Sickle cells produce functional immune modulators and cytotoxics

Area of Science:

• Hematology
• Gene Therapy
• Oncology

Background:

• Sickle red blood cells (SRBCs) naturally target hypoxic tumor environments.
• SRBCs can be engineered as drug delivery vehicles for enhanced anti-tumor effects.

Purpose of the Study:

• To develop novel methods for arming SRBCs with therapeutic payloads.
• To investigate the efficacy of a lentiviral vector for delivering cytotoxic and immune-modulating genes into SRBCs.

Main Methods:

• A lentiviral vector was engineered to express T cell cytolytics (perforin, granzyme) or immune modulators (superantigens SEG, SEI).
• The vector was used to transduce hematopoietic stem cells (HSCs) from humanized sickle cell knockin mice.
• Mice reconstituted with transduced HSCs were analyzed for transgene expression and SRBC function.

Main Results:

• Transduced HSCs generated SRBCs with sustained expression of therapeutic RNAs and proteins for over 10 months.
• Armed SRBCs expressing SEG/SEI induced robust T cell proliferation and cytokine responses.
• No toxicity was observed in the armed SRBCs.

Conclusions:

• The lentiviral vector effectively arms SRBCs with functional, erythroid-specific immune modulators and cytotoxics.
• Armed SRBCs represent a promising, non-toxic therapeutic strategy for solid tumor treatment, leveraging their tumor-homing and vascular occlusion capabilities.