Enhancing T-cell therapy with nanoparticle backpacks
We have recently focused on engineering strategies to enhance adoptive cell therapy (ACT) for cancer. ACT involves the isolation of tumor-specific T-cells from cancer patients, their expansion in cell culture into large numbers, and reinfusion into the patient with the goal of eradicating metastatic cancer through this expanded anti-tumor cell population. T-cell transfer has shown significant promise in early clinical trials, but strategies to enhance ACT T-cell functionality in vivo are needed. To this end, we developed a strategy combining nanomedicine with ACT, based on the chemical conjugation of drug-loaded nanoparticles (NPs) as synthetic “backpacks” to the surfaces of live lymphocytes for ACT. To maximize the drug cargo associated with each cell, nanoparticles were formed by reversibly crosslinking protein drugs into nanogels comprised >90 wt% of cytokine drug cargos of interest. We further interfaced drug release from these particles with the biology of the T-cells by designing reduction-sensitive crosslinks, that allow drug to be selectively released as T-cells are triggered through the T cell receptor and upregulate cell surface redox activity. ACT T-cells backpacked with these cytokine nanogels are capable of massive in vivo expansion and robust anti-tumor responses, while avoiding side effects commonly observed with systemically-administered immunomodulatory drugs.