Optimization of the formulation of T-cell targeted polymeric nanogels for CAR-T cell therapy
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Date
2022-07-12
Authors
Saber, Nadein Mohamed Abdelaleem
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Abstract
In recent years, CAR T-cell therapy has emerged as a promising new method for cancer treatment. It involves isolation of T-cells from patients’ blood, genetically modifying them ex-vivo with genes encoding a chimeric antigen receptor (CAR) that targets tumour antigens and reinfusing them back into the patient. CAR T-cell therapies have achieved impressive clinical success in treating some cancer patients. However, some major drawbacks have halted its widespread application, such as its complex manufacturing procedure that requires specialized facilities, and the very high cost of treatment which puts this therapy beyond the reach of many cancer patients. Furthermore, the ex-vivo modification of T-cells reduces their efficacy, and the reinfusion of large numbers of T-cells into the bloodstream results in numerous side effects. This is in addition to the lengthy treatment and hospitalization periods of the patient. A potential solution to overcome these complications, is the in-vivo programming of circulating T-cells into CAR-T cells. In this work, a polymeric nanogel particle formulation was optimized, where it can be used to specifically deliver CAR genetic constructs to target T-cells within the body. These particles are composed of numerous components including a cationic nanogel core, an anionic polymer coating, and surface targeting ligands. The nucleic acid cargo consists of a DNA construct encoding the CAR, and a mRNA encoding a transposase which facilitates the stable integration into the host cell. Using a full factorial DoE approach, the optimal ratios between these different components have been successfully determined, as well the optimal particle production procedure. Which together produced a particle with desirable physical characteristics, that is consistently produced, stable at storage conditions and stable in biological media.
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Keywords
Chimeric antigen receptor (CAR)-T cell therapy, Cancer immunotherapy