CLDN6/GPC3/Mesothelin/AXL-CAR-NK Cell Therapy for Advanced Solid Tumors

Phase I Trial to Evaluate Safety and Preliminary Efficacy of CLDN6/GPC3/Mesothelin/AXL-CAR-NK in Patients With CLDN6/GPC3/Mesothelin/AXL-positive Advanced Solid Tumors

This study is an open, exploratory clinical study to evaluate the safety and preliminary efficacy of Claudin6, GPC3, Mesothelin, or AXL targeting CAR-NK cells in patients with Claudin6, GPC3, Mesothelin, or AXL-positive advanced solid tumors (ovarian cancer and others)

Study Overview

• Status: Recruiting
• Conditions: Stage IV Ovarian Cancer; Endometrial Cancer Recurrent; Testis Cancer, Refractory; CAR NK
• Intervention / Treatment: Biological: Claudin6, GPC3, Mesothelin, or AXL targeting CAR-NK cells

Detailed Description

1. Choose appropriate advanced cancer patients with Claudin6, GPC3, Mesothelin, or AXL expression, with written consent for the study;
2. Perform PBMCs apheresis from the patient and isolate NK cells, transfect the NK cells with Claudin6, GPC3, Mesothelin, or AXL targeting CAR, amplify the number of transfected NK cells as needed, test the quality and killing activity of the Claudin6, GPC3, Mesothelin, or AXL-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;
3. 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; some CAR-NK cells are combined with Cannabidiol(CBD) or Nicotinamide adenine dinucleotide (NAD);
4. Evaluate the clinical results as needed.
5. Will also perform the similar clinical trial on different cancer types with Claudin6, GPC3, Mesothelin, or AXL expression.

• Study Type: Interventional
• Enrollment (Estimated): 200
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Bingjia He, MD; Phone Number: +862039195965; Email: 464677938@qq.com
• Study Contact Backup: Name: Zhenfeng Zhang, MD, PhD; Phone Number: +862039195966; Email: zhangzhf@gzhmu.edu.cn

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China
      • Recruiting
      • The Second Affiliated Hospital of Guangzhou Medical University
      • Contact: Zhenfeng Zhang, MD, PHD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. patients with advanced ovarian cancer or other cancers with expression of claudin6.
2. Life expectancy >12 weeks
3. Adequate heart,lung,liver,kidney function
4. Available autologous transduced NK cells with greater than or equal to 20% expression of Claudin6, GPC3, Mesothelin, or AXL-CAR determined by flow-cytometry and killing of claudin6-positive targets greater than or equal to 20% in cytotoxicity assay
5. Informed consent explained to, understood by and signed by patient/guardian. Patient/guardian given copy of informed consent. -

Exclusion Criteria:

1. Had accepted gene therapy before;
2. Tumor size more than 25cm;
3. Severe virus infection such as HBV,HCV,HIV,et al
4. Known HIV positivity
5. History of liver/renal transplantation
6. Active infectious disease related to bacteria, virus,fungi,et al
7. Other severe diseases that the investigators consider not appropriate;
8. Pregnant or lactating women
9. Systemic steroid treatment (greater than or equal to 0.5 mg prednisone equivalent/kg/day)
10. Other conditions that the investigators consider not appropriate. -

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CAR-NK cell therapy group; Appropriate patients who could benefit from the Claudin6, GPC3, Mesothelin, or AXL targeting CAR-NK cell therapy against solid cancers are chosen to be the CAR-NK cell therapy group.	Biological: Claudin6, GPC3, Mesothelin, or AXL targeting CAR-NK cells; Engineering Claudin6, GPC3, Mesothelin, or AXL 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, GPC3, Mesothelin, or AXL, and then transfusing them back the patients. In some cases, the CAR-NK cells will be combined with CBD or NAD to enhance the therapeutic efficacy.
Experimental: IL7/CCL19 secreting CAR-NK cell therapy group; Appropriate patients who could benefit from the Claudin6, GPC3, Mesothelin, or AXL targeting CAR-NK cell therapy against solid cancers are chosen to be the IL7/CCL19 secreting CAR-NK cell therapy group.	Biological: Claudin6, GPC3, Mesothelin, or AXL targeting CAR-NK cells; Engineering Claudin6, GPC3, Mesothelin, or AXL 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, GPC3, Mesothelin, or AXL, and then transfusing them back the patients. In some cases, the CAR-NK cells will be combined with CBD or NAD to enhance the therapeutic efficacy.
Experimental: PD1/PDL1/CTLA4-scfv secreting CAR-NK cell therapy group; Appropriate patients who could benefit from the Claudin6, GPC3, Mesothelin, or AXL targeting CAR-NK cell therapy against solid cancers are chosen to be the PD1/PDL1/CTLA4-scfv secreting CAR-NK cell therapy group.	Biological: Claudin6, GPC3, Mesothelin, or AXL targeting CAR-NK cells; Engineering Claudin6, GPC3, Mesothelin, or AXL 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, GPC3, Mesothelin, or AXL, and then transfusing them back the patients. In some cases, the CAR-NK cells will be combined with CBD or NAD to enhance the therapeutic efficacy.
Experimental: CAR-NK cell plus CBD therapy group; Appropriate patients who could benefit from the Claudin6, GPC3, Mesothelin, or AXL targeting CAR-NK cell therapy against solid cancers are chosen to be the CAR-NK cell plus CBD therapy group.	Biological: Claudin6, GPC3, Mesothelin, or AXL targeting CAR-NK cells; Engineering Claudin6, GPC3, Mesothelin, or AXL 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, GPC3, Mesothelin, or AXL, and then transfusing them back the patients. In some cases, the CAR-NK cells will be combined with CBD or NAD to enhance the therapeutic efficacy.
Experimental: CAR-NK cell plus NAD therapy group; Appropriate patients who could benefit from the Claudin6, GPC3, Mesothelin, or AXL targeting CAR-NK cell therapy against solid cancers are chosen to be the CAR-NK cell plus NAD therapy group.	Biological: Claudin6, GPC3, Mesothelin, or AXL targeting CAR-NK cells; Engineering Claudin6, GPC3, Mesothelin, or AXL 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, GPC3, Mesothelin, or AXL, and then transfusing them back the patients. In some cases, the CAR-NK cells will be combined with CBD or NAD to enhance the therapeutic efficacy.

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, GPC3, Mesothelin, or AXL- 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

Collaborators and Investigators

• Sponsor: Second Affiliated Hospital of Guangzhou Medical University
• Investigators: Principal Investigator: Zhenfeng Zhang, MD, PhD, Second Affiliated Hospital of Guangzhou Medical University

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2022
• Primary Completion (Estimated): June 1, 2030
• Study Completion (Estimated): May 31, 2036

Study Registration Dates

• First Submitted: June 5, 2022
• First Submitted That Met QC Criteria: June 5, 2022
• First Posted (Actual): June 8, 2022

Study Record Updates

• Last Update Posted (Actual): June 25, 2024
• Last Update Submitted That Met QC Criteria: June 22, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: Solid tumor; Nicotinamide adenine dinucleotide; Cannabidiol; Mesothelin; GPC3; Claudin6; CAR NK; AXL; PD1 antibody; PDL1 antibody; IL7; CCL19; CTLA1 antibody
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Uterine Neoplasms; Genital Neoplasms, Female; Uterine Diseases; Endocrine System Diseases; Gonadal Disorders; Endocrine Gland Neoplasms; Genital Neoplasms, Male; Testicular Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases, Male; Genital Diseases; Genital Diseases, Female; Testicular Neoplasms; Endometrial Neoplasms
• Other Study ID Numbers: ZZCARNK-017

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No