malignancies but faces limitations.
• Challenges include complex manufacturing, limited solid tumor efficacy, toxicity, poor tumor trafficking, off-tumor effects, and antigen escape.

Purpose of the Study:

• To develop a novel in vivo delivery platform for CAR T cell therapy.
• To overcome current limitations of ex vivo CAR T cell manufacturing and efficacy.

Main Methods:

• Utilized targeted lipid nanoparticles (LNPs) to deliver mRNA encoding a CD22 CAR.
• Employed a NANOBODY®-based targeting moiety to specifically deliver mRNA to CD8+ T cells in vivo.
• Evaluated transient CAR expression and therapeutic efficacy in a humanized Nalm6 tumor mouse model.

Main Results:

• Achieved transient functional CAR expression in vitro and in vivo.
• Demonstrated that in vivo reprogrammed T cells inhibit tumor cell growth in a mouse model.
• Showcased the LNP platform's ability for repeated dosing and minimized off-target expression.

Conclusions:

• The novel LNP-based platform enables in vivo T cell reprogramming for CAR therapy.
• This flexible approach overcomes key barriers of current CAR T cell therapies.
• The platform holds potential for treating hematologic malignancies and can be adapted for other diseases.