Emerging Immunotherapies and Their Impact on Gastrointestinal Cancer Surgery

Introduction

Gastric cancer is considered the fourth leading cancer in the world. It is also the fifth most common malignancy. It is a leading cause of death due to cancer and remains to be a significant treatment issue. Despite the use of advanced surgical procedures and chemoradiotherapy, the overall five-year survival rate of patients with advanced stages of gastrointestinal cancer is less than 15 percent. This is mainly due to the rapid progression of the disease, metastasis, and resistance to chemoradiotherapy. Immunotherapy has become a revolutionary approach to cancer treatment.

What Is Immunotherapy?

The term ‘cancer immunotherapy’ is a group of treatments used to strengthen immunity by triggering or regaining the ability of cytotoxic T cells or other such immune cells to destroy the cancerous cells. It can alter or strengthen the immune system to recognize and combat cancer cells. It is done in the following ways:

1. Stimulating the immune system's natural defenses to make it more effective in recognizing and eliminating cancer cells.

2. Creating substances similar to the components of the immune system and using them to repair or improve the immune system in recognizing and eliminating cancer cells.

3. New immunotherapy methods are being researched and rapidly discovered each day. It works well for some types of cancers, while some other types of cancers require other alternatives.

How Does Immunotherapy Work?

The body's immune system is a combination of organs, unique cells, and materials that help to protect the body from infections and other illnesses. They travel through the body to defend it from germs that cause infections. The immune system also keeps cancer at bay. The immune system monitors all the chemicals found in the body. It gets alerted on any foreign material it identifies and attacks it. For example, many proteins may not be present in the human body but can be present in bacteria. This is recognized as a foreign body for the immune system and attacks it. The immune system attacks and destroys any foreign body or cell unidentified as normal.

Immune cells are observed and are present around the tumor cells. Tumor-infiltrating lymphocytes, often known as TILs, indicate the immune system is reacting to the tumor. Individuals with TIL-containing tumors typically have better prognoses than those without them. Cancer cells have tactics to evade the immune system's destruction despite the immune system's ability to stop or delay the progression of cancer. The cancer cells may have some genetic changes that make them less identifiable to the immune system. They may also have other protein cells on their surface that can inhibit the immune system. They can also modify the normal healthy cells around the tumor so that they can affect the immune system’s ability to combat foreign bodies.

What Are the Types of Immunotherapy?

The various types of immunotherapy can include:

1. Immune Checkpoint Inhibitors: These are drugs that act as immunological checkpoint inhibitors. These medications enable a stronger immune cell response to malignancy by inhibiting them.

2. T-cell Transfer Therapy: It increases the innate capacity of the T-cell to combat a malignancy. The tumor cells are extracted for this treatment. The effective cells against a type of cancer are identified and replicated in the body or laboratory to attack the malignant cells. These are put in the body through a needle. Other names like adoptive cell therapy, adoptive immunotherapy, or immune cell therapy are also known for this therapy.

3. Monoclonal Antibodies: These are laboratory-produced immune system proteins engineered to bind to certain targets on cancer cells. Some monoclonal antibodies mark the cancerous cells, making them more easily recognizable and destroyed by the immune system. Hence, monoclonal antibodies are also called therapeutic antibodies.

4. Treatment Vaccines: It can strengthen the immune system’s defense against cancer cells to combat cancer. Vaccines for treatment are not the same as those that aid in disease prevention.

5. Immune System Modulators: It can strengthen the immune system's defense against cancer. While some of these substances have a more widespread effect on the immune system, others target particular areas of the immune system.

How Is Immunotherapy Used in Gastrointestinal Cancer?

Mule et al. introduced the concept of adoptive immunotherapy (AIT). It combines repeated injections of recombinant IL-2 (widely used cell culture for T-cell multiplication) with IL-2-produced Lymphokine-Activated Killer (LAK) cells to treat cancer. Despite being non-specific killer cells, LAK cells were considered effective against various tumors. However, their combined efficacy with high-dose IL-2 against metastatic GI cancer was shown to be restricted. High doses of IL-2 were found to cause severe toxicities like pulmonary edema, renal failure, fluid retention, and stimulation of vascular permeability leak that causes interstitial edema. Hence, they switched to Tumor-Infiltrating Lymphocytes (TIL), which seem to have significantly more therapeutic potential than LAK cells and are specific to tumor antigens.

Takayama et al. conducted randomized research to assess the effectiveness of autologous lymphocytes activated in vitro with recombinant IL-2 and solid-phase antibody to CD3 as adjuvant therapy for curatively resected HCC. These findings suggested that non-specific activated killer cell transfer could be useful in preventing intrahepatic cancer recurrence.

The subsequent development used antigen-specific cytotoxic T lymphocytes (CTL) to treat effector cells. Genetically modified T-cells like T‐cell receptor (TCR) T cells and Chimeric Antigen Receptor (CAR) T cells were developed. However, CAR-T treatments for gastrointestinal tumors are still under investigation. Gastrointestinal cancers may also be treated with immune checkpoint inhibitors. According to several clinical trials, patients with microsatellite instability-high (MSI-H) or Mismatch Repair Deficiency (dMMR) tumors, like gastrointestinal tract tumors, represent the most significant biomarkers. They can benefit from immune checkpoint inhibitors.

Conclusion

Despite the progressive advance of immunotherapy in cancer therapy, researchers and physicians face obstacles due to side effects, drug resistance, and low response rates. Additionally, some patient populations cannot undergo immunotherapy because it may not be beneficial for all types of cancer. Its success in gastroesophageal cancers still needs to be determined.