The Principles of Engineering Immune Cells to Treat Cancer

Abstract

Chimeric antigen receptor (CAR) T cells have proven that engineered immune cells can serve as a powerful new class of cancer therapeutics. Clinical experience has helped to define the major challenges that must be met to make engineered T cells a reliable, safe, and effective platform that can be deployed against a broad range of tumors. The emergence of synthetic biology approaches for cellular engineering is providing us with a broadly expanded set of tools for programming immune cells. We discuss how these tools could be used to design the next generation of smart T cell precision therapeutics.

Figure 1. Engineered Therapeutic T Cells Provide a Transformative New Platform for Interfacing with Complex Diseases such as Cancer

Therapeutic T cells combine elements of more traditional therapeutic approaches to yield an integrated smart sense-and-response agent. The emerging field of synthetic biology is providing tools and approaches to program therapeutic cells in diverse ways.

Figure 2. Platforms for Redirecting T Cells to Cancer

(A) T cell receptors (e.g., anti-NY-ESOI) or chimeric antigen receptors (e.g., anti-CD19 CAR). (B) CAR structure includes an extracellular antigen recognition domain fused to intracellular TCR signaling domains (CD3z) and co-stimulatory domains (e.g., CD28 or 4-1BB). (C) Current status of CD19 CAR therapies. (D) Current status of engineered T cells directed toward solid tumors.

Figure 3. Functional Needs for Optimal Anti-cancer T Cell Therapy

(A) Five major functional challenges for a therapeutic T cell. (B) Breaking down how, when, and where these five challenges arise as a therapeutic T cell interacts with cancer. (C) Diagram of different types of therapeutic T cells and how well they address these five challenges. The distance of points from the center indicate how effective a cell is at addressing a particular challenge. The overlaid plots trace early generations of CAR T cells, as well as ongoing and projected next-generation improvements.

Figure 4. Emerging New Engineering Solutions for Addressing the Functional Challenges of Anti-cancer T Cells

(A–D) New molecular tools for improving therapeutic T cell tumor recognition (A), proliferation and persistence (B), remodeling of the tumor microenvironment (C), and control (D).

Figure 5. Smart Cell Therapies May Fulfill Promise of Precision Medicine

(A) The design and implementation of therapeutic immune cells will, in principle, combine tumor informatics with systems and synthetic biology to construct cell therapies strategically optimized to recognize discriminating features and to attack tumor vulnerabilities. (B) The emerging synthetic biology toolkit for cell engineering may allow modular construction of precision therapeutic programs (here modeled by an illustrative program inspired by the Scratch graphical programming language). (C) Precision informatics combined with custom engineered therapeutic cells has the potential to provide true precision therapies.