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.

The Quantity of Autocrine IL-2 Governs the Expansion Potential of CD8+ T Cells

“…In clinical trials, retroviral vectors have been used already successfully to engineer T cells, such as to express tumor-or virus-specific TCRs, chimeric Ag receptors, immunosuppressive cytokines, or enzymatic genes (41,42). Although clinical responses are promising, some responses seem to be transient (43,44). Combining ex vivo expansion of diseasespecific T cells with transduction of the IL-2 gene and subsequent vaccination might be a promising approach to treat persistent viral infections and cancer.…”

Adenovirus Improves the Efficacy of Adoptive T-cell Therapy by Recruiting Immune Cells to and Promoting Their Activity at the Tumor

“…Although CD19-expressing hematologic malignancies in particular seem amenable to adoptive chimeric antigen receptor (CAR) T-cell therapy (2), efficacy in solid tumors is lacking possibly due to T-cell hypofunction (3)(4)(5). Recently, several approaches have been developed to improve the activity of genetically redirected antitumor T cells in solid tumors, with the main focus being on modification of T-cell costimulatory genes, receptor affinities, and optimal target molecules (3,4). Nevertheless, these advances alone may not be sufficient to reverse the effects of the immune-suppressive nature of the tumor microenvironment (TME).…”

To affinity and beyond: Harnessing the T Cell receptor for cancer immunotherapy

“…Of 8 clinical trials assessed reviewed by Kuert et al, 5 report therapy-associated toxicities and 3 of 8 trials reported lethal toxicities likely owing to specificity of transferred TCRs for tissue-restricted antigen. 84 2 of 3 studies with lethal toxicities were targeted to MAGE-A3 antigen. Autopsy of patients showed dysregulated brain function and pointed to a previously unappreciated expression of MAGE-family proteins in brain tissue.…”