PD-1 Inhibitors Plus Chemoradiotherapy for Metastatic Nasopharyngeal Carcinoma: an Open-label Single-arm, Phase II Trial

Nasopharyngeal carcinoma (NPC) is one of the most common malignant tumors of the head and neck, which is derived from the epithelial cells of the nasopharynx. According to the statistics of global cancer data in 2020, there are about 129100 newly diagnosed cases of nasopharyngeal carcinoma (NPC) in the world every year, the incidence rate is less than 5 / 100000, and about 73000 people die from NPC every year. There are obvious ethnic and regional differences in the incidence of nasopharyngeal carcinoma. From the global perspective, it is more likely to occur in the yellow race, and southern China and Southeast Asia are high incidence regions of nasopharyngeal carcinoma. According to statistics, the incidence rate of nasopharyngeal carcinoma in southern China is as high as 30.29/100000 males and 13.09/100000 females. The incidence rate of male was higher than that of female. Because nasopharyngeal carcinoma is sensitive to radiotherapy and chemotherapy, and because it is adjacent to the spinal cord, brainstem, temporal lobe, optic nerve, cochlea, mandible and other important tissue structures, it cannot be treated surgically. Therefore, radiotherapy (RT) or radiotherapy combined with chemotherapy (chemotherapy) is the standard treatment for nasopharyngeal carcinoma.

Although the diagnosis and treatment of nasopharyngeal carcinoma have been greatly improved under the background of the development of imaging technology and the era of precision radiotherapy, the situation it faces is still not optimistic. On the one hand, 4% - 10% of newly diagnosed nasopharyngeal carcinoma has distant metastasis; on the other hand, about 10% of nasopharyngeal carcinoma has local and regional recurrence after intensity modulated radiation therapy (IMRT) ± chemotherapy, and 15% - 30% of patients have distant metastasis after radical treatment. Therefore, recurrence and metastasis are still the main causes of treatment failure of nasopharyngeal carcinoma. This poses a severe challenge to the treatment mode of nasopharyngeal carcinoma (NPC).

In the era of traditional treatment, surgery is the first choice for the treatment of recurrent nasopharyngeal carcinoma. The standard treatment for patients with recurrent or metastatic nasopharyngeal carcinoma (R / M NPC) that cannot be cured by surgery is platinum based dual drug palliative systemic chemotherapy. At present, the GP regimen of gemcitabine combined with cisplatin is the standard first-line treatment for R / M NPC, but the progression free survival (PFS) of first-line chemotherapy is still less than 7 months, and the median overall survival (OS) is difficult to exceed 30 months [17]. In view of the limited progress of chemotherapy drugs, we urgently need new treatment schemes to prolong the survival time of R / M NPC patients. Immunotherapy is a hot topic in R / M NPC Research in recent years, and it is expected to prolong the long-term survival of patients. Immunotherapy also has a large number of clinical studies in R / M NPC patients, making the treatment of nasopharyngeal carcinoma enter an era of immunotherapy.

The occurrence of nasopharyngeal carcinoma is related to the chronic infection of Epstein Barr virus (EBV). Nasopharyngeal carcinoma cells infected with EBV express target proteins of CD4 and CD8 positive T cells (CD4 + T and CD8 + T), and nasopharyngeal carcinoma cells infected with EBV undergo four different latent cycles (phase 0-IV). The researchers found that NPC cells expressed specific latent proteins (EBNA1, LMP1, LMP2 and lmp2b) in latent phase II. Through basic research, it was found that these four latent proteins are EBV antigens expressed by nasopharyngeal carcinoma cells, contain more CD4 + T and CD8 + T cell epitopes, and are almost only expressed in nasopharyngeal carcinoma cells. Therefore, these four latent proteins are ideal targets for immune precision therapy. On the other hand, there are a large number of tumor infiltrating lymphocytes (TILs) in tumor tissues, including a large number of CD4 + T and CD8 + T lymphocytes, which can accurately attack EBV antigens expressed by nasopharyngeal carcinoma cells. However, in patients with nasopharyngeal carcinoma with high lymphocyte infiltration, tumor cells can still continue to grow. This phenomenon indicates that there is an immunosuppressive microenvironment in nasopharyngeal carcinoma. Immunotherapy can effectively improve the immunosuppressive microenvironment, making immunotherapy more widely used in the occurrence, development and clinical diagnosis and treatment of nasopharyngeal carcinoma. Inhibitory receptors expressed by T cells, antigen-presenting cells and other cells exert corresponding immune effects after binding with their corresponding ligands, which are collectively referred to as "immune checkpoints". Among them, programmed death receptor-1 (PD-1) and its ligand programmed death ligand-1 (PD-L1) are important targets of immunotherapy.

PD-L1 (also known as CD274 and B7-H1) is a type I transmembrane protein containing 290 amino acids in the immunoglobulin superfamily, which is similar to the immunoglobulin light chain. In 1999, it was found that it is expressed in the heart, placenta, lung and skeletal muscle and regulates T cell proliferation. Through anti-T cell receptor and CD28 costimulatory signal, it binds to its main receptor PD-1 in trans and CIS, thereby inhibiting the function of anti-tumor PD-1 positive T cells. PD-L1 also interacts in cis and trans with another known receptor, the immune co signaling molecule CD80, to prevent co stimulation of T cells. PD-1 / PD-L1 pathway maintains the normal immune state of the body. In the tumor microenvironment, PD-L1 expressed or overexpressed on the surface of tumor cells binds to the PD-1 target expressed on the surface of T cells, inhibits the normal function of T cells, weakens the recognition and response ability of T cells to tumor cells, thereby realizing tumor immune escape and forming an immunosuppressive microenvironment. In short, the main anti-tumor mechanism of PD-1 / PD-L1 inhibitors is to block PD-1 and its ligand PD-L1, which are involved in attenuating the activation pathway of T cells, and prevent or reverse the acquired peripheral tolerance to tumor antigens, thus leading to T cell recovery, reducing T cell failure or death, increasing T cell memory and anti-tumor immune cell infiltration in tumors, enhancing T cell activity, playing an anti-cancer role, and significantly prolonging the survival of patients. Some researchers further found that PD-L1 overexpression was common in NPC patients, which may be related to EBV infection. Comprehensive analysis shows that there are a large number of immune cells in NPC tissues, but due to EBV infection and other reasons, NPC cells overexpress PD-L1, resulting in immunosuppressive effect. The use of PD-1 immune checkpoint inhibitors can theoretically reactivate the immune response, so that lymphocytes infiltrating the tumor microenvironment of nasopharyngeal carcinoma can play an immune role, and ultimately achieve the goal of tumor suppression. Immunotherapy based on PD-1 / PD-L1 immune checkpoint inhibitors has made a breakthrough in the treatment of nasopharyngeal carcinoma. At present, many studies on anti-PD-1 monoclonal antibody in nasopharyngeal carcinoma have been officially published.