Engineering precision oncology: Targeting tumors and immune cells with lentiviral vectors

Area of Science:

• Gene Therapy
• Oncology
• Virology

Background:

• Lentiviral vectors (LVs) are key for gene delivery, but current standards (VSV-G pseudotyped LVs) have limitations for in vivo cancer therapy due to broad tropism and serum sensitivity.
• Precise targeting is crucial for effective and safe in vivo gene therapy in oncology.

Purpose of the Study:

• This review synthesizes advances in lentiviral vector pseudotyping and targeting strategies over the past two decades.
• The review aims to highlight innovations for reshaping vector tropism and enabling targeted gene delivery for cancer therapy.

Main Methods:

• Comparison of natural viral envelopes (measles virus, baboon endogenous retrovirus, Nipah virus, Sindbis virus) for specific cell transduction.
• Examination of next-generation retargeting innovations, including engineered receptor-binding domains, cytokine/antibody fragment display, and VSV-G mutants.
• Review of engineered virus-like particles (VLPs) for in vivo delivery of gene editing complexes (CRISPR-Cas9, base editing, prime editing).

Main Results:

• Donor-derived envelopes show potential for transducing hematopoietic, immune, and tumor cells.
• Engineered targeting strategies enhance specificity for T cells, B cells, hematopoietic stem cells, and tumor antigens.
• Engineered VLPs are emerging as precision tools for in vivo gene editing delivery.

Conclusions:

• Receptor-targeted lentiviral and VLP systems represent promising platforms for next-generation precision oncology.
• These systems enable selective in vivo CAR T/NK cell generation, targeted tumor modification, and cell-restricted gene editing.