Chimeric Antigen Receptors: A Paradigm Shift in Immunotherapy

Abstract

Cancer immunotherapy is emerging as an effective and dependable approach to induce durable responses and survival benefit in several cancers. Two approaches, one based on antibody therapy to block immune inhibitory checkpoints and the other on the genetic engineering of T lymphocytes, have yielded dramatic clinical results in recent years, earning cancer immunotherapy the title “breakthrough of the year” by the journal Science in 2013. Based on the success of targeting CD19 in B cell malignancies, chimeric antigen receptors (CARs) have established themselves as a powerful means to redirect and enhance the natural properties of both CD8+ and CD4+ T lymphocyte subsets. Dual-signaling CARs not only redirect and activate T cells but also reprogram their effector, metabolic, and survival functions, enabling the rapid manufacture of tumor-specific agents for any given cancer patient. This approach marks a major shift in cell-based therapy, which previously depended on the identification and expansion of rare naturally occurring T cells with therapeutic potential, but now relies on the genetic engineering and manufacturing of optimized T cell products. Several challenges remain to tailor this approach to tackle cell tumors, which will require identifying suitable CAR targets and overcoming multiple obstacles in a complex tumor microenvironment.