Combination Immunotherapy Targeting Sarcomas

Study Overview
=================
Brief Summary
-----------------
The aim of this clinical trial is to assess the feasibility, safety and efficacy of a combination low dose chemotherapy and immunotherapy in patients who have sarcoma that is relapsed or late staged. Another goal of the study is to assess the safety and efficacy of the therapy that combines multiple CAR T cells followed by sarcoma vaccines.

Detailed Description
-----------------
Patients with late staged and/or recurrent sarcoma have poor prognosis despite complex multimodal therapy. Therefore, innovative interventions are needed. Sarcoma is known to express increased levels of surface antigens that can be targeted by CAR-T cells. In addition, studies have shown that low dose chemotherapy such as doxorubicin may modulate surface PD-L1 level and enhance immunotherapy effects. This study will combine multiple CAR T cells with low dose chemotherapy to treat sarcoma, and followed by maintenance sarcoma vaccines. The purpose of this clinical trial will assess the feasibility, safety, efficacy and side effects of this combination therapy in patients who have sarcoma that is relapsed or late staged.

Official Title
-----------------
Safety and Efficacy Evaluation of a Combination Immunotherapy Targeting Sarcomas

Conditions
-----------------
Sarcoma, Osteoid Sarcoma, Ewing Sarcoma

Intervention / Treatment
-----------------
* Biological: Multiple sarcoma-specific CAR-T cells and sarcoma vaccines


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Stage Ⅲ，Ⅳ sarcoma patients or recurrent sarcoma patients; Age: ≥ 6 months and ≤80 years of age at the time of enrollment; At least 2 weeks since the last standard chemotherapy or radiotherapy and immunosuppressive therapy such as steroid hormone before enrollment; Side effects of chemotherapy have been well managed; Confirmed malignant cell expression of CART target antigens by IHC or flow Karnofsky /jansky score of 50% or greater; Expected survival > 8 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 sufficient autologous CART cells at does greater than 0.5x10^6 cells/kg body weight; Sign an informed consent and assent. Exclusion Criteria: The disease is progressing rapidly; The patient is receiving therapy of other new drugs and under evaluation; Evidence of tumor potentially causing airway obstruction; Epilepsy history or other CNS diseases; Patients who need immunosuppressive drugs; History of long QT syndrome or severe heart diseases; Uncontrolled active infection; Active hepatitis B virus, hepatitis C virus or 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 such as obstruction of lung function would preclude participation as outlined; Pregnant or lactating women; Patients previously experienced toxicity from cyclophosphamide and doxorubicin; Patients who have CNS sarcoma; In condition that may bring risks to subjects or interference to clinical trials.

Ages Eligible for Study
-----------------
Minimum Age: 1 Year
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Multiple sarcoma-specific CAR-T cells<br>Patients who have confirmed surface antigens including GD2, PSMA, Her2, CD276 or other markers | Biological: Multiple sarcoma-specific CAR-T cells and sarcoma vaccines<br>* 1 infusion, CART 1x10^6 1x10^7 cells/kg via IV and vaccines 1-5x10^6 irradiated cells via subcutaneous injection<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of CART cells infusion | Safety of CART cells in patients using CTCAE version 4.0 standard to evaluate the level of adverse events | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival Rate | Percentage of participants with objective response as determined by the investigator based on Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) | 1 year | 
| Treatment response rate of sarcomas | Defined as the proportion of patients who achieved complete remission (CR), partial remission (PR), stable disease (SD), or progressive disease (PD) based on CT imaging analysis. | 1 year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Sarcoma, Chemotherapy, Doxorubicin, CART, Vaccine