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Engineering Cellular Therapeutics

  • Author(s): Park, Jason Sun-Hyung
  • Advisor(s): Lim, Wendell A
  • et al.
Abstract

Living cells act as smart and powerful therapeutic agents within the body. With their ability to sense multiple environmental signals, integrate a wide array of information to make critical decisions, and execute complex tasks, cells exert disease-fighting effects in the body with a precision and sophistication that far exceeds that of the small molecule and protein-based therapeutics that currently dominate modern medicine. The remarkable disease-fighting capabilities of cells can be harnessed for therapeutic use, and cellular therapies are currently being explored for the treatment of conditions ranging from cancer and autoimmunity to spinal cord injury and neurodegenerative disorders.

Most cell therapy strategies today rely on the endogenous abilities of cells, but there is great untapped potential in using genetic engineering to tune, optimize, and direct their capabilities. A recent example is the use of genetic modification by researchers in adoptive T cell cancer immunotherapy to generate tumor-targeted T cells with highly potent anti-tumor and proliferative activity to effectively treat chemotherapy-resistant cancer patients.

We present several new tools for enhancing the therapeutic capabilities of engineered cells through genetic engineering. First, we describe a synthetic biology approach to orthogonal control over cell migration. Migration is a core capability of many cell types in the body that truly sets cells apart from small molecules and biologics. Specifically, we demonstrate the use of an engineered G protein-coupled receptor to direct the homing and migration of a variety of cell types toward an orthogonal small molecule drug source both in vitro and in a mouse. We also describe ongoing work using the engineered cell migration tool described above to enhance the infiltration of tumors by anti-tumor T cells.

Next, we discuss a project exploring the usage of two bacterial pathogen proteins, OspF from Shigella, and YopH from Yersinia Pestis, as reagents to precisely modulate MAPK signaling in yeast and in human T cells. Tools like these hold potential for use in the precise regulation of cellular signaling in therapeutic cells.

Finally, I conclude this dissertation with closing remarks on some of the challenges and opportunities ahead for this exciting field of scientific research.

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