**2.5. Adoptive cell therapy regimens**

The concept of ACT (adoptive cell therapy) was first proposed by Dietrich et al. [45]. It refers to the treatment of utilizing autologous or allogeneic immune cells by infusing them back into the patients after being amplified *in vitro* by certain means. Currently effector cells can be divided into two categories: the first type is non-specific immune cells, including autologous lymphokine-activated killer cells (LAK), cytokine-induced killer cells (CIK) and NK cells. Cells are isolated from peripheral blood cells and are stimulated by lymphokines or cytokines; another type of effector cells is antigen-specific T cells, including TILs, cytotoxic T cells (CTL) and genetically engineered T cells including T cell receptor transferred T-cells (TCR-T) and CAR-T [46].

The first ACT trial in human improved the survival of patients with metastatic cancer by reintroduction of CIK and recombinant IL-2 to their body, which has been successfully applied to the treatment of refractory metastatic melanoma, and for other types of cancer such as glioma, renal cell carcinoma, non-small cell lung cancer, etc. The objective response rate varies from 20 to 72% [47], encouraging its further usage in esophageal cancer, too.

So far, ACT treatment of esophageal cancer has been evaluated in several clinical trials. In the first published study by Besser et al. [48] and Toh et al. [49], mononuclear cells were isolated from peripheral blood of esophageal squamous cell carcinoma patients and were given autologous tumor cell stimulation *in vitro*. Latter results showed that half of the patients had an objective response, and 36% of the subjects achieved complete remission or partial remission. CTL and TIL cells are now hot spots for carrying out immunotherapy for solid tumors as the mechanism of killing tumor is rather clear.

TCR-T cells transduce the α and β chains of the antigen-specific high-affinity TCR into T cells and express them on the cell surface, thereby effectively identifying and killing the tumor cells expressing the antigen. Currently, the most common TAAs found in esophageal cancer are cancer testis MAGE-A3/4 and NY-ESO-1. Several studies [50, 51] showed that the expression ratio of MAGE-A3 in esophageal cancer was about 90%, and the expression rate of NYESO-1 in esophageal cancer was up to 40–90%. A preliminary phase 1 clinical trial of genetically engineered T cells was carried out by Kageyama et al. [52], TCR-T cells were readopted to patients with MAGE-A4-positive recurrent esophageal cancer, and administered the MAGE-A4 peptide vaccine subsequently, the level of TCR-T cells in the peripheral blood of 10 subjects was monitored for 5 months, and 5 of them were able to detect specific T cells continuously. Seven subjects appeared tumor progress after 2 months of treatment, but another 3 subjects survived more than 27 months.

CAR-T is another type of genetically engineered T cells. CAR-T was obtained by translocating chimeric antigen receptor such as CARs into T cells. Gross et al. [53] successfully constructed the structure of CARs into T cells for the first time to exert their specific killing function. Up to now, tens of clinical trial data of CAR-T treatment on malignant hematological malignancies have been published. The Novartis' tisagenlecleucel, a synthetic bioimmune product of anti-CD19 CAR-T cells has been approved by FDA on treating relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) in 2017 [54]. The early generation of CAR-T therapy for solid tumors did not appear ideal outcomes during clinical use [55]. The reasonable explanation might be lack of unique TAAs in solid tumors, less efficiency and persistency of T cell homing to tumor sites, and the intratumoral immunosuppressive environment strongly inhibited CAR-T cell function. Clinical trials targeting solid tumors using second or third-generation CAR techniques had been limited, but some of the more significant clinical trials are carrying out good results. Patients with metastatic or recurrent HER2-positive medulloblastoma treated with HER2-CAR-T had came out with stable conditions [56]. Feng et al. [57] showed the results of a clinical trial of an EGFR-CAR-T treatment for EGFR-positive relapsed/refractory NSCLC patients revealed partial remission in 2 of the 11 patients involved in the evaluation and 5 patients had a stable condition ranging from 2 to 8 months. There were no obvious adverse reactions in the entire clinical trial. In the treatment of esophageal cancer, no CAR-T therapy-related studies have been conducted yet. However, anti-tumor targets are now erupting in esophageal cancer. Points such as HER2 can also provide references for future steps in the development of research.
