**Author details**

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

The success of immunotherapy in some tumors came from years of research deep into the immune system and tumor itself and brought hope of healing cancer. It is worth mentioning that several immune checkpoint blockers have been or are being approved by the FDA, and it is expected that the next step will be to accelerate the pace of application of single drug or other treatment modes in combination within clinical usage. However, opportunities and challenges coexist, and there are still some key questions that have not been answered in immunotherapy. First of all, many targeted cancer drugs that treat cancer need to be explored to determine the biological dose that achieves the greatest clinical benefit with minimal toxicity. Second, given that most of the current immunotherapy is mainly to activate anti-tumor effects by activating the immune system, this kind of treatment requires patient to have some degree of immunity before receiving the initial immunotherapy. Therefore, it is imperative to fully evaluate patient's immune status and find biomarkers that predict the effectiveness of immunotherapy. In addition, there is abundant evidence that exposure to radiation and chemotherapy drugs may affect the rate of DNA mutations in tumor cells, prompting the formation of some new antigens. As the current immunotherapy is always combined with radiotherapy and chemotherapy, determining the proper dose for each regimen is the prereq-

cancer together with other solid tumors.

20 Esophageal Cancer and Beyond

**4. Conclusions and future directions**

uisite for maximum benefit of combined therapy.

Tian Wang and Yi Zhang\*

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

Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
