**1. Introduction**

Esophageal cancer is one of the leading culprits of mortality worldwide and is responsible for a total number of 746,000 [1] new cases and 439,000 [2] deaths every year. A large number of these cancers are diagnosed at an advanced stage and the metastasis causes bad outcomes. Endoscopic surgery, cytotoxic chemotherapy and radiotherapy remain to be the active and essential clinical treatment but only provide modest benefits, with median overall survival (OS) only in the range of 8–10 months [3]. After nearly 20 years of fast development, immunotherapy turned to be a promising method for treating esophageal cancer. Recent advances have brought some therapeutic regimens to be approved by Food and Drug Administration (FDA) then coming to clinical practice in first- and second-line settings (**Table 1**). The future

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


of immunotherapy is promising in treating solid tumors, yet still there is a desperate need for more effective and less toxic treatment options for patients with advanced esophageal cancer.

Immunotherapy for Esophageal Cancer http://dx.doi.org/10.5772/intechopen.78644 13

In recent years, emergence of immunotherapy towards cancer has improved the management of several malignancies dramatically, especially melanoma, renal cell carcinoma, nonsmall cell lung cancer and so on, shedding light on its usage on esophageal cancer as well. Identification of more suppressive factors in tumor microenvironment and insights into the biology of T cell functioning yielded a large number of diverse and novel anti-tumor regimens. Global efforts continue to explore how and when to integrate these agents in treatment of esophageal cancer. Immune checkpoint inhibition through antibodies that block cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) has led to meaningful improvements in survival [4]. Vaccine adjuvant administration has also reduced tumor recurrence to some degree. CAR-T (chimeric antigen receptor T-cell) immunotherapy is a typical example of recent advances in synthetic biology, genome engineering, and cell manufacturing that has made it possible to develop highly specific and potent tumor-reactive T cells and offer many opportunities for experimentation and broader clinical translation. Combined regimens of immunotherapy with other classical esophageal treating procedures will illuminate the future of clinical oncotherapy. Recent achievements, which are illustrated below, including finished or ongoing clinical trials and laboratory findings of immunotherapy for esophageal cancer, bringing optimism for meaningful changes in treatment algorithms

A few decades ago, several rare clinical regression of advanced cancer in response to immune stimulation aroused interests in the area of cancer treatment. A passionate handful of immunologists, oncologists and surgeons carried out forward-looking researches into the relations between tumor progress and body immune system. Their respectable efforts turned the seemingly insignificant clinical phenomenon into reproducible concrete success by revealing the

At the earliest period of cancer immunotherapies, the exact mechanism remained unknown and the anti-tumor growth effect was limited yet providing impetus for in-depth study. The first effective immunotherapies aiming at directly modulating cell function using wellcharacterized recombinant cytokines including interleukin-2 (IL-2) and interferon alpha (IFNα), yet the safety was lowered associated with substantial toxicity. Other cytokines, including IFNγ, IL-4, IL-7, IL-10, IL-12, IL-15, IL-18, IL-25, etc., failed to provide substantive benefit. The following breakthrough was the emerging conception of monoclonal antibodies (mAbs) targeting tumor cell surface receptor proteins (human epidermal growth factor receptor 2 (HER2)/Neu, epidermal growth factor receptor (EGFR), etc.) and were integrated into cancer care. Vaccination therapies using the modified peptide, whole tumor, recombinant proteins, dendritic cells (DCs), and adjuvants were only modestly successful. With

and for better outcomes in this fatal disease.

**2.1. History of immunotherapy**

hidden mechanisms of tumor response.

**2. Immunotherapy regimens for esophageal cancer**

ACT: adoptive cell therapy; CIK: cytokine-induced killer cells; CTL: cytotoxic T-cells; VEGFR: vascular endothelial growth factor receptors; PD: programmed cell death receptor; EC: esophageal cancer; ESCC: esophageal squamous cell carcinoma; GEJC: gastroesophageal junction carcinoma.

**Table 1.** Recent or completed clinical trials of potential therapeutic approaches for immunotherapy of esophageal cancer.

of immunotherapy is promising in treating solid tumors, yet still there is a desperate need for more effective and less toxic treatment options for patients with advanced esophageal cancer.

In recent years, emergence of immunotherapy towards cancer has improved the management of several malignancies dramatically, especially melanoma, renal cell carcinoma, nonsmall cell lung cancer and so on, shedding light on its usage on esophageal cancer as well. Identification of more suppressive factors in tumor microenvironment and insights into the biology of T cell functioning yielded a large number of diverse and novel anti-tumor regimens. Global efforts continue to explore how and when to integrate these agents in treatment of esophageal cancer. Immune checkpoint inhibition through antibodies that block cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) has led to meaningful improvements in survival [4]. Vaccine adjuvant administration has also reduced tumor recurrence to some degree. CAR-T (chimeric antigen receptor T-cell) immunotherapy is a typical example of recent advances in synthetic biology, genome engineering, and cell manufacturing that has made it possible to develop highly specific and potent tumor-reactive T cells and offer many opportunities for experimentation and broader clinical translation. Combined regimens of immunotherapy with other classical esophageal treating procedures will illuminate the future of clinical oncotherapy. Recent achievements, which are illustrated below, including finished or ongoing clinical trials and laboratory findings of immunotherapy for esophageal cancer, bringing optimism for meaningful changes in treatment algorithms and for better outcomes in this fatal disease.
