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.
Currently, chimeric antigen receptor modified T (CAR-T) cell therapy has achieved a series of achievements in hematological malignancies, however, it still has to face plenty of obstacles in more bulky solid tumors, such as absence of tumor specific antigens, complex immunosuppressive tumor microenvironment, and tumor heterogeneity, which may taken together to restrict the efficacy of CAR-T cells in eliminating solid tumors. Previous studies found that intratumoral hypoxic microenvironment facilitated the development and metastasis of tumor cells. Meanwhile, it was difficult for cytotoxic T cells including CAR-T cells to survive and expand in such a hypoxic microenvironment. 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,which has been demonstrated in animal models. Based on the preclinical data, investigators will further conduct this clinical trial in order to test the potential of this novel system targeting HER2 antigen in vivo. In dose escalation period, at least 9 eligible patients will be enrolled and receive 5 doses of HypoSti.CAR-HER2 T cell therapy (1 × 10\^6 cells/kg, 3 × 10\^6 cells/kg, 6 × 10\^6 cells/kg,1 × 10\^7 cells/kg, 1.5 × 10\^7 cells/kg) according to the "3+3" principle. In dose expansion period, additional 10 to 21 patients will be enrolled to receive HypoSti.CAR-HER2 T cell therapy at dose of recommended phase 2 dose (RP2D), which is determined by data from dose escalation period, including occurrence of dose limiting toxicities (DLT), pharmacokinetics/pharmacodynamics, efficacy and other parameters, to furtherly evaluate the safety and efficacy profiles of HypoSti.CAR-HER2 T cell therapy.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
30
Dose 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
Administered intravenously at dose of 100-200mg/m2 on day -5
Administered intravenously at a total dose of 15-30mg/kg on day -3 and day-2
Administered intravenously at dose of 30mg/m2/d on day -3 and day -2 only in the first infusion of HypoSti.CAR-HER2 T cells
Kaichao Feng
Beijing, Beijing Municipality, China
RECRUITINGIncidence 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
Time frame: Up to 12 months following the infusion of HypoSti.CAR-HER2 T cells
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.
Time frame: Up to 28 days following the infusion of HypoSti.CAR-HER2 T cells
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.
Time frame: Up to 28 days following the infusion of HypoSti.CAR-HER2 T cells
Objective response rate (ORR)
Objective response rate is defined as complete response (CR) or partial response (PR) by RECIST 1.1or iRECIST
Time frame: Up to 3 years
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.
Time frame: Up to 3 years
Duration of response (DOR)
Duration of response is defined as the time from objective response (OR) until documented tumor progression date among responders.
Time frame: Up to 3 years
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.
Time frame: Up to 3 years
Overall Survival (OS)
Overall Survival is defined as the time from HypoSti.CAR-HER2 T cell infusion to the date of death.
Time frame: Up to 3 years
Number and copy number of HypoSti.CAR-HER2 T cell
Number and copy number of HypoSti.CAR-HER2 T cell are assessed by number in peripheral blood and tumor tissue.
Time frame: Up to 3 years
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.