For the recurrent and metastatic tumors after first-line treatment (such as lung cancer, esophageal cancer and cervical cancer), the risk of conventional fractionated secondary radiotherapy is high because the tumor is close to the hollow organs (such as heart, lung and small intestine). According to previous studies, combined chemotherapy regimens are often used, but the disease control rate (DCR) is limited, and drug resistance and poor tolerance of patients are prone to occur. The immune checkpoint inhibitors (ICB) has been considered as a new strategy for maintenance treatment of patients with recurrent and metastatic tumors, but only some patients can respond for a long time. Therefore, how to improve the clinical response rate of ICB has become an urgent problem to be solved. Pulsed low dose rate radiotherapy (PLDR), a new radiotherapy technology emerging in recent years, is expected to become a new way to solve the above difficulties. Alpaloritovorelli antibodies (QL-1706) is a new type of combination antibody independently developed by Qilu Pharmaceutical Co., Ltd. It is composed of IgG4 antibody targeting PD-1 (ipalorimab), and IgG1 antibody targeting CTLA-4 (tuvonralimab) in a fixed proportion. It has the synergistic mechanism of blocking PD-1 and CTLA-4 at the same time. The combination of these two antibodies forms a powerful synergistic effect and forms positive feedback in the tumor immune cycle. Pulsed low dose rate radiotherapy (PLDR) is a safe and feasible option for recurrent tumors with high risk of re-radiotherapy. It also has therapeutic advantages for refractory and massive tumors. The advantages of combined vascular targeting and chemotherapy have been initially demonstrated. As a new anti-tumor therapy, immunotherapy has shown clinical benefits in many types of cancer, but the overall effective rate is still limited, which may be due to the immune "desertification" of the tumor microenvironment. PLDR irradiation is expected to reverse the tumor inhibitory microenvironment by inducing the release of tumor associated antigen and increasing the killing function of T cells, activate tumor immunity and improve the response rate of immunotherapy. Based on this, this study plans to take the lead in carrying out this prospective clinical study through the combination of PLDR external irradiation and ICB treatment (QL-1706).
For the recurrent and metastatic tumors after first-line treatment (such as lung cancer, esophageal cancer and cervical cancer), the risk of conventional fractionated secondary radiotherapy is high because the tumor is close to the hollow organs (such as heart, lung and small intestine). According to previous studies, combined chemotherapy regimens are often used, but the disease control rate (DCR) is limited, and drug resistance and poor tolerance of patients are prone to occur. The immune checkpoint inhibitors (ICB) has been considered as a new strategy for maintenance treatment of patients with recurrent and metastatic tumors, but only some patients can respond for a long time. Therefore, how to improve the clinical response rate of ICB has become an urgent problem to be solved. Pulsed low dose rate radiotherapy (PLDR), a new radiotherapy technology emerging in recent years, is expected to become a new way to solve the above difficulties. PLDR technology was first proposed by Tom é et al in 2007, and was first applied to the re-radiotherapy of recurrent tumors by Richards and Charlie Ma et al. The primary principle is the low-dose high radiosensitivity (HRS) of radiobiology, that is, a certain low-dose level of radiotherapy can increase the radiosensitivity of tumor cells and reduce the toxicity of normal tissues at the same time. Alpaloritovorelli antibodies (QL-1706) is a new type of combination antibody independently developed by Qilu Pharmaceutical Co., Ltd. It is composed of IgG4 antibody targeting PD-1 (ipalorimab), and IgG1 antibody targeting CTLA-4 (tuvonralimab) in a fixed proportion. It has the synergistic mechanism of blocking PD-1 and CTLA-4 at the same time. The combination of these two antibodies forms a powerful synergistic effect and forms positive feedback in the tumor immune cycle. The combination antibody can maintain normal PD-1 antibody exposure in vivo and reduce the half-life of CTLA-4 antibody with lower toxicity and better tolerance. At present, sufficient preclinical studies of alpaloritovorelli antibodies have been completed, and a number of clinical studies are under way. The mechanism of action, safe dose range, mode of administration, toxicity characteristics and pharmacological characteristics are clear. Clinical research data show that the combination antibody of alpaloritovorelli is safe, controllable and tolerable in patients with solid tumors, and has shown encouraging efficacy in cervical cancer and other multiple tumors. Based on the results of DUBHE-C-206 trial, the combination antibody was approved by the China food and Drug Administration on September 30 of 2024, and the phase I safety test has been completed in the United States. Pulsed low dose rate radiotherapy (PLDR) is a safe and feasible option for recurrent tumors with high risk of re-radiotherapy. It also has therapeutic advantages for refractory and massive tumors. The advantages of combined vascular targeting and chemotherapy have been initially demonstrated. As a new anti-tumor therapy, immunotherapy has shown clinical benefits in many types of cancer, but the overall effective rate is still limited, which may be due to the immune "desertification" of the tumor microenvironment. PLDR irradiation is expected to reverse the tumor inhibitory microenvironment by inducing the release of tumor associated antigen and increasing the killing function of T cells, activate tumor immunity and improve the response rate of immunotherapy. Based on this, this study plans to take the lead in carrying out this prospective clinical study through the combination of PLDR external irradiation and ICB treatment (QL-1706).
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
90
Radiation 5 times per week, 2Gy each time which divided into 10 pulse doses, each pulse interval was 3 minutes, the dose rate was 0.067 Gy/min, and each treatment time was 30 minutes.
PLDR external irradiation therapy was administered simultaneously with 5mg/kg Alpaloritovorelli antibodies for a 3-week regimen, the following maintenance treatment was 2 years.
Objective response rate (ORR)
The proportion of patients whose tumor volume shrinks by 30% and can be maintained for more than four weeks, which is the sum of complete remission and partial remission (CR+PR).
Time frame: 6-12 months
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