A single-arm clinical study on the efficacy and safety of the novel oncolytic virus Ad-TD-nsIL12 combined with PD-1 inhibitors in the treatment of recurrent high-grade glioma

This study is a single-arm, single-center, exploratory clinical trial evaluating the preliminary efficacy and safety of the oncolytic virus Ad-TD-nsIL12 in combination with a PD-1 inhibitor for the treatment of recurrent HGG. It is planned to enroll 12-15 HGG patients and use a treatment regimen of Ad-TD-nsIL12 combined with a PD-1 inhibitor to preliminarily assess the efficacy and safety of this regimen.

Inclusion Criteria:

1. Willing and able to provide written informed consent for the study
2. Be at least 18 years old from the date of signing the informed consent form
3. Patients with high-grade glioma (HGG) who have recurred/progressed after receiving standard treatment and confirmed to meet the 2021 edition of the World Health Organization (WHO) classification criteria for central nervous system tumors by histopathology
4. According to the RANO 2.0 evaluation criteria, there is at least one measurable lesion, that is, the maximum vertical diameter of the lesion is ≥ 10mm
5. No diagnosis of immunodeficiency
6. Suitable for placement of Omaya capsule as judged by the investigator and eligible for intratumoral administration
7. KPS score ≥ 50 points, predicted survival ≥ 2 months
8. Organ function is good, as defined below:

1) Blood routine (no blood transfusion or other treatment within 14 days): absolute neutrophil value ≥1.5×10^9/L, platelet count ≥100×10^9/L, hemoglobin ≥90g/L, white blood cell count ≥3.0×10^9/L; 2) Coagulation function: thromboplastin time (APTT) ≤ 1.5 times the upper limit of normal (ULN), international normalized ratio (INR) ≤ 1.5 times ULN; 3) Liver function: total bilirubin (TBIL) ≤1.5 times ULN, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 times ULN; 4) Renal function: serum creatinine ≤1.5 times ULN, or creatinine clearance ≥ 50 mL/min 9. Echocardiography shows normal cardiastolic function, left ventricular ejection fraction (LVEF) ≥50%, no pericardial effusion and severe arrhythmias 10. Participant has no active pulmonary infection 11. Participants are able to have gadolinium contrast enhanced scans 12. Participants and partners of childbearing potential and sexual activity must be willing to use a medically approved effective method of contraception, such as double-barrier contraception, during treatment and for 6 months after the last dose, and men agree not to donate sperm 13. Females of childbearing potential must have a negative blood pregnancy test result within 7 days prior to the first dose and are willing to undergo additional pregnancy testing during the study. Females of childbearing potential who have not been surgically sterilized (i.e., bilateral tubal ligation, bilateral oophorectomy, or total hysterectomy) or who are not postmenopausal; Menopause is the cessation of menstruation for 12 months in women over 45 years of age ≥ and excludes other causes of amenorrhea. In addition, serum follicle-stimulating hormone (FSH) levels in women under 50 years of age must be in the postmenopausal range to confirm menopause 14. Good compliance, willing and able to follow all research processes, and cooperate with observation and follow-up

Exclusion Criteria:

1. Received treatment with any other unmarketed investigational drug within 4 weeks prior to the first dose
2. Major organ surgery (excluding needle biopsy) or significant trauma within 4 weeks before the first dose, or need to undergo elective surgery during the study
3. Those who have a history of cell therapy, gene therapy, or oncolytic virus treatment
4. Patients who are unable to undergo magnetic resonance imaging (MRI) or single-photon emission computed tomography (SPECT) due to obesity or the presence of certain metals in the body, especially pacemakers, infusion pumps, metal aneurysm clips, metal prostheses, joints, rods, or plates
5. Known psychiatric disorder or substance abuse that would interfere with cooperation with the requirements of the study
6. Adverse reactions of previous anti-tumor therapy have not recovered to CTCAE 6.0 grade ≤ grade 1 (except for toxicities judged by the investigator to have no safety risk, such as alopecia, grade 2 peripheral neurotoxicity, etc.)
7. Pregnant or breastfeeding women
8. Presence of active hepatitis B or hepatitis C virus infection
9. History of immunodeficiency, including HIV/AIDS infection
10. Patients with active infection or uncontrollable infection requiring intravenous systemic treatment, or unexplained fever >38.5°C during screening and before the first dose
11. Allergy to immunotherapy and related drugs
12. Patients with current heart disease or poorly controlled hypertension requiring treatment
13. Patients with current unstable or active ulcers or gastrointestinal bleeding. 14. Patients with a history of organ transplantation or awaiting organ transplantation

15. Severe coagulation disorders or other obvious evidence of bleeding risk; History of gastrointestinal bleeding; Any other bleeding event ≥ CTCAE2 level in the past 6 months 16. Participants who have received systemic steroid drugs (> 10 mg/day of prednisone or equivalent) or other immunosuppressive agents within 14 days before the first dose; The following are excluded: treatment with topical, ocular, intraarticular, intranasal, and inhaled corticosteroids; Short-term use of corticosteroids for prophylaxis (e.g., for contrast allergy prevention) 17. History of severe cardiovascular disease, such as ventricular arrhythmias requiring clinical intervention; QTc interval> 480 ms; Acute coronary syndrome, congestive heart failure, stroke, or other grade III or above cardiovascular events within 6 months prior to the first dose; New York Heart Association (NYHA) cardiac function classification ≥ class II or left ventricular ejection fraction (LVEF) < 50% 18. Other incurable malignancies within the past 3 years or at the same time, except for carcinoma in situ that is considered clinically curable, such as cervical cancer in situ and basal cell carcinoma of the skin 19. Participants have active or previously suffered autoimmune diseases with the possibility of recurrence (including but not limited to: systemic lupus erythematosus, rheumatoid arthritis, vasculitis, etc.), except for clinically stable autoimmune thyroiditis 20. Individuals who have received live attenuated or recombinant vaccines within 4 weeks before the first administration, or inactivated vaccines within 2 weeks before the first administration 21. Individuals who have previously received immunotherapy and experienced irAE with a grade ≥3 22. Individuals with a history of encephalitis, multiple sclerosis, or other central nervous system infections 23. Individuals with cerebral herniation syndrome 24. Individuals deemed by the researchers to be unsuitable for participation in this clinical study for other reasons