Gastric cancer immunotherapy represents a modern approach to treating stomach cancer, utilizing the body’s natural defense mechanisms. This treatment aims to empower the immune system to recognize and eliminate cancer cells. It functions by enhancing the immune system’s inherent capabilities, offering a focused strategy against the disease.
How Immunotherapy Works Against Cancer
The immune system constantly surveys the body, identifying and neutralizing foreign invaders like bacteria and viruses, as well as abnormal cells, including cancerous ones. Immune cells, particularly T cells, are equipped to detect specific markers on these problematic cells, initiating a targeted response to destroy them. This natural surveillance mechanism helps to prevent or slow cancer growth.
Cancer cells, however, can develop sophisticated strategies to evade this immune detection. They may undergo genetic changes that make them less recognizable to immune cells or produce proteins on their surface that inactivate immune cells. Some cancer cells can also alter surrounding healthy cells, creating an environment that interferes with the immune response.
Immune checkpoints are proteins on immune cells that regulate immune responses. These checkpoints normally prevent the immune system from overreacting and attacking healthy tissues. Cancer cells can exploit these checkpoints by displaying partner proteins that bind to the checkpoints on T cells, sending an “off” signal that prevents the T cells from attacking the tumor.
Immune checkpoint inhibitors are designed to block these interactions. By preventing the “off” signal, these inhibitors effectively “release the brakes” on the immune system, allowing T cells to remain active and identify and attack cancer cells more effectively. This enables the immune system to mount a strong anti-tumor response, shrinking tumors or slowing their growth.
Immunotherapy Approaches for Gastric Cancer
For gastric cancer, a primary focus of immunotherapy involves immune checkpoint inhibitors, particularly those targeting the PD-1/PD-L1 pathway. Programmed death-1 (PD-1) is a protein on T cells, while its partner, programmed death-ligand 1 (PD-L1), is on the surface of some gastric cancer cells. When PD-1 binds to PD-L1, it signals the T cells not to attack the cancer cells, suppressing the immune response.
Drugs like nivolumab (Opdivo), pembrolizumab (Keytruda), and tislelizumab (Tevimbra) are PD-1 inhibitors that block this interaction. These inhibitors have shown efficacy in treating advanced gastric cancer and are approved for use in various settings, including first-line therapy.
Another immune checkpoint protein targeted in cancer treatment is CTLA-4 (cytotoxic T-lymphocyte-associated protein 4). While PD-1/PD-L1 inhibitors are more commonly used in gastric cancer, research is exploring dual blockade strategies. For instance, a bispecific antibody called cadonilimab, which inhibits both PD-1 and CTLA-4, has shown promise in improving survival for patients with specific types of gastric cancer, even those with low PD-L1 expression.
Combination therapies are employed for gastric cancer. Immunotherapy drugs like nivolumab and pembrolizumab are administered alongside chemotherapy. This approach combines the immune-boosting effects of immunotherapy with the direct cancer-killing effects of chemotherapy, potentially leading to more comprehensive tumor control.
Patient Eligibility and Treatment Outcomes
Determining who can benefit from gastric cancer immunotherapy involves specific biomarker testing. One important biomarker is the expression level of PD-L1 on tumor cells and tumor-associated immune cells. PD-L1 expression is measured using a combined positive score (CPS), which considers the number of PD-L1-positive tumor cells and immune cells relative to the total number of tumor cells. High PD-L1 expression indicates a greater likelihood of response to PD-1/PD-L1 inhibitors.
Another significant biomarker is microsatellite instability-high (MSI-H) status or a deficiency in mismatch repair (dMMR) genes. Tumors with MSI-H/dMMR have more genetic mutations, which can make them more recognizable to the immune system. Approximately 6% of advanced gastric cancer patients exhibit MSI-H/dMMR status. Patients with MSI-H/dMMR gastric cancer respond well to anti-PD-1 therapy, with higher objective response rates compared to those without MSI-H.
Immunotherapy is considered for patients with advanced or metastatic gastric cancer, or when other treatments like chemotherapy have not been fully effective. While immunotherapy has shown promising results, including durable responses, it is not universally effective. The overall effectiveness can vary, and a significant proportion of patients may not respond to treatment.
The selection of appropriate patients is an ongoing area of research, focusing on identifying additional biomarkers that can more accurately predict treatment response. This personalized approach aims to maximize immunotherapy’s benefit while minimizing unnecessary treatments for those less likely to respond.
Managing Immunotherapy Side Effects
Immunotherapy can lead to a distinct set of side effects known as immune-related adverse events (irAEs). These occur because the activated immune system, while targeting cancer cells, can sometimes also attack healthy tissues and organs. These side effects can emerge at any point during treatment or even after it has concluded.
Common irAEs can affect various organ systems. Skin problems, such as rashes, dry skin, or itching, are common. Gastrointestinal issues like diarrhea and colitis (inflammation of the colon) are also common. Fatigue is another side effect.
Endocrine disorders, including hypothyroidism, hyperthyroidism, thyroiditis, and diabetes, can arise due to the immune system affecting endocrine glands. Less common but more severe irAEs include pneumonitis (inflammation of the lungs) or myocarditis (inflammation of the heart muscle).
Early detection and prompt management of irAEs are very important to prevent serious complications. If mild side effects occur, careful observation may be sufficient. For more severe reactions, classified as Grade 2 or 3, immunotherapy may need to be temporarily halted, and treatment with corticosteroids, which suppress the immune system, is initiated. With timely intervention, patients recover from these adverse events without lasting severe consequences.