Radioimmunotherapy (RIT) is a therapeutic method that uses substances that bind to tumor antigens, such as monoclonal antibodies, as targeting carriers, and tumor treatment drugs coupled with radionuclides are injected into the body to specifically bind to tumor cell-associated antigens to kill tumors with minimal damage to normal tissues. Monoclonal antibodies are used for targeted therapy in two ways: 1. Direct action: killing tumor cells through the cytolytic effect of antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). 2. Indirect action: monoclonal antibodies are used as targeting vehicles coupled with cytotoxic drugs (radionuclides, chemotherapeutic agents, toxins, etc.). After targeting the tumor, the cytotoxic effect is used to kill the tumor cells. The mechanism of action of radioimmunotherapy is mainly indirect. There are significant differences between cancer cells and normal cells. In different stages of the cellular change cycle, cancer cell degeneration and cell death occupy a high percentage, along with loss of cell membrane integrity and abnormal cell membrane surface permeability. In contrast, only few cells in healthy individuals necrotize at a very slow rate and the necrotic tissue is removed by tissue in a rapid and orderly manner; they die with only nuclear fragmentation , without paradoxical membrane permeability. Previous treatments have focused on killing living cancer cells, neglecting degenerating necrotic cells. It has been measured that, unlike normal tissues, about 50% of tumor cells undergo degeneration soon after division. Due to the lack of blood supply and abnormal response of macrophages in tumors, the degenerated cells become more and more numerous and form a large area of necrosis, which is a typical feature of malignant tumors. Since malignant tumors have necrotic areas, and at the same time degenerated or necrotic cells have membrane permeability, monoclonal antibody TNT to tumor cell nuclei can cross the tumor cell membrane and reach the necrotic area to bind with antigen in the nucleus. Pharmacodynamic, pharmacokinetic, immunohistochemical and biodistribution studies of the radioactive 131I-labeled monoclonal antibody chTNT revealed that the antibody binds to all malignant solid tumors with necrotic tissue. The tumor cell nucleus monoclonal antibody chTNT offers a new approach to the treatment of solid tumors. It is a monoclonal antibody against the nucleus of insoluble, non-spreading necrotic cells, targeting the tumor degenerating cells to reach the site of tumor necrosis; at the same time, the radionuclide bound to the monoclonal antibody chTNT kills the living tumor cells at the edge of the necrotic zone, causing new necrosis, followed by the expansion of the monoclonal antibody chTNT to the new necrotic zone and so on, expanding the necrotic zone and destroying the tumor from the inside out. This will destroy the tumor from inside out and achieve the therapeutic purpose. At present, the monoclonal antibodies used in clinical treatment and diagnosis are all mouse-derived antibodies, and the repeated use of mouse-derived antibodies as exogenous macromolecular proteins often induces the production of human anti-mouse antibodies (HAMA), which makes the treatment unable to be carried out repeatedly and seriously affects the effect. In order to reduce the immunogenicity of antibodies and improve their functions, some amino acid sequences of mouse-derived antibodies can be replaced by some amino acid sequences of human antibodies using the principle of genetic engineering technology, while retaining the specific site of antigen binding of mouse antibodies. chTNT is a chimeric antibody formed by fusing the variable region of mouse-derived antibodies with the constant region of human antibodies, which can reduce the immune response induced by mouse-derived antibodies. The immunogenicity of chTNT is greatly reduced, and no HAMA reaction occurred in any of the nearly 200 clinical studies conducted in China. Radionuclide 131I is a more desirable nuclide with low price. The half-life (T1/2) = 8.08 days, mainly releases β and γ rays, the main role of β rays range: average 0.4 L, the longest 2 L. Particle energy: 0.6 Mev. and easy to measure the amount of radiation, the procedure of radioactive antibody labeling is also relatively simple. 131I is labeled to chTNT antibody by labeling technique, and 131I is delivered to the tumor site in a targeted manner using the property that chTNT can bind specifically to tumor cells. Radioactive 131I kills living tumor cells at the edge of the necrotic zone. Iodine [131I] tumor cell nucleus human-mouse chimeric monoclonal antibody injection (131I-chTNT) as a novel monoclonal antibody for the directed treatment of solid tumors has the following characteristics: (1) Durable effectiveness. Currently, most clinical therapeutic monoclonal antibodies are tumor cell membrane monoclonal antibodies, which can only reach the surface of solid tumors and have limited efficacy, while 131I-chTNT injection exerts the monoclonal guiding effect of chTNT and the radiotherapeutic effect of 131I, with long-lasting efficacy. (2) Clinical utility. chTNT is a chimeric monoclonal antibody, which greatly reduces the possibility of HAMA, making the clinical use of radioimmune-directed therapy for malignant tumors a reality. Foreign literature reports that 131I-chTNT has affinity for a variety of solid tumors, with good localization and radioactive uptake in the center of tumor lesions, and the tumor/organ ratio can reach about 5-30 times after 3 days of drug administration. Due to the specific pathological nature of glioma and its infiltrative growth pattern, postoperative recurrence or rapid enlargement of residual tumor is almost inevitable. Systematic and regular comprehensive treatment is an effective measure to delay the patient’s life and improve the quality of survival. Radiotherapy is an important component of comprehensive treatment. However, traditional transcranial external irradiation is currently under severe challenge because the lethal dose of tumor cells should reach 7300-8000 Rad, but when external irradiation is greater than 6000 Rad it can lead to subacute or chronic brain necrosis (radiation encephalopathy) and cause more neurological dysfunction. Therefore, most specialist physicians control the total amount of radiation within 6000Rad. Intratumoral brachytherapy can avoid this drawback and achieve good therapeutic effect, which is being concerned and recommended by specialists. The dose absorbed by the irradiated tissue during external radiotherapy is about 2-4Gy per minute, while intra-stromal radiotherapy is only 0.3-1.0Gy per hour. This continuous low dose rate radiotherapy can make the proliferating tumor cells accumulate in the G2 phase (radiosensitive phase), while the normal acyclic neuronal cells stay in the G1 phase (radiosensitive phase). In addition, there are many hypoxic cells in malignant glioma tissues, which are three times less sensitive to radiation than normal oxygenated cells and are highly dependent on oxygen effect during external radiotherapy, while intratumoral brachytherapy in hypoxic state can hinder subacute brain necrosis, help repair of radiation damage, and is less dependent on oxygen effect. Intratumoral brachytherapy at 0.4-0.6 Gy/h can inhibit mitosis of tumor cells, so the regeneration rate of tumor cells is significantly reduced compared with external radiotherapy. In addition, the isotopes releasing β-rays are mostly chosen for intratumoral brachytherapy. The average survival of patients with malignant glioma of the brain is only 52 weeks, which is one of the worst prognosis of human tumors. The incidence of glioma accounts for about 50% of all brain tumors, and the clinical research on the treatment strategy of glioma is still how to kill the remaining tumor cells or inhibit their proliferation by various means on the basis of surgical resection of the main body of the tumor. In the past two years, the authors have used the monoclonal antibody-labeled I131 (131I-chTNT) solution developed by Shanghai Mei En Biotechnology Co., Ltd. to perform radioimmunotherapy in 56 cases of intra-tumoral glioma interstitial fluid, and achieved good results. The treatment methods, results and related factors are discussed. 1. Clinical data There were 56 cases in this group, including 38 males and 18 females, aged 18-70 years old, with an average of 36 years old. All cases were confirmed by surgical pathology as malignant glioma of the brain, including 34 cases of glioblastoma and 22 cases of astrocytoma (grade II-III). The first surgery was performed in 20 cases, and the rest were operated after recurrence. 2. Treatment selection The key issue in mono-directed radiotherapy is the size of the dose of nucleotide delivered to the tumor site. We have administered the drug via three routes according to the manufacturer’s requirements, namely: intrathecal injection; cerebral artery interventional injection; and chemotherapy intracapsular injection. As a result, according to the post-administration ECT nucleotide aggregation concentration test, the concentration of intra-chemotherapy capsular administration was much higher than that of intrathecal and intra-arterial administration, so we chose the route of intra-chemotherapy capsular proximity radiotherapy. The timing of treatment is generally chosen to give the drug 7 days after surgery to avoid the effect of nucleotide on incision healing. 3. Treatment method During surgery, according to the size and location of the tumor, the tumor was removed as much as possible while protecting the brain function. After complete hemostasis of the tumor cavity, the drug outlet end of the Omaya chemotherapy capsule was placed into the tumor cavity, fixed with silk thread, and the silicone pump of the drug inlet end was buried under the scalp, avoiding the scalp incision. On the 4th day after surgery, 1.5ml of compound iodine solution was given orally 3 times/day for 10 days to seal the thyroid gland and reduce the damage of radiation to the thyroid gland. The 131I-chTNT 30mci was injected into the chemotherapy capsule 7 days after surgery, and the injection was repeated once after 15-20 days. The second administration is a course of treatment, and if a second course of treatment is necessary, the interval should be one month. 4. Side effects ① Myelosuppressive vegetative, some patients have reversible white blood cell and platelet decline, which can recover by itself after the end of treatment. Some patients can use pro-blood recovery drugs. ②A few patients have fever, malaise, nausea, loss of appetite reaction, which can be relieved by itself after the end of treatment. ③A few patients had liver function changes, mainly elevated transaminases, which could recover on their own after the end of treatment. (iv) None of the cases in this group showed any impairment of thyroid function. 5. Results All patients were reexamined with CT or MRI 2 months after the last injection and compared with the imaging data before the injection. Among the cases in this group, significant effect (CR): tumor lesions disappeared in 21 cases (37.5%), effective (PR): lesions shrunk by 50% in 24 cases (42.8%), marginally effective (MR): tumor shrunk between 25% and 50% in 7 cases (12.5%), and deteriorated (PD): 4 cases (7.1%). The follow-up period was 6 months-2 years and 2 months, with an average of 1 year and 2 months. 55 cases survived at 6 months, with a survival rate of 98.2%, 54 cases survived at 1 year, with a survival rate of 96.4%, and 52 cases survived at 2 years, with a survival rate of 92.8%. There were 4 cases of death, among which 1 case died of tumor stroke 4 months after treatment; 1 case died of severe intracranial infection after shunt 9 months after treatment; 1 case died of tumor implantation metastasis 1 year and 3 months after treatment; 1 case died of tumor recurrence 1 year and 4 months after treatment. 6. Issues related to the efficacy ① Remove the tumor as much as possible during surgery to relieve the cranial hypertension and provide the time for the next treatment. ② Perform the first treatment as early as possible after surgery to ensure the reliability of early strikes. ③Nuclear dose can be increased to 40mci for those with better general condition, and reduced to 20mci for the old and weak. ④Tumor pathological grade is positively correlated with the efficacy. ⑤ Timely interventional chemotherapy will improve the sensitivity of internal radiotherapy. ⑥The efficacy is positively correlated with the patient’s general condition and negatively correlated with the patient’s age and disease duration.
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