**3. Combined treatment**

positive patients (n = 35), but there was no statistical difference in OS compared to HLA-A\*2402-negative patients (n = 25) (4.6 mo vs. 2.6 mo, P > 0.05), yet there is a significant difference in PFS (P = 0.032) [42]. In a tumor vaccine trial hosted by Saito et al. [43] (n = 20), 4 patients with high levels of MAGE-A4 or MHC class I antigen in autologous tumor cells not only showed MAGE-A4 specific immune responses after vaccination, but compared with patients without using antibodies, their OS was also significantly prolonged. Wada et al. [44] used NY-ESO-1 as a cancer vaccine in 8 patients with esophageal cancer. The results showed that 7 patients had an immune response. Of the 6 patients evaluated for efficacy, 1 patient experienced partial remission, 2 patients continued to maintain progression-free status, and 2 patients had mixed clinical responses. Given the preliminary results of these peptide vaccines in clinical trials, safety inspections and the related researches combined with radiotherapy and chemotherapy are also being carried out gradually in treating multiple cancer types

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)

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

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

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

to 72% [47], encouraging its further usage in esophageal cancer, too.

as the mechanism of killing tumor is rather clear.

including esophageal cancer.

18 Esophageal Cancer and Beyond

and CAR-T [46].

**2.5. Adoptive cell therapy regimens**

Currently, comprehensive therapy shed light on tumor treatment to a large degree. Clinical practice has proven that it is difficult to achieve the best results with any single treatment method. Therefore, the principle of treatment for most tumors depends on comprehensive treatment. Recent research results showed that the combined usage of immunotherapy and chemotherapy in a variety of cancer treatment achieved better results than a single therapy, it can not only reverse the immunosuppression effects caused by the late stage of the tumor, increase the cross-presentation of tumor antigens, promote the proliferation of killer T cells and make it more easy to kill tumor cells, but can also reduce the incidence of adverse reactions from chemotherapy and reduce drug resistance of tumor cells to some extent. Combination of chemotherapy and immunotherapy has been a common available method in some cancer types. Neoadjuvant chemotherapy regimens together with HER2-targeted therapy achieved pathologic complete response in relapse-free survival among patients with breast cancer [58]. New treatment targeting specific mutant genes illustrated clinical success in a phase II study of metastatic melanoma combined with interleukin-2 aldesleukin and BRAF inhibitor vemurafenib [59]. The effectiveness of combined therapy can even cover the metastatic areas, in melanoma brain metastases, complete intracranial response was observed after using dual checkpoint-inhibition of talimogene laherparepvec (T-Vec), pembrolizumab and whole brain radiotherapy. Additionally, immunotherapy also showed potential augmented effect plus cryotherapy [60], focused ultrasound therapy [61] and photothermal therapy [62], etc. Tumor vaccine also took another leap when combined with other immunotherapies, clinical results showed that nivolumab in combination with talimogene laherparepvec (T-Vec) in resected melanoma carried out better outcomes [63]. The clinical value of immunotherapy and radiotherapy showed even more outstanding clinical effects, anti-tumor immune response was enhanced by anti-PD-1 immunotherapy in recurrent nasopharyngeal carcinoma, showing a bright prospect of further combination [64]. In treating esophageal cancer, there are also many creative comprehensive treatment methods that are constantly developing. In patients with drug-resistant esophageal cancer, a phase Ib/II study of low-dose decitabine-primed chemoimmunotherapy showed undeniable safety and efficacy [65]. A combination therapy of multi-peptide vaccine with chemoradiation therapy performed satisfying safety thus can be an effective treatment for patients with unresectable ESCC [66]. Novel multitarget tyrosine kinase inhibitor anlotinib in a third-line treatment of refractory advanced non-small-cell lung cancer (RA-NSCLC) provided significant PFS benefits compared with placebo, and accompanied with acceptable toxicity [67]. Though has a guaranteed future, there need to be more rational and effective trials of combinations to be excavated in the field of treating esophageal cancer together with other solid tumors.

Immunotherapy has a broad application prospect in the treatment of malignant tumors. The high frequency of esophageal cancer mutations and the effective results of immunotherapy highlighted in other gastrointestinal cancers provide strong evidence for the study of esophageal cancer immunotherapy. Treatment strategies combined with existing or new treatment

Immunotherapy for Esophageal Cancer http://dx.doi.org/10.5772/intechopen.78644 21

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modes will be the direction of future esophageal cancer treatment.

Biotherapy Center, The First Affiliated Hospital of Zhengzhou University,

\*Address all correspondence to: yizhang@zzu.edu.cn

1007/s00262-014-1521-3. PMID: 24487923

13666180420110239. PMID: 29676233

omto.2017.12.003 eCollection 2018 Mar 30. PMID: 29367945

2003;**349**:2241-2252. DOI: 10.1056/NEJMra035010 PMID: 14657432

**Author details**

**References**

Tian Wang and Yi Zhang\*

Zhengzhou, Henan, China

PMID: 29705787

PMID: 25957861
