The Multi-Purpose Tool of Tumor Immunotherapy: Gene-Engineered T Cells

Abstract

A detailed summary of the published clinical trials of chimeric antigen receptor T cells (CAR-T) and TCR-transduced T cells (TCR-T) was constructed to understand the development trend of adoptive T cell therapy (ACT). In contrast to TCR-T, the number of CAR-T clinical trials has increased dramatically in China in the last three years. The ACT seems to be very prosperous. But, the multidimensional interaction of tumor, tumor associated antigen (TAA) and normal tissue exacerbates the uncontrolled outcome of T cells gene therapy. It reminds us the importance that optimizing treatment security to prevent the fatal serious adverse events. How to balance the safety and effectiveness of the ACT? At least six measures can potentially optimize the safety of ACT. At the same time, with the application of gene editing techniques, more endogenous receptors are disrupted while more exogenous receptors are expressed on T cells. As a multi-purpose tool of tumor immunotherapy, gene-engineered T cells (GE-T) have been given different functional weapons. A network which is likely to link radiation therapy, tumor vaccines, CAR-T and TCR-T is being built. Moreover, more and more evidences indicated that the combination of the ACT and other therapies would further enhance the anti-tumor capacity of the GE-T.

Keywords: Adoptive T cell therapy; Gene-engineered T cell; Tumor associated antigen; Tumor immunotherapy; Viral vectors and non-viral vectors..

Figure 1

CAR-T immunotherapy is rapidly developing in China and CD19 is the dominant TAA (The vast majority of the data comes from: clinicaltrials.gov.) Figure 1A is indicated the numbers of new initiated CAR-T clinical trials each year and the United States and China account for most of them. But, Israel, Japan, Sweden, United Kingdom and Australia have also carried out similar clinical trials, as well. Figure 1B is indicated the antigen distribution of CAR-T immunotherapy targeting (in total). It is very clearly that CD19 is the dominant TAA. At the same time, a wide variety of TAAs are selected.

Figure 2

The speed of TCR-T therapy development is in a stable level and NY-ESO is the dominant TAA (The vast majority of the data comes from: clinicaltrials.gov.) Figure 2A-B is indicated the numbers of new initiated TCR-T clinical trials each year and the United States is the dominant leader. But, United Kingdom, China, Japan, Netherlands and Canada have also carried out similar clinical trials in recent year. Figure 2C-E is indicated antigen distribution of TCR-T immunotherapy targeting (in total). It is very clearly that NY-ESO-1 is the dominant TAA. At the same time, a wide variety of TAAs are selected.

Figure 3

The multidimensional interaction of TAAs and tumors in TCR-T gene therapy A tumor can be killed by a variety of antigenic peptide-specific TCR-T. At the same time, an antigen peptide-specific TCR-T can kill a variety of different organ-derived tumors. Footers: AML: acute myelogenous leukemia; MDS: myelodysplastic syndrome; CML: chronic myelogenous leukemia; NSCLC: non-small cell lung cancer

Figure 4

Some strategies to optimize the security and efficacy of genetically T cells immunotherapy Six strategies in different directions were applied for optimizing the safety and efficacy of ACT.

Figure 5

The weapons of gene-modified T cells. In order to confer T cells the stronger anti-tumor ability, seven different weapons are equipped on the gene-modified T cells bodies.