The Efficacy of Bevacizumab and Serplulimab Combined With Recombinant Mutant HumanTumor Necrosis Factor(rmhTNF-NC) in the Treatment of Malignant Ascites

Inclusion Criteria:

* Age ≥18 years old, gender unlimited;
* Malignant ascites confirmed by histology or cytology as originating from digestive system tumors (malignant confirmed by ascites cytology or clinically diagnosed as peritoneal metastases by imaging and symptoms);
* Patients with more than a moderate amount of abdominal fluid, who have failed initial treatment or have been treated with conventional chemotherapy drugs and/or biological response modulators intravenously. Moderate ascites is defined as:

  * B ultrasound examination of ascites ≥3cm in lying position;
  * Accompanied by clinical symptoms (chest tightness, shortness of breath, abdominal distension and discomfort, which were judged by researchers to be related to abdominal fluid accumulation);
* ECOG physical status is 0-2;
* Expected survival time \>3 months;
* Cardiopulmonary function is basically normal;
* For adequate organ function, subjects must meet the following laboratory criteria:

  * Peripheral blood imaging: WBC≥4.0×109/L, PLT≥80×109/L, Hb≥90g/L;
  * Renal function: serum creatinine ≤2×ULN and creatinine clearance (calculated by Cockcroft-Gault formula) ≥40 ml/min;
  * Liver function: total bilirubin ≤1.5× upper limit of normal value (ULN); Or total bilirubin \>ULN but direct bilirubin ≤ ULN; Aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤2.5×ULN (ALT or AST ≤5×ULN in patients with liver metastasis);
  * Good coagulation function, defined as International standardized ratio (INR) or prothrombin time (PT) ≤1.5 times ULN;
* Thyroid stimulating hormone (TSH) ≤ULN; If abnormal, T3 and T4 levels and clinical manifestations should be investigated, and comprehensive assessment of non-acute activity can be included;
* Non-surgical sterilization or female patients of reproductive age who are required to use a medically approved contraceptive method (such as an IUD, contraceptive pill or condom) during the study treatment period and for 6 months after the end of the study treatment period; Women of reproductive age who were not surgically sterilized had to be negative for serum or urine HCG within 7 days prior to study enrollment. And must be non-lactation period; For men whose partners are women of childbearing age, effective contraception should be used during the trial and within 6 months after the last administration of the study drug;
* Voluntarily enrolled in this study, with good compliance, signed written informed consent, and able to cooperate with follow-up observation.

Exclusion Criteria:

* History of allergy to tumor necrosis factor and its derivatives, bevacizumab analogues, and Serplulimab;
* Malignant diseases other than digestive tract neoplasms were diagnosed within 5 years prior to initial administration (excluding radical basal cell carcinoma of the skin, squamous epithelial carcinoma of the skin, and/or carcinoma in situ after radical resection);
* Received any other investigational drug therapy or participated in an interventional clinical investigator within 7 days prior to initial dosing; Or received anti-tumor drug treatment (including Chinese herbal medicine with anti-tumor indication) within 7 days prior to the first use of the study drug;
* Pregnant or lactating women, women of childbearing age who did not want to use contraception during the study period; Or the man is unwilling to use effective contraception during treatment and during the following 1 year;
* Significant damage to the function of important organs;
* Patients with obvious bleeding tendency;
* Clinically significant or uncontrolled heart disease, including unstable angina pectoris, acute myocardial infarction within 6 months prior to first dosing, New York Heart Association Class III/IV congestive heart failure, and uncontrolled arrhythmia (in subjects who are allowed to wear a pacemaker or have atrial fibrillation and have a well-controlled heart rate);
* Presence of ECG changes or medical history that investigators consider clinically significant; Screening QTcF interval \>480 ms, subjects with indoor block (QRS interval \>120 ms) can use JTc interval instead of QTc interval (if JTc is used instead of QTc, JTc must be ≤340 ms);
* Uncontrolled hypertension, systolic blood pressure \>160 mmHg or diastolic blood pressure \>100 mmHg after optimal medical treatment, history of hypertensive crisis or hypertensive encephalopathy;
* Severe acute infection that is not under control; The patient is having fever (\> 38℃), or has suppurative and chronic infection, and the wound is prolonged and does not heal;
* Patients with encapsulated abdominal effusion confirmed by imaging; A definite diagnosis of abdominal infection;
* Persons infected with acute or chronic active hepatitis B or hepatitis C, hepatitis B virus (HBV) DNA\>2000IU/ml or 104 copies /ml; Hepatitis C virus (HCV) RNA\> 103 copies /ml; Hepatitis B surface antigen (HbsAg) and anti-HCV antibodies were both positive. After nucleotide antiviral therapy, those who were lower than the above criteria could be included in the group. A known history of human immunodeficiency virus (HIV) infection or a confirmed positive immunotest result;
* Patients with obvious evidence of bleeding tendency or history within 3 months prior to enrollment (hemorrhage \>30 mL within 3 months, hematemesis, stool, and blood in the stool), hemoptysis (\>5 mL fresh blood within 4 weeks); People with a history of inherited or acquired bleeding or coagulation disorders. Have clinically significant bleeding symptoms or definite bleeding tendency within 3 months, such as gastrointestinal bleeding, hemorrhagic gastric ulcer, etc.; Arterial or venous thrombotic disease was present 6 weeks before enrollment;
* Known history of allogeneic organ transplantation and allogeneic hematopoietic stem cell transplantation;
* Had a major surgical procedure (craniotomy, thoracotomy, or laparotomy) within 4 weeks prior to the first dose of study therapy or expected to require major surgery during study therapy;
* Complications of toxicity and/or major surgery have not fully recovered before starting treatment;
* Women who are pregnant or nursing, or who are expected to become pregnant or give birth during the study period from screening visits to completion of safety follow-up visits (male subjects to 90 days after the last dosing);
* Radiotherapy was received within 4 weeks prior to the first administration of the study drug. Subjects must have fully recovered from radiation-related toxicities without the need for corticosteroid therapy, confirming the rule out of radiation pneumonia. For palliative radiotherapy for non-CNS disease, a 2-week washout period is allowed;
* Patients with uncontrollable neurological, mental illness or mental disorder, poor compliance, unable to cooperate with and describe the response to treatment; Patients with uncontrolled primary brain tumor or central nervous metastases, with obvious cranial hypertension or neuropsychiatric symptoms;
* There are other conditions that researchers consider inappropriate to participate in this experiment.