Immunotherapy represents a significant advancement in cancer treatment, empowering the body’s own immune system to recognize and eliminate cancer cells. While effective for many patients, leading to durable responses, its effectiveness may diminish over time. This article explores how healthcare professionals identify a reduced response, the biological reasons it might stop working, and subsequent treatment avenues.
Signs of Diminished Response
Monitoring immunotherapy effectiveness involves clinical assessments and diagnostic tests. Healthcare teams regularly utilize imaging scans, such as CT, MRI, and PET scans, to measure tumor size and activity. A primary indicator of diminished response is measurable tumor progression on these scans, indicating cancer growth despite treatment. Blood tests, including tumor and inflammatory markers, can also indicate disease progression or lack of benefit.
Patients often experience changes signaling a reduced response. These can include a return or worsening of previous cancer-related symptoms, such as increased pain, fatigue, or unexplained weight loss. New symptoms may also emerge. Open communication with the care team about these changes is important for timely evaluation.
True disease progression must be differentiated from pseudo-progression. Pseudo-progression occurs when imaging scans initially show an increase in tumor size or new lesions. This temporary change is due to immune cell infiltration into the tumor, causing swelling before the immune system reduces the tumor burden. Careful monitoring and follow-up scans are used to distinguish this from actual disease progression.
Reasons for Immunotherapy Resistance
Immunotherapy resistance is complex, involving interactions between cancer cells and the immune system. Some tumors exhibit primary resistance, meaning they never respond. This can occur if tumor cells lack specific targets that immune checkpoint inhibitors block, such as insufficient PD-L1 expression. Some are “cold tumors,” lacking immune cells in their core, making them less visible to immune attack.
Genetic characteristics within the tumor can also contribute to primary resistance. Mutations or alterations in cancer cells may enable them to avoid immune recognition or destruction. These genetic factors can create a microenvironment that suppresses immune cell function, preventing an effective anti-tumor response. Understanding these intrinsic properties helps explain why some cancers are less susceptible to immunotherapy.
For tumors that initially respond, acquired resistance can develop over time. Cancer cells adapt through mutations to evade the immune system. They might lose expression of specific antigens that immune cells recognize as foreign, making them invisible. They can also develop new pathways to suppress immune cell activity.
Immune cell exhaustion, particularly T-cell exhaustion, is another mechanism of acquired resistance. When T-cells are subjected to chronic stimulation, they can become functionally impaired. These exhausted T-cells lose their ability to produce anti-tumor cytokines and proliferate effectively. This exhaustion is a significant barrier to sustained immunotherapy effectiveness.
Changes within the tumor microenvironment also contribute to acquired resistance. The tumor microenvironment can become increasingly immunosuppressive. This involves an increase in suppressive immune cells, such as regulatory T cells (Tregs) or myeloid-derived suppressor cells (MDSCs), which dampen anti-tumor immune responses. Alterations in signaling molecules and the extracellular matrix can further shield cancer cells from immune attack.
Next Steps in Treatment
When immunotherapy is no longer effective, the care team evaluates alternative systemic therapies based on the cancer type, previous treatments, and the patient’s overall health. Chemotherapy remains a common option, using drugs to kill rapidly dividing cancer cells. Targeted therapies focus on specific molecular abnormalities within cancer cells. For certain cancers, hormone therapy may be considered if tumor growth is influenced by hormones.
Clinical trials play a role in exploring novel treatment options. These research studies investigate new drugs, combinations, or therapeutic approaches, such as advanced adoptive cell therapies like CAR T-cell therapy. Participating in a clinical trial offers access to cutting-edge treatments, potentially leading to new breakthroughs. These trials are carefully designed and monitored, contributing to scientific understanding while seeking potential benefit.
When disease progression is confined to specific areas, local therapies may be considered. Radiation therapy uses high-energy beams to destroy cancer cells in a targeted region. Surgical removal of a tumor may also be an option if localized and resectable. These localized approaches can help control the disease, potentially improving quality of life.
Beyond active anti-cancer treatments, supportive care and palliative care are important components of managing the disease. Supportive care focuses on preventing and managing the side effects of cancer and its treatment. Palliative care aims to improve quality of life, providing relief from symptoms and stress. These services are provided throughout the illness, regardless of whether further anti-cancer treatment is pursued.
Subsequent treatment decisions involve collaborative discussion between the patient, family, and oncology team. This ensures all available options, benefits, risks, and alignment with patient goals are discussed. The goal is to determine the most appropriate path, prioritizing disease control and quality of life.