Currently, scientists lack the ability to reprogram selected immune cells to exhibit all the functions that, from a clinical standpoint, physicians might wish them to have. Our goal is to resolve this problem by marrying concepts from materials science, immunology, and genetic engineering to developnovel (and somewhat unconventional) therapeutics that directly reprogram immune cells inside the body. In this talk, I will highlight two examples:In the first segment, I will introduce a new mRNA nanoparticle reagent our group developed to program tumor-recognizing capabilities into circulating T cells, thus avoiding the need to manipulate them in the laboratory. To deliver IVT mRNA encoding disease-specific receptor genes into human lymphocytes, we used a biodegradablepoly(β-amino ester) (PBAE) polymer formulation as a carrier matrix. Cationic PBAE self-assembles into nanocomplexes with anionic nucleic acids via electrostatic interactions. The particles are made cell-targeting by coupling an anti-CD8 antibody to polyglutamic acid (PGA), forming a conjugate that was electrostatically adsorbed to the particles. We demonstrate in mouse models of human leukemia, prostate cancer and hepatitis B-induced hepatocellular carcinoma, that repeated infusions of these polymer nanocarriers can deliver tumor-specific CARs or virus-specific TCR transgenes into sufficient numbers of host T cells that they induce disease regression at levels similar to bolus infusions of ex vivo-engineered lymphocytes. In the second part of my presentation, I will describe a new approach to genetically reshape the behavior of phagocytes as key players of the innate immune system, with the goals of killing diseased cells (e.g. cancer cells) while leaving healthy tissues untouched, and promoting healing in organs previously thought out of reach. Lastly, I will discuss steps towards clinical translation of these nanodrugs.

Synthetic mRNA nanocarriers for the in situ programming of disease-specific immune cells

ACS Fall 2020 Virtual Meeting

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