Enhancing the Specificity of T-Cell Cultures for Adoptive Immunotherapy of Cancer

Abstract

Adoptive immunotherapy is a promising approach for the treatment of cancer; however, autoimmunity against normal tissue can be a serious complication of this therapy. We hypothesized that T-cell cultures responding maximally only when engaging two antigens would be more specific for tumor cells, and less active against normal cells, as long as the tumor expressed both antigens, while normal cells expressed only one of the antigens. A model system was developed consisting of cell lines expressing either folate binding protein or erbB-2, representing 'normal' tissue, and cells expressing both antigens representing tumor tissue. Human T-cell cultures were produced using two chimeric antigen receptor vectors ('dual transduced'), or using a single chimeric antigen receptor vector (monospecific). Dual-transduced T cells responded less against 'normal' cells compared with tumor cells. This relatively simple procedure produced T-cell cultures that were as active against a tumor as the monospecific cultures used traditionally, but had lower activity against model normal cells.

An oxygen sensitive self-decision making engineered CAR T-cell

“…Such approaches mainly relied on expressing a CAR with two targeting moieties19 or expressing two CARs (targeting distinct antigens) in the same T-cell. This has been achieved by splitting the activation and costimulation on the two receptors1516 (logic AND gate) or by combining activating and inhibiting CARs (logic NOT gate)18. More recently, Lim and coworker improved the AND gate combinatorial detection of multiple antigens strategy by implementing an engineered Notch-based receptors that will function independently from the TCR pathway activated by the CAR2021.…”

“…The past years have seen the emergence of strategies to spatiotemporally control CAR T-cells, including those relying on the addition of exogenous small molecules or monoclonal antibodies to regulate67891011 or terminate121314 CAR T cell functions. Alternatively, to achieve optimal tuning of CAR T-cell targeting and functional properties, researchers have developed novel approaches based on the use of combinatorial antigen targeting, such as trans-signaling CARs151617, inhibitory CARs18, tandem CARs19 and synthetic Notch receptors2021. Integration of endogenous environmental signals, in addition to antigen recognition, may represent a valuable advancement to improve the control of the CAR T-cell technology.…”

Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape

“…tissues, a CAR that provides suboptimal activation and a chimeric costimulatory receptor that recognizes a second antigen have been used to selectively "sense" and destroy tumors that express both antigens but do not affect tumors expressing either antigen alone (36)(37)(38).…”

CAR therapy: the CD19 paradigm

“…CAR therapy, based on second-generation CARs, can be further enhanced in several ways. CARs may be combined with costimulatory ligands (87), CCRs (88)(89)(90)(91), or cytokines such as IL-15 (92,93) or IL-12 (59,94,95) to further enhance T cell potency, specificity, and/or safety. CARs may also be combined with other immune enhancers, such as anti-PD-1/PD-L1 antibodies (96), lenalinomide (97), or indoleamine 2,3-dioxygenase (IDO) inhibitors (98).…”