Genetically engineered CAR T-immune cells for cancer therapy: recent clinical developments, challenges, and future directions

Abstract

Cancer immunotherapy offers tremendous clinical outcomes in cancer management with the potential to induce sustained remission in patients with refractory disease. One of these immunotherapy modalities is the adoptive transfer of autologous T-cells that are genetically engineered ex vivo to express chimeric antigen receptors (CARs). These receptors can direct T-cells to the surface antigens of tumor cells to initiate an efficient and specific cytotoxic response against tumor cells. This review elucidates the structural features of CAR T-cells and their different generations reaching the recent 4th generation (TRUCK). The step-wise treatment process using CAR T-cell therapy and some of the updated prominent clinical applications of this treatment modality in both hematologic and solid malignancies are also covered in the present review. The success of CAR T-cell therapy is still encountered by several limitations for a widespread clinical application of this treatment modality, these challenges along with the recent innovative strategies that have been developed to overcome such drawbacks, as well as, the approaches and future directions aiming for a commercial low cost CAR T-cell immunotherapy modality, are all covered in the present review.

Natural killer cells in clinical development as non-engineered, engineered, and combination therapies

“…Following CAR-T models [ 203 ], several NK cell product developers have included an inducible human caspase 9 transgene (iCasp9) in their CAR designs. The iCasp9 is fused to the human FK506-binding protein (FKBP), and administration of a small molecule, the chemical inducer of dimerization (CID) Rimiducid, results in dimerization and activation of the iCasp9-CID complex, which in turn activates the caspase signaling cascade leading to NK cell apoptosis [ 204 , 205 ]. Anti-CD19 scFv-CAR-NK cells from MD Anderson and Takeda are equipped with iCasp9 (Additional file 2 : Table S2, rows 12–13 and 16; Additional file 4 : Table S4, row 11).…”

Recent findings on chimeric antigen receptor (CAR)-engineered immune cell therapy in solid tumors and hematological malignancies

“…To improve the limitations of the first CAR generation, in the second generation of CARs, two intracellular signaling domains (such as CD28 or 4–1BB) were introduced to the cytoplasmic tail of CARs [ 21 ]. In the third generation of CARs, Three costimulatory domains were introduced to improve T-cell activation signals and modify T-cell survival, produce more cytokines, and have a better antitumor cytotoxic effect [ 22 , 23 ]. Finally, by adding a cytokine inducer to the base of a second-generation or the third-generation construct, the fourth generation of CAR T-cells, also known as T-cells redirected for universal cytokine killing (TRUCKs), was established [ 24 , 25 ].…”