Adoptive T cell transfer for cancer immunotherapy in the era of synthetic biology

Abstract

Adoptive T cell transfer for cancer and chronic infection is an emerging field that shows promise in recent trials. Synthetic-biology-based engineering of T lymphocytes to express high-affinity antigen receptors can overcome immune tolerance, which has been a major limitation of immunotherapy-based strategies. Advances in cell engineering and culture approaches to enable efficient gene transfer and ex vivo cell expansion have facilitated broader evaluation of this technology, moving adoptive transfer from a "boutique" application to the cusp of a mainstream technology. The major challenge currently facing the field is to increase the specificity of engineered T cells for tumors, because targeting shared antigens has the potential to lead to on-target off-tumor toxicities, as observed in recent trials. As the field of adoptive transfer technology matures, the major engineering challenge is the development of automated cell culture systems, so that the approach can extend beyond specialized academic centers and become widely available.

Figure 1. Engineered T cells that have retargeted specificity

Bispecific and tri-specific T cells are created by introduction of genes that encode TCRs and CARs of desired specificity and affinities for tumors. The T cells retain expression of the endogenous TCR, unless this is knocked down using various approaches. CARs target surface antigens in an MHC-independent fashion. Costim, cosignaling domain such as CD28 or 4-1BB; LAT, linker for activation of T cells; scFv, single-chain variable fragment; ZAP70, zeta chain associated protein kinase 70 kDa.

Figure 2. Cell culture approaches

CTLs express αβ TCRs and are stimulated by APCs that express MHC class I. Feeder cells or artificial APC (aAPC) that express the costimulatory ligands 4-1BBL and CD83 or beads coated with agonistic antibodies enhance growth and function. T cells can be stimulated by beads or cell based aAPC in the presence of various cytokines.