CAR-T cells: Early successes in blood cancer and challenges in solid tumors

Abstract

New approaches to cancer immunotherapy have been developed, showing the ability to harness the immune system to treat and eliminate cancer. For many solid tumors, therapy with checkpoint inhibitors has shown promise. For hematologic malignancies, adoptive and engineered cell therapies are being widely developed, using cells such as T lymphocytes, as well as natural killer (NK) cells, dendritic cells, and potentially others. Among these adoptive cell therapies, the most active and advanced therapy involves chimeric antigen receptor (CAR)-T cells, which are T cells in which a chimeric antigen receptor is used to redirect specificity and allow T cell recognition, activation and killing of cancers, such as leukemia and lymphoma. Two autologous CAR-T products have been approved by several health authorities, starting with the U.S. Food and Drug Administration (FDA) in 2017. These products have shown powerful, inducing, long-lasting effects against B cell cancers in many cases. In distinction to the results seen in hematologic malignancies, the field of using CAR-T products against solid tumors is in its infancy. Targeting solid tumors and trafficking CAR-T cells into an immunosuppressive microenvironment are both significant challenges. The goal of this review is to summarize some of the most recent aspects of CAR-T cell design and manufacturing that have led to successes in hematological malignancies, allowing the reader to appreciate the barriers that must be overcome to extend CAR-T therapies to solid tumors successfully.

Keywords: Chimeric antigen receptor (CAR); Genetic engineering; Immunotherapy; T cell therapy.

Graphical abstract

Figure 1

Structures of the first through fourth generations of chimeric antigen receptors. All generations of CARs have a typical structure comprised by an extracellular antigen-binding domain (single-chain fragment variable, peptides, nanobodies, cytokines or other ligands), a hinge region (CD28, CD8, IgG1 or IgG4), a transmembrane domain (CD8α, CD4, CD3ζ, CD28, or ICOS) and intracellular signaling domains. The first-generation CARs have only the CD3ζ intracellular activation domain, while an additional co-stimulatory domain was added to second-generation CARs (e.g., CD28, 4-1BB, OX40, ICOS, CD27, KIR2DS2, and MYD88-CD40). The third-generation CAR has two co-stimulatory domains in tandem. The fourth-generation of CAR-T cells, also called armored CAR-T cells, has the same structure of second or third generation CAR. However, their producing vectors were armored with the advantage to secrete some additional molecules that give anti-tumor properties, such as the release of cytokines, chemokines, enzymes, ligands, receptors, peptides or monoclonal antibodies against different therapeutic targets.

Figure 2

Manufacture of autologous CAR-T immunotherapy for B-cell ALL and NHL: T cells engineered to express a CAR, enabling CAR-armed T cells to attack tumors.