Resistance to PD-1/PD-L1 inhibitors has been observed previously in both melanoma and advanced kidney cancer patients treated with PD-1/PD-L1 inhibitors, as evidenced by tumor re-expansion after a period of stable disease control and resistance as assessed by irRC (Immune-Related Response Evaluation Criteria) or iRECIST (Immunotherapy Efficacy Evaluation Criteria in Solid Tumors). Some patients develop resistance right after starting the drug, which we call primary resistance. In other patients, the drug is effective in controlling the tumor for a period of time, and then resistance occurs, which we call secondary resistance.
The reasons for resistance include the emergence of a new immune escape pathway, TIM-3, mutations in important genes (JAK2, β2MG, etc.), defects in the tumor antigen delivery pathway, and dysregulation of immune metabolism. For example, the presence of TIM-3 is like a “roadblock” for PD-1/PD-L1 inhibitors to “go all the way” to bind PD-1 or PD-L1, while JAK2 gene mutations can turn the immune system into The JAK2 gene mutation turns the immune system “blind”, so that even though PD-1/PD-L1 inhibitors activate lymphocytes, they don’t find the tumor cells to attack.
Co-reviewed by: Guangdong Provincial People’s Hospital Guangdong Lung Cancer Institute Dr. Zhen Wang, deputy chief physician Kai Yin