The potential and promise for clinical application of adoptive T cell therapy in cancer

Abstract

Adoptive cell therapy has revolutionized cancer treatment, especially for hematologic malignancies. T cells are the most extensively utilized cells in adoptive cell therapy. Currently, tumor-infiltrating lymphocytes, T cell receptor-transgenic T cells and chimeric antigen receptor T cells are the three main adoptive T cell therapies. Tumor-infiltrating lymphocytes kill tumors by reinfusing enlarged lymphocytes that naturally target tumor-specific antigens into the patient. T cell receptor-transgenic T cells have the ability to specifically destroy tumor cells via the precise recognition of exogenous T cell receptors with major histocompatibility complex. Chimeric antigen receptor T cells transfer genes with specific antigen recognition structural domains and T cell activation signals into T cells, allowing T cells to attack tumors without the assistance of major histocompatibility complex. Many barriers have been demonstrated to affect the clinical efficacy of adoptive T cell therapy, such as tumor heterogeneity and antigen loss, hard trafficking and infiltration, immunosuppressive tumor microenvironment and T cell exhaustion. Several strategies to improve the efficacy of adoptive T cell therapy have been explored, including multispecific chimeric antigen receptor T cell therapy, combination with immune checkpoint blockade, targeting the immunosuppressive tumor microenvironment, etc. In this review, we will summarize the current status and clinical application, followed by major bottlenecks in adoptive T cell therapy. In addition, we will discuss the promising strategies to improve adoptive T cell therapy. Adoptive T cell therapy will result in even more incredible advancements in solid tumors if the aforementioned problems can be handled.

Keywords: Adoptive cell therapy; Chimeric antigen receptor; Immunotherapy; T cell receptor; Tumor-infiltrating lymphocytes.

Fig. 1

Process of TIL treatment. The tumor was excised by surgery and prepared into a single-cell suspension by mechanically cut and digestive enzymes. Different types of TILs proliferated on cell plates with high dose of IL-2, producing billions of TILs within three weeks. Any TILs that have anti-tumor effect were left as the positive TIL populations after culturing with the tumor cells of patients. TILs were then expanded to treatment levels by rapid expansion phase. Patients underwent lymphodepletion prior to receiving TILs, and then 10–150 billion TILs and high dose of IL-2 were administered into them. By Figdraw

Fig. 2

Differences between T cell receptor-transgenic T (TCR-T) cells and chimeric antigen receptor (CAR) T cells. A Transgenic TCRs were capable of forming functional TCR-CD3 complexes and did not differ from the standard TCR structure of an α/β chain heterodimer. Major histocompatibility complex (MHC)-presented intracellular peptide antigens were recognized by TCRs. The two intracellular CD3 domains triggered downstream TCR signaling upon antigen recognition. B CARs, unlike TCRs, were unable to assemble CD3 complexes, and the single-chain fragment variable (scFv) did not require MHC to recognize surface antigens. By Figdraw

Fig. 3

Summary of major barriers of Adoptive cell therapy (ACT) in solid tumors. Some of the most difficult barriers to the development of ACT in solid tumors included tumor heterogeneity, antigen loss, hard trafficking and infiltration, an immunosuppressive tumor microenvironment, and T cell exhaustion. By Figdraw