Chimeric antigen receptor modified T (CAR-T) cell therapy still has multiple difficulties in solid tumors, such as absence of tumor specific antigens, complex immunosuppressive tumor microenvironment, and tumor heterogeneity. In this study, investigators developed a novel hypoxia-stimulated CAR expression system (HypoSti.CAR) that could enable CAR-T cell effectively expand and survive in hypoxic tumor microenvironment. After accomplishment of animal model verification, investigators conduct this clinical trial in order to assess the in vivo safety, feasibility and efficacy of HypoSti.CAR-HER2 T cells in HER2 antigen positive advanced solid tumors.
1. Age from 18 to 75 years with estimated life expectancy >3 months.
2. Histopathological confirmed advanced or metastatic solid tumors failed to at least first-line treatment or initially diagnosed advanced/metastatic solid tumors that have no NCCN guideline recommended standard first-line therapy. HER2 antigen expression percentage ≥ 30%.
3. Have at least one measurable target lesion.
4. Fresh solid tumor samples or formalin-fixed paraffin embedded tumor archival samples within 6 months are necessary; Fresh tumor samples are preferred. Subjects are willing to accept tumor rebiopsy in the process of this study.
1. Active, known or suspected autoimmune diseases.
2. Known brain metastases or active central nervous system (CNS). Subjects with CNS metastases who were treated with radiotherapy for at least 3 months prior to enrollment, have no central nervous symptoms and are off corticosteroids, are eligible for enrollment, but require a brain MRI screening.
3. Subjects are being treated with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of enrollment.
4. History of severe hypersensitive reactions to other monoclonal antibodies.
Single group
HypoSti.CAR-HER2 T cells
Biological/VaccineDose escalation: dose -1 (1×10\^6 cells/kg) ,dose 1 (3×10\^6 cells/kg) , dose 2 (6×10\^6 cells/kg), dose 3 (1×10\^7 cells/kg), dose 4 (1.5×10\^7 cells/kg). Dose expansion: RP2D
Albumin-bound paclitaxel
DrugAdministered intravenously at dose of 100-200mg/m2 on day -5
Cyclophosphamide
DrugAdministered intravenously at a total dose of 15-30mg/kg on day -3 and day-2
Fludarabine
DrugAdministered intravenously at dose of 30mg/m2/d on day -3 and day -2 only in the first infusion of HypoSti.CAR-HER2 T cells
Incidence of treatment related adverse events
Treatment related adverse events are defined as any medical events since the initiation of preconditioning chemotherapy. Adverse events will be graded by CTCAE V5.0
Incidence of dose limiting toxicities (DLTs)
Dose limiting toxicities are defined as HypoSti.CAR-HER2 T cell related adverse events within the first 28 days that meet the following criteria: grade 3 or higher CRS or CRES, grade 3 or higher cutaneous/ mucosal toxicity, and any other grade 4 toxicities.
Determination of the maximum tolerated dose (MTD)
Maximum tolerated dose is defined as the highest dose that is less than or equal to 2 DLT among 6 subjects.
Objective response rate (ORR)
Objective response rate is defined as complete response (CR) or partial response (PR) by RECIST 1.1or iRECIST
Time to response (TTR)
Time to response is defined as the time from HypoSti.CAR-HER2 T cell infusion to first assessed CR or PR by investigators according to RECIST 1.1or iRECIST.
Duration of response (DOR)
Duration of response is defined as the time from objective response (OR) until documented tumor progression date among responders.
Progression Free Survival (PFS)
Progression Free Survival is defined as the time from HypoSti.CAR-HER2 T cell infusion to documented disease progression or death.
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Chinese PLA General Hospital
Lead sponsor
Fudan University
Collaborator
