Double or nothing on cancer immunotherapy

Abstract

Engineered T cells expressing two receptors distinguish malignant cells from healthy cells even in the absence of a tumor-specific antigen.

Figure 1

Strategy for designing T cells to attack tumor cells and spare normal tissues. In this scenario, antigens A and B are expressed on tumor cells, but neither are truly tumor specific. Antigen A is expressed on normal tissue 1, and antigen B is expressed on normal tissue 2; tumor cells uniquely express both antigens. T cells are transduced with a CAR that recognizes antigen A with low affinity and a CCR that recognizes antigen B with high affinity. When the engineered T cells encounter normal tissue 1 (a), they are not activated because the signal from the low-affinity CAR alone (dashed line) is not strong enough. When they encounter normal tissue 2 (b), they are also not activated because they do not receive a CAR signal (which mimics a TCR signal). The T cells become activated only when they receive both CAR and CCR signals upon encounter with tumor cells expressing both antigens A and B (c).