Exploratory Study of MSLN-CAR T Cells Secreting PD1/CTLA-4 Nanoantibody for the Treatment of Advanced Solid Tumors

This is a single arm, open-label, dose escalation clinical study to evaluate the safety and tolerability of autologous mesothelin (MSLN)-targeted chimeric antigen receptor (MSLN-CAR) T cells secreting PD-1 and CTLA-4 nanobodies (αPD1/CTLA-4-MSLN-CAR T cells) in patients with solid tumors.

Study Overview

• Status: Recruiting
• Conditions: Solid Tumor
• Intervention / Treatment: Biological: αPD1/CTLA4-MSLN-CAR T cells

• Study Type: Interventional
• Enrollment (Estimated): 16
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Yong Xia; Phone Number: 021-67091399; Email: xiay@shcell.com

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China
      • Recruiting
      • Shanghai Mengchao Cancer Hospital
      • Contact: Lou jinxing

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients must have a histological or cytological diagnosis of advanced solid tumors, such as non-small-cell lung cancer and mesothelioma；
• Patients must have failed established standard medical anti-cancer therapies；
• Greater than or equal to 18 years of age and less than or equal to 70 years of age on day of signing informed consent；
• Life expectancy ≥3 months；
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1；
• Staining of MSLN must be greater than 50% of the cells in the tumor tissue and with apparent expression in the membrane. PD-L1 expression must be positive. Tissue obtained for the biopsy must be ≤3 year prior to enrollment for screening；

• Satisfactory organ and bone marrow function as defined by the following:

  1. Adequate bone marrow function in the opinion of the Investigator for lymphocyte-depleting chemotherapy: absolute neutrophil count must be greater than ≥ 1.5×10^9/L, lymphocyte count must be greater than ≥ 0.5×10^9/L, platelets must be greater than ≥ 90×10^9/L, hemoglobin must be greater than ≥ 90g/L without transfusion within 7 days or dependency on EPO;
  2. Total bilirubin must be less than or equal to two times (≤2.0x) the institutional normal upper limit; transaminases, serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST), must be less than or equal to 2.5 times (≤2.5x) the institutional normal upper limit (≤2.5x if there is hepatic metastasis);
  3. Creatinine must be less than or equal to one and one half times (≤ 1.5x) the institutional normal upper limit or eGFR ≥ 60ml/min/1.73m^2 [eGFR=186×（age）-0.203×SCr-1.154（mg/dl）,for female the eGFR shoud be timed by 0.742];
  4. International normalized ratio (INR) or the PT is not greater than one and one half times (≤ 1.5) the upper limit of normal;
  5. Lung function: ≤ CTCAE grade 1 dyspnea and SaO2≥ 91%;
  6. Cardiac function: cardiac ejection fraction (LVEF) must be greater than fifty percent (≥50%) by echocardiogram or MUGA one month before enrollment.
• Subjects must have measureable disease as defined by RECIST 1.1 criteria;
• Subjects sufficiently understand the trial and willingly sign the informed consent;
• Male and Female subjects agree to use approved contraceptive methods (e.g. birth control pills, barrier device, intrauterine device, abstinence) during the study and for at least 12 months following the last dose of the study cell infusion and until no CAR-T cells can be detected after two consecutive PCR tests.

Exclusion Criteria:

• Prior therapy with targeted therapy or cell therapy against MSLN；
• Prior therapy with any gene therapy (including CAR-T cell therapy) or any T cell therapy home and abroad；
• Active bacteria, viral or fungal infection, and not contained after anti-infective therapy (positive results in the blood ≤72 hours before infusion);
• Patient is positive for Syphilis, Human Immunodeficiency Virus (HIV) , active Hepatitis B (HBsAg reactive) or Hepatitis C (HCV RNA (qualitative) is detected);
• Patient has a medical condition such as autoimmune disease or organ transplantation that requires chronic systemic steroid therapy or requires any other form of immunosuppressive medication;
• History of severe cardiac or pulmonary disease, including hypertension that cannot be controlled by medication, and any of the conditions occurred within the past 6 months: congestive heart failure (New York Heart Association functional classification ≥3), cardiac angioplasty and stents, myocardial infarction, unstable angina, or other clinically significant heart disease；
• Detectable clinically relevant central nervous system (CNS) metastases and/or pathology such as epilepsy/seizure, brain Ischemia/ hemorrhage, dementia, cerebellar disease, or autoimmune disease affecting central nervous system；
• Patient has a history or current evidence of any condition such as neurotic, psychiatric, immune, metabolic and infectious disease, on any therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating Investigator；

• Patient has a known history of a hematologic malignancy, or of another malignant primary solid tumor concurrently, with the exception of :

  1. Patients with in situ cervical cancer or breast cancer with no evidence of disease for ≥ 3 years after curative treatments;
  2. Patients who underwent successful definitive resection of in situ cancer with no evidence of disease for ≥5 years;
• Has had chemotherapy, radioactive, small molecules, biological cancer therapy, immunotherapy or other investigational drugs within 2 weeks prior to the initiation of the study；
• Pregnant or breastfeeding women;
• Investigators think that patient has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study and cooperation with the requirements of the trial, uncontrolled medical, psychological, familial, sociological, or geographical conditions, or is not in the best interest of the patient to participate.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: CAR T cells; αPD1/CTLA4-MSLN-CAR T Cells

Biological: αPD1/CTLA4-MSLN-CAR T cells; BZE2209 is prepared by non-viral vector technology consisting of autologous CD3+T cells expressing mesothelin-specific chimeric antigen receptor (CAR), PD1 nanoantibody and CTLA4 antibody with dimethyl sulfoxide as medium. It can be used for direct intravenous infusion. Autologous CD3+ T cells were transfected with plasmids expressing anti-mesothelin-specific CAR, anti-PD1 nanoantibody and anti-CTLA-4 antibody by electroporation in vitro. Mesothelin-specific CAR is a single-domain antibody (VHH) derived from alpaca, which is composed of a binding domain and a CD28 and CD3ζ chain signal transduction domain.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose-limiting toxicity（DLT）	Safety	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peak Plasma Concentration (Cmax)	Pharmacokinetics (PK)	Month 12
Pharmacodynamics (PD)	PD of IL-2, IL-4, IL-6, IL-8, IL-10, IL-15, IFN-γ, TNF-α and MCP1 will be analysed after CAR T cell infusion	Day 28
Objective response rate (ORR)	Clinical response will be assessed by RECIST 1.1.	Month 12
Maximum tolerated dose (MTD)	Tolerability	28 days
Progression-free survival (PFS)	PFS of patients receiving αPD1/CTLA4-MSLN-CAR T cells	Month 12
AUC	Pharmacokinetics (PK)	Month 12

Collaborators and Investigators

• Sponsor: Shanghai Cell Therapy Group Co.,Ltd
• Investigators: Principal Investigator: Jinxing Lou, Shanghai Mengchao Cancer Hospital

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2023
• Primary Completion (Estimated): July 30, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: January 31, 2024
• First Submitted That Met QC Criteria: February 7, 2024
• First Posted (Actual): February 8, 2024

Study Record Updates

• Last Update Posted (Actual): February 8, 2024
• Last Update Submitted That Met QC Criteria: February 7, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms
• Other Study ID Numbers: BZE2209-A-01

Drug and device information, study documents

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