Is immunotherapy effective for esophageal cancer?

There are two main categories of immunotherapy strategies available – active and passive immunization. Each is subdivided, along with immune checkpoint inhibitors, monoclonal antibody therapies, vaccine therapies, and peripatetic cell therapies. Among them, immune checkpoint inhibitors are the most advanced in the treatment of esophageal cancer, and other therapies are under investigation. In this article, we will describe each of them.

Active immunization: the equivalent of “teach a man to fish”

These methods work on the immune system itself to induce the body’s immune response against cancer cells.

It is characterized by a long-lasting anti-tumor effect and an “immune memory” that “recognizes” the same tumor antigen when it is encountered again, resulting in a stronger immune response.

Immune checkpoint inhibitors, cytokine therapy, and therapeutic vaccines are common approaches to active immunotherapy.

1. Immune checkpoint inhibitors

Immune checkpoints are molecules that are expressed on immune cells and regulate immunity. Tumor cells can activate these molecules, inhibit immune cells, escape surveillance, and survive.

Immune checkpoint inhibitors are drugs developed to target the immune checkpoint, allowing immune cells to “revive” and destroy cancer cells.

Immunotherapy for esophageal cancer is based on programmed cell death protein 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) monoclonal antibodies. The mechanism of action is shown in the figure below:

To learn more about immune checkpoint inhibitors, please read:

2. Cytokine therapy

The main cytokines are: interferon, interleukin-2, colony-stimulating factor, etc., which are produced by lymphocytes, monocytes and other cells.

Interferon inhibits vascular endothelial cells, avoiding vascular proliferation in tumor cells and cutting off the grain of tumors.

Interleukin-2 stimulates immune monocytes to release anti-tumor substances such as interferon and tumor necrosis factor; it also regulates natural killer cells, which are the body’s “workhorses” against foreign invaders.

Cytokine therapy amplifies the immune killing effect and has been used for tumors such as melanoma and kidney cancer. However, the side effects are significant, and there are no clinical trials in esophageal cancer.

3. Therapeutic vaccines

Vaccines for infectious diseases involve injecting small amounts of attenuated or non-virulent viruses or bacteria into the body to activate the immune system to “fight” against them and thus defend against the corresponding “invaders. Tumor vaccine therapy adopts a similar principle by introducing tumor-associated antigens (TAAs) into the body to stimulate a specific anti-tumor immune response.

Using this principle, some doctors have tried to “heat shock” excised esophageal cancer tissue by “arming” it with heat shock proteins as antigens on dendritic cells, a type of immune cell, and injecting them into the patient. It was found that patients who received the vaccine in combination with radiation therapy had improved two-year survival rates.

Other potential tumor vaccine targets include NY-ESO-1, TTK, and others, and tumor vaccines made with these tumor-specific antigens could theoretically be effective, but none have been effective in clinical trials.

There are relatively few studies on immunotherapy of esophageal cancer vaccines, and they are still in phase I clinical trials.

Passive immunization: the equivalent of “giving a man a fish”.

Passive immunization: the equivalent of “giving a man a fish.

Passive immunotherapy does not require “mobilization” of the patient’s own immune system, but rather the physician directly inputs drugs or immune cells with anti-tumor activity into the patient’s body to kill the tumor. This is a shorter duration of treatment than active immunotherapy, which “brings in outside help”.

The main methods of passive immunization are monoclonal antibody therapy and secondary immunotherapy.

1. Monoclonal antibody therapy

The epidermal growth factor receptor (EGFR) is an important link in the proliferation signaling pathway of cancer cells, and cetuximab (cetuximab) can pinch this pathway, and several clinical trials have demonstrated its therapeutic effect on esophageal cancer.

A phase II European study found that in patients with locally advanced esophageal cancer given preoperatively with cetuximab, Folfox-4 chemotherapy (a chemotherapy regimen based on 5-fluorouracil + calcium folinic acid + oxaliplatin), and radiation, the median survival after treatment was 16 months, with 3-year survival rates of 57% and 41% for patients with squamous and adenocarcinoma, respectively.

Another phase I/II study found that patients with locally advanced esophageal cancer given preoperative radiotherapy in combination with cetuximab had a 1-year survival rate of 86%.

The study in the Chinese population found that for patients with stage II-IVa squamous carcinoma, radiotherapy combined with cetuximab (without surgery) resulted in 1- and 2-year progression-free survival rates of 85.5% and 75.1% after 2 years of follow-up.

At present, studies using monoclonal antibodies to treat esophageal cancer are mainly in phases I and II, and there is a lack of large-scale phase III clinical trials with large samples.

2. Relay immunotherapy

Adoptive cell therapy (ACT) is the process of taking immune cells from your own body or another person’s body, expanding them outside of the body, and then infusing them back into the patient to directly kill the tumor and also to mobilize the body’s immune function to fight the tumor.

What is being tried in China is the application of cytokine-induced killer cell therapy. Wang Zhiyu et al found that multiple cytokine-induced killer (CIK) cells, when infused back into patients with intermediate to advanced esophageal cancer, achieved an objective remission rate of 44. 4% and a clinical benefit rate of 80. 6%.

Subsequent immunotherapy is still being explored because of the lack of specific targets in solid tumors and poor progress.

In summary, the initial efficacy of immunotherapy for esophageal cancer has brought light to patients, and scientists are exploring ways to further screen and expand the beneficiary population.

Recent or completed clinical trials in esophageal cancer immunotherapy (as of December 2018)