| Description |
Remodeling of cell surface to install new features has continuously attracted attention for cell therapy. This dissertation focuses on a method of cell surface engineering using bioactive molecules to transiently award distinct functions to ordinary cells. Spontaneous incorporation of lipid-conjugated biomaterials to the cell membrane through hydrophobic interaction provides the basis for noninvasive cell surface modification. First, mesenchymal stem cells (MSCs) were surface-engineered to embed a recombinant protein, stromal-derived factor 1 (SDF-1), for an enhanced target-specific homing effect. The SDF-1-embedded MSCs showed augmented migration towards the concentration gradient of their molecular target, CXC chemokine receptor 4 (CXCR4). Next, Jurkat cells were surface-engineered with magnetic resonance imaging (MRI) contrast agents to demonstrate the suitability of surface engineering in cell tracking. The contrast agent-embedded Jurkat cells were detectable by MRI. To demonstrate the applicability of this technology in translational research, immune effector cells were surface-engineered with antibody-drug conjugates (ADCs) and their combined efficacy was examined in animal tumor models. This combination of chemotherapy and immunotherapy showed significant efficacy in treating cancers; however, the immunomodulatory effects of chemotherapy were difficult to control. This observation was due to the off-target toxicity of chemotherapy that damages the host immune cells: many cancer patients often require replenishment of immune cells after a series of chemotherapy in order to benefit from immunotherapy. In order to overcome the challenge, new chemoimmunotherapeutic strategies require sufficient immunomodulatory ability of chemotherapy, targeted chemotherapy for reduced toxicity, and enhanced recruitment of immune cells to the tumor tissue. Surface engineering to affix chemotherapeutic agents on the cell membrane of immune effector cells is therefore an attractive approach. In the main study of this dissertation, natural killer 92 (NK92) cells were surface-engineered to carry ADCs on their membranes. A lipid-conjugated model ADC, trastuzumab-DM1 (T-DM1), homogeneously modified the allogeneic NK92 cells without affecting the viability of NK92 cells. T-DM1-embedded NK92 (SE-NK/T-DM1) cells exerted strong anti-cancer activity through targeted chemoimmunotherapy. Although a wide range of experimental observations has proven that the SE-NK/T-DM1 cells are effective over the co-treatment of T-DM1 and NK92 cells, further investigations should be conducted to validate their potential for clinical application. |
