Reprogramming Cancer Cells into Antigen Presenting Cells: Cancer Vaccination with mRNA Enabled by Charge-Altering Releasable Transporters

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Cancer vaccines have the potential to provide potent and personalized therapeutics with long-lasting effects for treatment of the ~100 million people worldwide currently affected by this disease. While recent advances have led to the first FDA-approved cancer vaccines, treatments that are broadly effective across patient populations remain elusive. As such, there is a critical need to develop cancer vaccines that operate via fundamentally new mechanisms that enable greater potency. The overall goal of this work is to leverage recent advances in gene delivery and cell reprogramming to develop a cancer vaccine that directly reprograms cancer cells into anti-tumor immune cells. The proposed work will be executed in the lab of Prof. Robert Waymouth (chemistry) at Stanford and in close collaboration with Prof. Paul Wender (chemistry), Prof. Ravindra Majeti (medicine), and Prof. Ronald Levy (medicine). Through this interdisciplinary collaboration of chemists and cancer immunologists, vaccines that operate by a unique cell reprogramming mechanism will be developed and the efficacy of these vaccines will be evaluated in cell lines and vertebrate models. One critical barrier that hinders the potency of current cancer vaccination approaches is insufficient activation of immune cells (T cells) due to inefficient antigen presentation or lack of costimulatory signals. To overcome this barrier, a new cancer vaccination strategy will be developed that directly reprograms cancer cells into immune cells that exhibit cancer-derived antigens and the proper costimulatory molecules for efficient T cell activation. To realize this goal, gene delivery vehicles will be developed for cancer cell reprogramming and relationships between their molecule structure and function (i.e. protein expression and biodistribution) will be elucidated (Aim 1). These gene delivery vehicles will be used to reprogram cancer cells into antigen presenting cells (APCs) using cell lines and vertebrate models (Aim 2). The ability of reprogrammed APCs to elicit a cancer- targeted immune response and establish immunological memory will be investigated (Aim 3). These studies are anticipated to lay the groundwork for future application of this technology in the clinic and add to the growing body of knowledge on gene delivery, cell reprogramming, and cancer vaccine development. In line with the mission of the NIH, the fundamental knowledge and therapeutic technology developed through this work will improve the future of human health by helping to treat cancer, one of the most prevalent and deadly diseases. The candidate will use this postdoctoral training fellowship to grow as an intellectual and researcher in the biological sciences by learning a suite of new experimental techniques and theoretical concepts that compliment her expertise in chemistry. The unique support provided by this fellowship, the chosen sponsor (Prof. Waymouth), key collaborators (Professors Wender, Majeti, and Levy), and research institution (Stanford) will enable the applicant to progress as a researcher and mentor and engage in professional development activities to accelerate the trajectory of her future career towards becoming a professor at an R1 institution.