Immunotherapy of Malignant Disease Using Chimeric Antigen Receptor Engrafted T Cells

Abstract

Chimeric antigen receptor- (CAR-) based immunotherapy has been under development for almost 25 years, over which period it has progressed from a new but cumbersome technology to an emerging therapeutic modality for malignant disease. The approach involves the genetic engineering of fusion receptors (CARs) that couple the HLA-independent binding of cell surface target molecules to the delivery of a tailored activating signal to host immune cells. Engineered CARs are delivered most commonly to peripheral blood T cells using a range of vector systems, most commonly integrating viral vectors. Preclinical refinement of this approach has proceeded over several years to the point that clinical testing is now being undertaken at several centres, using increasingly sophisticated and therapeutically successful genetic payloads. This paper considers several aspects of the pre-clinical and clinical development of CAR-based immunotherapy and how this technology is acquiring an increasing niche in the treatment of both solid and haematological malignancies.

Expression of inhibitory receptors on intratumoral T cells modulates the activity of a T cell-bispecific antibody targeting folate receptor

“…Aside from blockade of immune checkpoints, such as cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed death-1 (PD-1), [2][3][4][5] recombinant antibody-based technologies, which redirect T-cells against tumor cells, represent a promising clinical approach to harness and empower T-cells with the capacity to effectively combat cancer. 6,7 These dual specific antibodies target the T-cell receptor by binding to CD3e on T-cells with one arm, while the other arm engages a tumor cellselective surface antigen. Cross-linking of effector and target cells via such T-cell bispecific antibodies (TCBs) induces formation of an immunological synapse and polyclonal T-cell activation, which ultimately results in potent killing of the bound tumor cells.…”

Chimeric Antigen Receptor T Cells for the Treatment of Cancer and the Future of Preclinical Models for Predicting their Toxicities

“…In this approach, T-cells isolated from patients are engineered to express an activating fusion receptor that binds directly to a cell surface target that is found on tumour cells alone, or also on healthy cell types that are dispensable or whose function can be replaced [1,2].…”

Overcoming the Challenge of Transduction of Human T-cells with Chimeric Antigen Receptor (CAR) Specific for ERBB2 Antigen

“…T-cells of the immune system can eradicate disease at extreme specificity by identifying the antigen expressed by the antigen presenting cells (Maher 2012). T-cell receptors (TCRs) present on the T-cells engage antigens that are presented by the major histocompatibility complex (MHC) molecules (Maher 2012).…”

“…T-cell receptors (TCRs) present on the T-cells engage antigens that are presented by the major histocompatibility complex (MHC) molecules (Maher 2012). In most inflammatory conditions, an adaptive immune response is triggered following the presentation of peptides (non-self) by MHC molecules to immune cells.…”

“…A CAR links an antigen specific singlechain antibody fragment (scFv) to intracellular signalling domains, CD28 and CD3-ζ chain of the T-cell receptor (TCR) (Porter et al 2011). The scFv segment of the CAR is able to directly target and bind to the TAA on the tumor cells, bypassing the MHC immune recognition (Maher 2012). Thus, genetically-modified T-cells to express CAR retain its immunogenic functions against tumor cells.…”