CLDN6-CAR-NK Cell Therapy for Advanced Solid Tumors

Study Overview
=================
Brief Summary
-----------------
This study is a single-arm, open, exploratory clinical study to evaluate the safety and preliminary efficacy of Claudin6 targeting CAR-NK cells in patients with Claudin6-positive advanced solid tumors (ovarian cancer and others)

Detailed Description
-----------------
Choose appropriate advanced cancer patients with Claudin6 expression, with written consent for the study; Perform PBMCs apheresis from the patient and isolate NK cells, transfect the NK cells with Claudin6 targeting CAR, amplify the number of transfected NK cells as needed, test the quality and killing activity of the Claudin6-CAR-NK cells and then transplant back the patients via systemic or local infusions (via artery or intra-tumor), and follow up closely to collect related results as needed; To enhance the killing capability, some CAR-NK cells are genetically engineered to express and secret IL7/CCL19 and/or SCFVs against PD1/CTLA4/Lag3; Evaluate the clinical results as needed. Will also perform the similar clinical trial on different cancer types with Claudin6 expression.

Official Title
-----------------
Phase I/IIa Trial to Evaluate Safety and Preliminary Efficacy of CLDN6-CAR-NK in Patients With CLDN6-positive Advanced Solid Tumors

Conditions
-----------------
Stage IV Ovarian Cancer, Testis Cancer, Refractory, Endometrial Cancer Recurrent, CAR NK

Intervention / Treatment
-----------------
* Biological: Claudin6 targeting CAR-NK cells


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: patients with advanced ovarian cancer or other cancers with expression of claudin6. Life expectancy >12 weeks Adequate heart,lung,liver,kidney function Available autologous transduced NK cells with greater than or equal to 20% expression of claudin6-CAR determined by flow-cytometry and killing of claudin6-positive targets greater than or equal to 20% in cytotoxicity assay Informed consent explained to, understood by and signed by patient/guardian. Patient/guardian given copy of informed consent. - Exclusion Criteria: Had accepted gene therapy before; Tumor size more than 25cm; Severe virus infection such as HBV,HCV,HIV,et al Known HIV positivity History of liver/renal transplantation Active infectious disease related to bacteria, virus,fungi,et al Other severe diseases that the investigators consider not appropriate; Pregnant or lactating women Systemic steroid treatment (greater than or equal to 0.5 mg prednisone equivalent/kg/day) Other conditions that the investigators consider not appropriate. -

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CAR-NK cell therapy group<br>Appropriate patients who could benefit from the claudin6 targeting CAR-NK cell therapy against solid cancers are chosen to be the CAR-NK cell therapy group. | Biological: Claudin6 targeting CAR-NK cells<br>* Engineering Claudin6 targeting CAR combined with/or without IL7/CCL19 and/or scfv against PD1/CTLA4/Lag3 secreting vector into NK cells, which are isolated from patients with advanced ovarian cancer or other cancers with expression of Claudin6, and then transfusing them back the patients.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety by Common Terminology Criteria for Adverse Events (CTCAE) V5.0 | The type, frequency, severity, and duration of adverse events as a result of Claudin6- CAR-NK cells infusion will be summarized. | After CAR-NK cells infusion, up to 52 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | Per Response Evaluation Criteria in Solid Tumours (RECIST 1.1) assessed by MRI or CT. ORR defined as the proportion of patients in whom a complete response (CR) or partial response (PR) is observed as best overall response, prior to progression or further anti-cancer therapy. | After CAR-NK cells infusion, up to 52 weeks. | 
| Disease control rate (DCR) | Disease control rate (DCR) defined as the proportion of patients in whom a CR or PR or stable disease (SD) (per RECIST 1.1, SD assessed at least 6 weeks after the first dose) is observed as best overall response. | up to 52 weeks. | 
| Duration of response (DOR) | Duration of response (DOR) defined as the time from first objective response (CR or PR per RECIST 1.1) to first occurrence of objective tumor progression (Progressive disease (PD) per RECIST 1.1/recurrence) or death from any cause, whichever occurs first. | up to 36 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Solid tumor, Claudin6, CAR NK