Immunotherapy, which uses the body’s immune system to fight cancer, has revolutionized treatment for many malignancies. This strategy, often involving checkpoint inhibitors, has led to durable responses in some patients, even those with advanced disease. However, the therapy is not universally effective. A significant number of patients either do not respond initially or experience disease progression after an initial benefit. Understanding why immunotherapy fails and what steps follow is a necessary part of the cancer journey, as average response rates typically range from 20 to 50 percent.
Defining Non-Response and Progression
Determining if immunotherapy is failing requires careful clinical assessment, which is more complex than with traditional treatments. Oncologists measure tumor response by tracking changes in the size of measurable lesions over time. True non-response is termed progressive disease, defined as the cancer continuing to grow, often by 20% or more. A complicating factor is pseudo-progression, where the tumor appears to grow on imaging before shrinking.
This temporary increase is caused by the infiltration of immune cells, such as T-cells, into the tumor mass, leading to swelling and inflammation, not cancer cell growth. The medical team must distinguish this temporary flare-up from genuine disease progression, often requiring repeat imaging after four to eight weeks. Patients may also achieve stable disease, where the cancer neither shrinks significantly nor grows progressively. Clearer indications of treatment failure include the appearance of new lesions or a rapid, accelerated growth pattern known as hyper-progression.
Biological Mechanisms of Immunotherapy Resistance
Resistance to immunotherapy is categorized as primary or acquired. Primary resistance occurs when the tumor never responds, suggesting intrinsic mechanisms prevent the immune system from launching an effective attack. This is common in “cold” tumors, which lack infiltrating T-cells and have few genetic mutations, offering fewer targets for immune recognition.
The tumor microenvironment also contributes to primary resistance by creating a highly immunosuppressive state. Cells in this environment release inhibitory molecules, such as cytokines, that suppress T-cell function and block their ability to kill cancer cells. Furthermore, some tumors fail to express necessary proteins, like MHC Class I molecules, which are required to display tumor antigens, making the tumor invisible to T-cells.
Acquired resistance develops when tumor cells evolve under the selective pressure of immunotherapy, evading a previously successful immune response. Mechanisms include cancer cells losing the expression of target proteins required for antigen presentation. Alternatively, the tumor may upregulate alternative immune checkpoints or release more immunosuppressive factors, causing T-cells to become exhausted. These genetic changes allow the cancer to bypass the drug’s effect and resume growth.
Clinical Assessment for Stopping Immunotherapy
The decision to stop immunotherapy is guided by objective evidence of disease progression and the patient’s overall well-being. If imaging suggests growth, a confirmation scan is often performed to rule out pseudo-progression before determining failure. If the cancer continues to grow, the medical team analyzes the rate of progression and the patient’s symptoms to decide if treatment should be discontinued.
Advanced techniques, such as liquid biopsies, measure circulating tumor DNA (ctDNA) in the blood. A rising ctDNA level indicates true progression, while a falling level supports a diagnosis of pseudo-progression, aiding decision-making. A physical biopsy of the growing tumor may also be performed to check for new resistance markers, such as changes in PD-L1 expression. The final decision is shared between the patient and the oncologist, balancing tumor growth measures with quality of life. Continuing a failing therapy risks side effects and delays more effective treatment, while rapid decline or widespread progression warrants a strategy switch.
Alternative Strategies After Immunotherapy Failure
When immunotherapy fails, alternative strategies are tailored to the specific cancer type and the mechanisms of resistance.
- Traditional treatments, such as chemotherapy, are a common next step, using powerful drugs to directly kill rapidly dividing cancer cells.
- Targeted therapies are an important option if genetic testing reveals a new mutation that can be addressed with a specific drug, such as a BRAF inhibitor for melanoma or an EGFR inhibitor for lung cancer.
- The original immunotherapy may be re-challenged, either by using a different checkpoint inhibitor or by combining it with another treatment modality to overcome resistance. Combining immunotherapy with radiation therapy can sometimes induce a stronger immune response against the tumor, known as the abscopal effect.
- For patients with localized areas of progression (oligoprogression), doctors may use local treatments like surgery or focused radiation therapy to address the growing tumor sites.
- Enrolling in a clinical trial offers access to novel, experimental agents or combination strategies, which can be a valuable path when standard options have been exhausted.