Immunotherapy can be “drug resistant”
Immunotherapy is not a panacea and, like other treatments, resistance can occur. The characteristics of resistance can be divided into primary resistance, acquired resistance, and adaptive immune resistance.
Primary resistance
Primary resistance is when a tumor patient’s initial immunotherapy is ineffective. We know that immunotherapy is not effective in all lung cancer patients. In the Keynote-024 study, the PD-1 inhibitor pembrolizumab alone was 45% effective in treating patients with non-small cell lung cancer (NSCLC) with high PD-L1 expression. This shows that even in highly selected populations, a significant proportion of patients still develop primary resistance, i.e., ineffective on first use. The probability of primary resistance is even higher in patients treated with second-line immunotherapy, with an efficiency of only about 20%.
Acquired resistance
Acquired resistance, also known as secondary resistance, is when a tumor patient is initially effective on immunotherapy, but after a period of use, resistance develops and disease progresses. Also in the Keynote-024 study, the median progression-free survival (PFS) for first-line treatment with pembrolizumab was 10.3 months. This means that secondary resistance occurs at an average of about 10 months after treatment with immune drugs.
Adaptive drug resistance
Adaptive immune resistance is when a tumor that would otherwise be recognized and attacked by the immune system “escapes” immune surveillance and attack through some adaptive changes. It can manifest as primary resistance, acquired resistance, or mixed efficacy. The mechanisms are extremely complex and include lack of antigenic mutations, loss of tumor antigen expression, loss of HLA expression, and so on. The professional community is still researching and there is much uncharted territory to be explored.
What happens after immunotherapy resistance?
What happens after immunotherapy resistance?
For primary resistance, the best approach is to reduce the occurrence of primary resistance by combining two immunotherapy drugs, such as combining a PD-1/PD-L1 inhibitor with a CTLA-4 inhibitor, or chemotherapy with a PD-1/PD-L1 inhibitor, or radiotherapy with a PD-1/PD-L1 inhibitor. For example, in patients with PD-L1 less than 1%, combination immunotherapy, such as chemotherapy combined with PD-1 inhibitors, can be used. Chemotherapy can destroy tumor cells, causing them to release more tumor-related specific antigens, making it easier for the body’s initial T cells to recognize tumor antigens, which in turn can be activated, differentiate, proliferate, and exert tumor-killing ability, making it easier to obtain an immune response than with single drugs. It is important to be alert to the fact that the toxic side effects of combination therapy are also increased.
What if the tumor load remains the same, or shrinks further, when immunotherapy is started and the tumor progresses with continued treatment? This is called acquired resistance, and clinicians will recommend that you have another tissue biopsy and genetic testing of the tumor tissue to look for possible causes of resistance. Depending on the results of genetic testing, you may be able to choose a treatment option that may target a specific genetic variant.
For example, it has been shown that tumor cells carrying mutations in the B2M gene and JAK1/JAK2 mutations are important causes of resistance to acquired immunotherapy. “JAK (Janus kinase, a tyrosine kinase) is an important link in the pathway between tumor and immune system. Combining immunotherapy with JAK inhibitors in patients with JAK mutations has the potential to reverse drug resistance. Several JAK inhibitors have been approved in the United States, but the indications are mainly for autoimmune-related diseases and not yet for lung cancer.
However, in most cases, whether primary resistance, or acquired resistance, the mechanisms have not been fully elucidated, so the common approach now is to change treatment regimens and continue different regimens of chemotherapy or radiation therapy.
In clinical practice, your doctor may individualize the management of immunotherapy resistance depending on your specific situation. There are now studies summarizing the outcomes of patients with advanced NSCLC (N=26) who have received immunotherapy resistance. More than half of the patients continued with their original PD-1/PD-L1 inhibitor after disease progression; more than half received topical therapy; and 1/4 of the patients continued PD-1/PD-L1 inhibitor therapy after receiving topical therapy. These patients who continued with PD-1/PD-L1 inhibitors had a 2-year survival rate of 92%. Although the number of patient cases in this study is small, it still suggests that after disease progression on immunotherapy, clinicians can make a clinical decision to continue treatment with the original regimen of PD-1/PD-L1 inhibitors or to change to another therapeutic treatment regimen, all in the context of your specific situation, based on a comprehensive assessment.
We recommend that you see your doctor before changing your treatment regimen, and that you do not take advice from the Internet or other lay people that could delay your disease.
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Co-reviewed by: Guangdong Provincial People’s Hospital Guangdong Lung Cancer Institute Dr. Wang Zhen, Associate Chief Physician Dr. Liu Siyang