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Cellular biofactories for therapeutic protein synthesis in tumor microenvironment

Parijat Bhatnagar

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National Institutes of Health (NIH)
T cells undergo an intelligent decision-making process based on the inhibitory and excitatory chemotactic inputs; and extravagate to the tumor microenvironment through solid tissue barriers. Investigators' long-term goal, to be pursued in R33 phase, is to develop T cells into a platform vector technology for active drug- transport to the solid tumors. In this R21 application, their objective is to engineer a robust mechanism to transform autologous T cells into biofactories for autonomous synthesis of cytocidal secretory proteins upon stimulation by the tumor cells. Autonomous synthesis of Protein-of-Interest (PoI) with spatiotemporal resolution will enable targeting of tumor burden with cellular resolution and molecular specificity. Their central hypothesis is that T cells can be genetically encoded for robust modulation and biosynthesis of therapeutic proteins at the tumor site. They have chosen ovarian cancer that expresses Folate Receptor alpha (FRa) as disease model, and an apoptotic protein for its cytotoxic therapeutic value. However, the rationale for developing T cells as protein biofactories is that this is a platform technology and their specificity can be modified totarget any cancer and autonomously synthesize any PoI in situ. To aid this R21 effort, they have developed cell lines expressing bioluminescent and fluorescent reporters expressed only when stimulated by tumor cells. With following specific aims, they will advance this project towards itsgoals: (1) To develop robust control on biosynthesis of protein-of-interest (PoI); (2) To develop Tcells as biofactories for autonomous secretion of antitumor apoptotic protein. It is expected that this R21 phase will lead to T cells that will not activate in healthy tissues (enhanced safety) andhyperactivate specifically in the tumor microenvironment (enhanced efficacy). The impact of this research will also be felt on ongoing T-cell therapy trials by reducing the incidences of graft-versus-host-disease (GVHD). This pioneering approach builds upon ongoing T-cell immunotherapy trials, which are currently limited to control minimal residual disease (MRD) and is administered after chemotherapy. Proposed research is transformative, firstly because it will expand the scope of T-cell engineering to replace systemic chemotherapies. This will then be used for reduction of tumor burden rather than keeping MRD in check. Secondly, therapeutic proteins of non-human origin are efficiently degraded and removed by the immune system. This is a barrier to their in vivo application. The use of autologous T cells for biosynthesis of therapeutic proteins at the target site will eliminate any immunogenicity issues. Unusually high impact is expected because the specificity of T cells can be redirected towards the surface markers on different cancers and therefore be used to target multitude of cancers.

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