Safety and Efficacy Evaluation of 4th Generation Safety-engineered CAR T Cells Targeting Sarcomas

Patients with late staged and/or recurrent sarcoma have poor prognosis despite complex multimodal therapy. Therefore, novel curative approaches are needed.This study will combine two different ways to fight sarcoma: antibodies and CAR-T cells. Several immune checkpoint antibodies have been examined on various tumors with good outcomes. Sarcoma is known to express increased levels of surface antigens that can be targeted by CAR-T cells. Thus, in this study, the 4SCAR-IgT cells targeting sarcoma surface antigens will be infused in dose escalation cohorts.This study will assess the feasibility, safety, efficacy and side effects of CAR T cells immunotherapy in patients who have sarcoma that is relapsed or late staged.

Inclusion criteria

• Stage Ⅲ，Ⅳ sarcoma patients or recurrent sarcoma patients;
• Age: ≥ 18 and ≤65 years of age at the time of enrollment;
• At least 4 weeks since any chemotherapy or radiotherapy and at least 1 week since immunosuppressive therapy such as using steroid hormone before enrollment;
• Side effects of chemotherapy have been well managed;
• Malignant cells are target antigen positive(higher than ++) confirmed by IHC, quantitative PCR or sequencing;
• Karnofsky /jansky score of 50% or greater;
• Expected survival > 6 weeks;
• ANC≥ 1×10^6/L，PLT ≥ 1×10^8/L;
• Pulse oximetry of≥90% on room air；
• Adequate hepatic function,defined as aspartate aminotransferase(AST)< 5 times upper limit of normal(ULN),serum bilirubin < 3 times ULN;
• Adequate renal function,defined as serum creatinine less than 2 times ULN,if serum creatinine more than 1.5 times ULN,creatinine clearance rate test is needed;
• Patients must have autologous transduced T cells at levels greater than 15%;
• Sign an informed consent and assent.

Exclusion criteria

• The disease is progresseing rapidly;
• The patient is receiving therapy of other new drugs;
• Evidence of tumor potentially causing airway obstruction;
• Epilepsy history or other CNS diseases;
• Patients who need immunosuppressive drugs because of GVAD;
• History of long QT syndrome or severe heart diseases;
• Uncontrolled active infection;
• Active hepatitis B virus,hepatitis C virus and HIV infection;
• Receiving systemic corticosteroid 2 weeks before enrollment except for inhaled steroids;
• Previous treatment with any gene therapy;
• Creatinine>2.5mg/dl or ALT/AST>3 times normal or bilirubin>2.0 mg/dl;
• Patients who have other uncontrolled diseases would preclude participation as outlined;
• Pregnant or lactating women;
• Patients previously experienced toxicity from cyclophosphamide;
• Patients who have CNS sarcoma;
• In condition that may bring risks to subjects or interference to clinical trials.