T-Cell Gene Therapy in Cancer Immunotherapy: Why It Is No Longer Just CARs on The Road

Abstract

T-cells have a natural ability to fight cancer cells in the tumour microenvironment. Due to thymic selection and tissue-driven immunomodulation, these cancer-fighting T-cells are generally low in number and exhausted. One way to overcome these issues is to genetically alter T-cells to improve their effectiveness. This process can involve introducing a receptor that has high affinity for a tumour antigen, with two promising candidates known as chimeric-antigen receptors (CARs), or T-cell receptors (TCRs) with high tumour specificity. This review focuses on the editing of immune cells to introduce such novel receptors to improve immune responses to cancer. These new receptors redirect T-cells innate killing abilities to the appropriate target on cancer cells. CARs are modified receptors that recognise whole proteins on the surface of cancer cells. They have been shown to be very effective in haematological malignancies but have limited documented efficacy in solid cancers. TCRs recognise internal antigens and therefore enable targeting of a much wider range of antigens. TCRs require major histocompatibility complex (MHC) restriction but novel TCRs may have broader antigen recognition. Moreover, there are multiple cell types which can be used as targets to improve the “off-the-shelf” capabilities of these genetic engineering methods.

CAR-T cells: Early successes in blood cancer and challenges in solid tumors

“…In the case of TCR-T, T cells are adapted to express a TCR capable of interacting with a cancer-specific peptide-MHC (P-MHC). This peptide can be a tumor-associated antigen (TAA) overexpressed by the tumor or a neo-antigen, which differs from a wild-type antigen through mutations that cannot be recognized through self-tolerance mechanisms 158 , 159 . TCRs must be compatible with human leukocyte antigen (HLA), recognizing P-MHCs, and promoting cancer cell death 160 .…”

Nanomedicine-Mediated Optimization of Immunotherapeutic Approaches in Cervical Cancer

“…T cell receptor immunotherapy utilizes lymphocytes obtained from a patient's peripheral blood, genetically modified through the insertion of αand β-chain T-cell receptors. These modified receptors are capable of recognizing specific MHC antigens [52]. Hence, T-cell receptor therapy involves selecting and targeting specific intracellular and extracellular antigens by modified T-cell receptors, in contrast to TIL therapy, where endogenous tumor-directed lymphocytes are chosen [48].…”

“…CAR T-cell therapy enhances and localizes apoptotic activity in cancer cells by redirecting T-cell killing to malignant cells expressing specific antigens [52]. CAR antigen targeting is mediated by extracellular light and heavy chain immunoglobulins which attach to T-cell receptors, enhancing the activation and persistence of CAR T cells [55,56].…”

Clinical Development of Gene Therapies: The First Three Decades and Counting

“… 45 Similarly, some of the ground work for the chicken β-actin promoter used in the approved AAV-based products was conducted more than two decades before the respective clinical programs were initiated. 46 In CAR T cell development, 47 the concept of using genetically modified lymphocytes to treat hematological malignancies was supported by the observations of immunocompetent donor T cells mediating antileukemic effects, which were made almost 40 years before approval of CAR T products. 48 Subsequently, the first notable reports on what would become CAR T cells appeared in the late 1980s.…”