Chimeric antigen receptor modified T (CART) cell therapy has been identified as a breakthrough therapy in hematologic malignancies. However, CART cell therapy yielded no satisfactory efficacy data in the study of solid tumors. One of major challenges is the complicated immunosuppressive tumor microenvironment (TME) in solid tumors. It has been reported that transforming growth factor-β (TGF-β) is one of the major regulatory factors in the TME. In this study, we construct CAR-EGFR-TGFβR-KO T cell by knocking out TGF-β receptor Ⅱ through CRISPR/Cas9 in order to study the anti-tumor activities and safety profiles of CAR-EGFR-TGFβR-KO T cell in previously treated advanced EGFR positive solid tumors.
Chimeric antigen receptor modified T (CART) cell therapy has been identified as a breakthrough therapy in hematologic malignancies. Different from the promising efficacy in leukemia, lymphoma and multiple myeloma, however, CART cell therapy yielded no satisfactory efficacy data in the study of solid tumors. One of major challenges is the complicated immunosuppressive tumor microenvironment (TME) in solid tumors. It has been reported that transforming growth factor-β (TGF-β) is one of the major regulatory factors in the TME, which plays a key role in promoting tumor initiation, metastasis, and suppressing anti-tumor immunity. In this phase Ⅰstudy, we plan to construct CAR-EGFR-TGFβR-KO T cell by knocking out TGF-β receptor Ⅱ through CRISPR/Cas9 in order to study the anti-tumor activities and safety profiles of CAR-EGFR-TGFβR-KO T cell in the treatment of previously treated advanced EGFR antigen overexpressing solid tumors.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
30
Enrolled patients will be administered TGFβR-KO CAR-EGFR T Cells in 3+3 based escalation manner. The infused CAR+ T cell dose in phase IA will be started initially at 1-2×10\^5/kg, dose 2 will be 1×10\^6/kg,and dose 3 will be 1×10\^7/kg, if DLT occurs in dose level 3, the following dose will return to 5×10\^6/kg. In expansion period, the dose of infused CAR+ T cells will be determined by the recommended cell dose from phase IA.
Chinese PLA General Hospital
Beijing, Beijing Municipality, China
RECRUITINGNumber of subjects occuring treatment related adverse events
Determining the safety profile following the initiation of treatment and grading these toxicities by CTCAE v5.0
Time frame: Up to 24 weeks following the infusion of TGFβR-KO CAR-EGFR T cells.
The percentage of enrolled patients that respond to TGFβR-KO CAR-EGFR T cell therapy.
Overall response rate is defined as the sum of partial responses and complete responses
Time frame: Up to 24 weeks following the infusion of TGFβR-KO CAR-EGFR T cells.
The percentage of enrolled patients alive and without progression at 6 months
Progression free survival (PFS) is defined as the time from enrollment to documented disease progression or death. Progression will be defined clinically or on imaging as per immune related response evaluation criteria in solid tumors (irRECIST) definition.
Time frame: 6 months
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