TCR-Engineered T Cells Meet New Challenges to Treat Solid Tumors: Choice of Antigen, T Cell Fitness, and Sensitization of Tumor Milieu

Abstract

Adoptive transfer of T cells gene-engineered with antigen-specific T cell receptors (TCRs) has proven its feasibility and therapeutic potential in the treatment of malignant tumors. To ensure further clinical development of TCR gene therapy, it is necessary to target immunogenic epitopes that are related to oncogenesis and selectively expressed by tumor tissue, and implement strategies that result in optimal T cell fitness. In addition, in particular for the treatment of solid tumors, it is equally necessary to include strategies that counteract the immune-suppressive nature of the tumor micro-environment. Here, we will provide an overview of the current status of TCR gene therapy, and redefine the following three challenges of improvement: "choice of target antigen"; "fitness of T cells"; and "sensitization of tumor milieu." We will categorize and discuss potential strategies to address each of these challenges, and argue that advancement of clinical TCR gene therapy critically depends on developments toward each of the three challenges.

Keywords: T cell avidity; T cell co-stimulation; T cells; TCR affinity; TCR transgenes; antigens; inhibitory micro-milieu; solid tumors.

Figure 1

Key achievements in the field of TCR gene therapy directed against solid tumors. (A) Timeline of selected preclinical findings that have contributed to the development of TCR gene therapy. (B) Timeline of clinical findings with TCR gene-engineered T cells. Details with respect to clinically used TCRs can be found in Table 2.

Figure 2

Three challenges that determine the success rate of TCR gene therapy. In this figure, recent and successful strategies to improve TCR gene therapy have been categorized along three renewed challenges: “choice of target antigen”; “fitness of T cells”; and “sensitization of micro-milieu for T cell therapy.” Boxes provide selected strategies that are discussed in more detail in Sections “Choice of Target Antigen,” “Fitness of T cells,” and “Sensitization of Micro-Milieu for T Cell Therapy.” We propose that advancement of clinical TCR gene therapy is guided by the principles of these challenges. *Independent of choice of target antigen, it is recommended to perform stringent in silico analysis and preclinical tests to confirm that healthy cells do not express the target antigen prior to proceeding with the clinical testing of TCR-engineered T cells. **Strategies to reduce or prevent TCR mis-pairing do not only enhance T cell avidity but also reduce the potential risk of off-target toxicity. APC, antigen-presenting cells; DC, Dendritic cells; MDSC, myeloid-derived suppressor cells; Th, T helper cells; Treg, T regulatory cells.