As a matter of fact, tumor immunotherapy is divided into two categories. One is to show immune cells the tumor features, then direct them to locate and kill tumor cells. And another immunotherapy is to unblock the tumor immune tolerance or shielding effect to monitor and attack tumor cells.The first method is usually applied to immune cells due to the use of the body’s own immune cells, while the latter is used for small molecule drugs and antibody drugs mainly to block the immune signal, such as PD-1/PD-L1.
As two main technologies of tumor immunotherapy, CAR-T (Chimeric Antibody Receptor Engineered T Cell) and genetically modified T cell receptors (Gene Modified TCR) both have a long history. One of the commonalities of these two techniques is to improve the ability of T cell receptors to recognize and attack specific antigenic cell antigens by means of genetic modification. And therefore, they are collectively referred to as “T cell receptor redirection” technology.
Fig.1 T cells with engineered specificity (Makalowski, 2015)
CAR-T directly changes one part of TCR into a specific antibody, allowing T cells to directly attack cancer cells under the guidance of antibodies. The T cell usually invades into cancerous tissue with its ability to identify cancer cells. In fact, we can find T cells with specific recognition ability for cancer cell-associated antigen (TumorAsociation Antigen, TAA), including CEA, Her-2, CD19, gp100, MART-1, MAGA-A3, NY-ESO-1, etc. These TAAs have the relatively specific expression in different cancers and thus become the target of the immune system. Nonetheless, these natural antitumor T cells can’t attack cancer cells effectively with the weak recognization ability. In this case, the partial affinity of these TCRs for the corresponding TAA can be enhanced by partial gene modification. That’s why “Gene-modified TCR” technology is also known as “Affinity-Enhanced TCR” technology.
Infusion of modified T cells can also cause fatal toxicity because the target expression of normal organizations leads to acute irreversible cardiopulmonary toxicity. All targeted toxicity is because that transformed T cells can not distinguish between the expression of antigen-targeted normal cells and tumor cells. The toxicity of high-affinity TCR-modified T cells may be related to the affinity maturation process, since the production of high-affinity TCRs for “non-tumor targeting” will be limited under physiological conditions. It is necessary to carefully screen high affinity TCRs, and to study its target protein other than the epitope recognition in the TCR designing process. It is reported that specific TCR-T cells infusing HLA-A2 / MAGE-A3 can produce neurotoxicity.
The greatest uncertainty about the use of modified T cells is whether the new enhanced cellular effects induced by biosynthesis can cause accidental target sterilization. Non-tumor targeted toxicity of CAR-T cells and off-target toxicity of TCR cells are of particular interest. There are many ways to mitigate these problems. We found that transfection of T cells with mRNA encoding CAR to limit CAR expression only in transfected T cells was helpful in assessing the direct toxicity of the cells. When the toxic reaction occurs, stopping the cell infusion will rapidly weaken the toxicity. Researchers have also proposed a number of methods for inducing gene modification of T cell apoptosis, likely to be integrated so that T cells can be removed on demand to meet stringent safety requirements.
Reference
1. Makalowski, Jennifer, and Hinrich Abken. “Can Redirected T Cells Outsmart Aggressive Melanoma? The Promise and Challenge of Adoptive Cell Therapy.” Melanoma-Current Clinical Management and Future Therapeutics. IntechOpen, 2015.