Brain Gliomas, GBM, High-Grade Gliomas
Conditions
Keywords
B7-H3, CAR-γδT, allogeneic
Brief summary
B7-H3 is expressed at low levels in normal tissues but overexpressed in various tumor tissues. The ubiquitous expression of B7-H3 in tumors of different grades is a key feature for brain gliomas. The immunohistochemistry study showed that B7-H3 is abundantly expressed on both glioma (especially high-grade glioma) cells and tumor-associated endothelial cells. For GBM, the expression of B7-H3 is intensely positive, especially on tumor cells and vascular endothelial cells, which makes B7-H3 a potential immunotherapeutic target. γδ T cells recognize tumor cells without being restricted by MHC molecules, and thus can be used in allogeneic therapy without the risk of causing graft-versus-host disease. This study is an open-label, single-arm, dose-escalation and dose-expansion clinical study aimed at evaluating the safety and efficacy of allogeneic B7-H3 CAR γδT in patients with malignant glioma.
Interventions
BIOLOGICALAllogenic B7-H3 CAR-γδT cell(QH104)
Dose escalation (3+3) : dose 1 (1 × 10\^7 CAR+cells) , dose 2 (3 × 10\^7 CAR+cells), dose 3 (6× 10\^7 CAR+cells), once every 4 weeks via an Ommaya reservoir or intrathecal administration. Dose expansion 1: dose of RP2D, once every 4 weeks via an Ommaya reservoir or intrathecal administration. Dose expansion 2: 3 × 10\^7 CAR+cells, every two weeks for three consecutive months, then changed to once every 4 weeks via an Ommaya reservoir or intrathecal administration.
Sponsors
Dushu Lake Hospital Affiliated to Soochow University
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* 1)Age 18-70 years old (both ends included), both male and female; * 2)At least one evaluable lesion, with previous biopsy or histopathological confirmation of high-grade glioma (WHO grade 3-4), and after comprehensive treatment, imaging examination indicates continued progression or recurrence; * 3\) The pathological tissues removed by surgery can be used for immunohistochemical detection of target proteins (paraffin sections should be within half a year), and the expression of B7-H3 is positive; * 4\) KPS ≥ 60 points; * 5)Expected survival \> 3 months; * 6)Substantially normal bone marrow reserve function and normal liver and renal function (laboratory tests need to be fulfilled before receiving QH104 Cell Injection for the first time):White blood cell count (WBC) ≥ 3 x 10\^9/L;Lymphocyte count (LY) ≥ 0.8 x 10\^9/L;Hemoglobin (Hb) ≥ 90g/L;Platelet (PLT) ≥80×10\^9/L;Albumin transaminase (ALT) & albumin transaminase (AST) \<1.5×ULN;Serum creatinine (Cr) \<1.5 x ULN;Total bilirubin \< 1.5 x ULN;PT & PTT ≤ 1.25 x ULN. * 7)No obvious hereditary diseases; * 8)Normal cardiac function with cardiac ejection index \>55%; * 9)No bleeding and coagulation disorders; * 10)Women of childbearing age (15-49 years old) must have had a pregnancy test with a negative result within 7 days prior to the start of treatment, and subjects are willing to use contraception during the clinical trial and for 3 months after the last cell infusion; * 11\) Sign the informed consent form.
Exclusion criteria
* 1)Pregnant and lactating women; * 2)Those with organ failure:Heart: Class III and IV;Liver: up to grade C of the Child-Turcotte Liver -Function Classification;Kidney: chronic kidney disease stage 4 or above; renal insufficiency stage III or above;Lungs: symptoms of severe respiratory failure with involvement of other organs;Brain: central nervous system abnormalities or impaired consciousness; * 3)patients with combined second tumors; * 4)patients with active hepatitis B or C virus, HIV infection, or other untreated active infection; * 5)any severe, uncontrolled systemic autoimmune disease or any unstable systemic disease, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, ulcerative colitis, Crohn's disease, and temporal arteritis; * 6)Current systemic use of steroid cell (except for recent or current use of inhaled steroids) substances; * 7\) have a chronic disease requiring immunologic or hormonal therapy; * 8\) have an allergy to immunotherapy and related cells; * 9\) 10)Patients with a history of organ transplantation or who are awaiting organ transplantation; * 10)Participation in other clinical trials within the previous 30 days; * 11)Those who are not suitable for clinical trials for other reasons in the opinion of the investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Incidence of Adverse Events (AEs) | 12 months | AE is defined as any adverse medical event from the date of the cell infusion to 12 months after B7-H3 CAR-γδT cells infusion. Among them, cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome (ICANS) were graded according to American Society for Transplantation and Cellular Therapy (ASTCT) criteria, graft-versus-host disease (GVHD) according to criteria defined by the Mount Sinai Acute GVHD International Consortium. Other AEs were graded according to common terminology criteria for adverse events (CTCAE) v5.0. |
| Phase 1:Incidence of Dose-Limiting Toxicities (DLTs) | 28 days after the first dose of B7-H3 CAR-γδT cells | DLT was defined as B7-H3 CAR-γδT cells-related events with onset within first 28 days following infusion |
| Phase 1:Maximum tolerated dose (MTD) | 28 days after the first dose of B7-H3 CAR-γδT cells | — |
| Phase 1: Recommended phase 2 dose (RP2D) | 28 days after the first dose of B7-H3 CAR-γδT cells | — |
Secondary
| Measure | Time frame |
|---|---|
| Pharmacokinetics: copy number of B7-H3 CAR-γδT cells in cerebrospinal fluid(CSF) | 28 days after the first dose of B7-H3 CAR-γδT cells |
| Disease Control Rate (DCR) | 6 months |
| Pharmacodynamics: Peak level of cytokines in CSF | 28 days after the first dose of B7-H3 CAR-γδT cells |
| Phase 2: Overall survival (OS) | 6 months, 9 months and 12 months |
| Phase 2: Progression Free Survival (PFS) | 6 months |
Countries
China
Outcome results
None listed