Engineered TCR-T Cell Immunotherapy in Anticancer Precision Medicine: Pros and Cons

Abstract

This review provides insight into the role of engineered T-cell receptors (TCRs) in immunotherapy. Novel approaches have been developed to boost anticancer immune system, including targeting new antigens, manufacturing new engineered or modified TCRs, and creating a safety switch for endo-suicide genes. In order to re-activate T cells against tumors, immune-mobilizing monoclonal TCRs against cancer (ImmTAC) have been developed as a novel class of manufactured molecules which are bispecific and recognize both cancer and T cells. The TCRs target special antigens such as NY-ESO-1, AHNAK^S2580F or ERBB2^H473Y to boost the efficacy of anticancer immunotherapy. The safety of genetically modified T cells is very important. Therefore, this review discusses pros and cons of different approaches, such as ImmTAC, Herpes simplex virus thymidine kinase (HSV-TK), and inducible caspase-9 in cancer immunotherapy. Clinical trials related to TCR-T cell therapy and monoclonal antibodies designed for overcoming immunosuppression, and recent advances made in understanding how TCRs are additionally examined. New approaches that can better detect antigens and drive an effective T cell response are discussed as well.

Keywords: ImmTAC; T-cell receptors; immunosuppression; immunotherapy; suicide genes.

Figure 1

Adoptive T cell therapy. In adoptive cell therapy (ACT), cells are collected from cancer tissues/T cells which are then isolated from other cells, genetically manipulated by engineered TCR or CAR, co-cultured and proliferated, and eventually sent back into circulation.

Figure 2

The interaction between peptide MHC and T cells. Cytotoxic T cells (CD8⁺) recognize MHC-I, CD3 coupled TCRs which activate T cell signaling cascade, including calcium-dependent and protein kinase C signaling pathways (PKC). Calcium is required for activation of nuclear factor of activated T cells (NFAT) leading to expression and secretion of Interleukin (IL)-2 and activation of PKC leading to tuning and regulating the production and secretion of ILs, including IL-2, T cell migration, T cell proliferation, and autoimmunity and graft rejection. CD4⁺ T cells are able to switch off the immune system by promoting regulatory T cells (Treg). In order to activate T cell proliferation, TCR also triggers p38MAPK and PI3K/Akt pathways. Once CD4 or CD8 activates TCR, it then activates Lymphocyte-Specific Protein-Tyrosine Kinase (Lck) which triggers phosphorylation of CD3 ζ chains.

Figure 3

TCRs vs CAR and genetically modified T cells in immunotherapy. Cancer targeting receptors, TCR and CAR, are introduced to the activated T cells to empower them against special type of cancer. ζ subunit of CD3 on the surface of T cell is essential for triggering signaling cascade of T cells. In contrast to TCR which needs to be activated by endogenous CD3, CARs are hybrid receptors manufactured from a single-chain variable fragment (scFv) attached to ζ subunit of CD3. Both introduced and endogenous TCRs recognize HLA peptides on cancer cells. The CARs, instead, do not recognize HLA directly which trigger T cell signaling cascade in a TCR-independent manner.

Figure 4

The mechanism of ImmTAC action. ImmTACs are designed to activate T cells against cancer and virus-infected cells. ImmTAC is specific to both MHC-peptides (pHLA) located on the surface of the tumor and CD3s located on T cells. The ImmTAC is able to directly activate CD3 and its corresponding pathways in activated T cells. In fact, the specific role of CD4 and CD8 is to stabilize the immune synapse, an important process of T cells shortened and empowered by ImmTACs.

Figure 5

HSV-TK/GCV system vs inducible caspase-9 system. The herpes simplex virus–Thymidine Kinase/ganciclovir (HSV-TK/GCV) system eliminates tumorigenic cells and it is efficient and specific against inducible pluripotent stem cells (iPSC) that can kill the cells whose HSV-TK expression has been silenced. The HSV-TK/GCV system is used as a safety switch and it produces a toxic compound that kills the transduced cells. Another method in suicide gene therapy is introducing inducible caspase-9 (iC9) into iPSC. The iC9 dimerization activates iC9 which then triggers a caspase cascade leading to elimination of tumors originating from iPSC. Specific chemical inducers of dimerization (CID) induce iC9.