An Introduction to ACT Family: TIL, TCR-T, CAR-T, and CAR-NK

With the advancement of science and technology, many medical challenges are gradually being overcome. For hematological malignancies, the most popular treatment is CAR-T (chimeric antigen receptor T cells) therapy. Extremely high cost, groundbreaking efficacy, and improvement of the problem that has plagued the medical community for years are all eye-catching words that can be used to describe CAR-T as an advanced cell therapy.

Everything develops with a history, and scientific research is no exception. CAR-T therapies are a type of adoptive cell transfer (ACT) therapy, and the family includes TIL, TCR-T, CAR-NK and other approaches that have been studied historically or hold promise for the future.

• TIL

TIL (tumor-infiltrating lymphocytes) therapy, which usually extracts TIL from the patient's tumor tissue, expands and cultures them in vitro, and then injects them back into the patient, was introduced in 2002 by Steven Rosenberg from the National Cancer Institute (NCI) for the treatment of patients with metastatic melanoma.

However, TIL therapy has a variety of limitations, such as the fact that not all patients' tumor tissues produce lymphocytes, that the extracted lymphocytes may not have anti-tumor activity, and that even if they do, patients may not be able to wait for the 8-week culture process. As a result, despite therapeutic response rates of up to 50%, TIL therapy has not been widely used.

These limitations have prompted researchers to seek more broadly relevant T cells. In treating hundreds of melanoma patients before and after TIL therapy, researchers found that TILs from different patients recognized some of the same antigens that were highly expressed by tumor cells, such as MART-1 and gp100. Based on these findings, T cells that target these specific antigens would have potential therapeutic effects. These attempts to push T cell therapy into the era of targeting and recombinant modification.

• TCR-T

TCR-T (T-cell receptor-engineered T cells) is an artificial TIL produced by introducing antigen-specific TCRs into the patient's T cells through a gene transfer method, which avoids the complex isolation of TILs. This method was intensively investigated by Steven Rosenberg's team, and preliminary clinical trial results were published in 2006, with 2 out of 12 melanoma patients responding to treatment. Although the response rate was much lower than that of TIL therapy, it was the first evidence of the therapeutic effect of genetically modified T cells.

TCR-T therapy has demonstrated some therapeutic potential, but there are still many limitations, such as human leukocyte antigen (HLA) matching and the required presentation of antigens to the cell surface.

• CAR-T and CAR-NK

The emergence of CAR-T therapy has greatly expanded the scope of application of T-cell therapy, which is also based on the introduction of antigen-specific CARs into the patient's T-cells through gene introduction methods to perform tumor-killing functions. At present, CAR-T therapy has developed to the fourth generation, and the design of it is usually to regulate CAR-T cells to achieve solid tumor-killing effect, such as adding suicide genes to reduce the damage to own normal tissues after tumor removal, or adding cytokines, chemokine receptor structure to achieve tumor tissue infiltration.

Compared with CAR-T cells, CAR-NK cells are more likely to achieve allogeneic transfusion back. Currently, research on CAR-NK includes both autologous and allogeneic settings. In the autologous setting, cytokine release syndrome and neurotoxicity are reduced compared with CAR-T cells. Besides, the use of IPSC (induced potential stem cells) provides an unlimited number of NK cells, and the response to malignant cells is rapid without causing GVHDs (graft versus host diseases).

"Recent studies about CAR-NK cell therapy renewed the attention in the context of cancer immunotherapy, as these redirected effector cells might be used in the development of the off-the-shelf anti-cancer immunotherapeutic products," as introduced by a scientist from Creative Biolabs, a biotech company focusing on CAR technologies, "the future cell therapy will definitely be a product of multidisciplinary and multi-method intersection, and the combination with monoclonal antibodies, oncolytic viruses and chemotherapeutic drugs will certainly make cell therapy more outstanding."

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