Mitragotri, SamirPrakash, Supriya2024-03-2520232023-11-212023Prakash, Supriya. 2023. Polymer Micropatches as Cell Engagers for Cancer Immunotherapy. Doctoral dissertation, Harvard University Graduate School of Arts and Sciences.30639701https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37378115Adoptive transfer of immune cells has emerged as a potential therapeutic approach against various cancers. The effectiveness of cell-based therapies is limited by an inability to control the cell phenotype post in vivo transfer. This results in a loss of activation over time, accelerated by the immunosuppressive tumor microenvironment in many solid tumors. To overcome this challenge, I set to create a platform that can be attached to adoptively transferred cells and leverage cell biology to provide continuous activation to the carrier cell. I designed a modular platform, Micropatches as Cell Engagers (MACE), which is comprised of Poly(lactide-co-glycolic) acid (PLGA) disc-shaped microparticles, surface modified with antibodies designed to target specific receptors on the carrier cell. These antibodies can mediate attachment to the carrier cell, provide activation signals, or both. I first developed MACE for activation of Natural Killer (NK cells), modifying the MACE surface with a combination of anti-CD45, anti-NKp30/anti-NKp46 antibodies. MACE exhibited strong adhesion to NK cells and induced their activation without the need of co-administered cytokines. The activation induced by MACE was greater than that induced by nanoparticles, attesting to the unique role of MACE geometry in the activation of NK cells. MACE-bound NK cells remained viable, exhibited trans-endothelial migration and anti-tumor activity in vitro. MACE-bound NK cells activated T cells, macrophages and dendritic cells in vitro. Adoptive transfer of NK-MACE also demonstrated superior anti-tumor efficacy in a murine melanoma lung metastasis model compared to unmodified NK cells. To further demonstrate the versatility of MACE, I then modified this platform to modulate another cell type – B cells. B cells are a largely overlooked cell type in the field of adoptive cell therapies, however, they are key players in mediating adaptive immune responses through antibody production and antigen presentation. I utilized MACE to improve the antigen presenting function of adoptively transferred B cells for use as a cell-based cancer vaccine. I modified MACE with a combination of anti-IgM and anti-CD40 antibodies. MACE could be robustly attached to B cells and provide simultaneous survival and activation signals to the carrier cell, resulting in increased survival and activation of B cells, and enhanced antigen presentation by B cells to CD8+ and CD4+ T cells. MACE-bound B cells retained the ability to home to secondary lymphoid organs in vivo. Adoptive transfer of antigen peptide pulsed MACE-B cells delayed the progression of subcutaneous ovalbumin expressing tumors in a murine model significantly, compared to the adoptive transfer of B cells alone. Overall, MACE is a versatile and effective way of activating different immune cells to improve the efficacy of cell based anti-cancer therapies.application/pdfenB cellsCancerCell TherapyImmunotherapyMicroparticlesNK cellsBioengineeringThesis or Dissertation2024-03-250000-0003-0772-8822