Allogeneic B7H3 CAR-γδT Cell Therapy for Advanced Solid Tumors

Official title

Clinical Study of the Safety and Tolerability of B7H3 CAR-γδT Cell Injection in the Treatment of Advanced Solid Tumors

Overview

γδT cells can directly recognize non-peptide tumor antigens, such as IPP phosphorylated metabolites, without relying on specific major histocompatibility complexes (MHCs). This unique characteristic leads to a lower risk of graft-versus-host disease (GVHD). The clinical safety of γδT cells in allogeneic tumor therapies has been validated multiple times, highlighting their significant potential in developing universal CAR-T cell therapies. B7H3 (CD276), a member of the B7 negative co-stimulatory molecule family, is minimally expressed or absent in normal tissues but highly expressed in various tumor tissues. As a result, B7H3 is regarded as a highly promising tumor-associated antigen and a universal drug target with substantial therapeutic potential. By utilizing γδT cells as carrier cells, the development of universal B7H3 CAR-γδT cell injections for advanced solid tumors can effectively address risks such as autologous cell preparation failure and treatment delays. This innovative approach offers a highly efficient solution for solid tumor treatment and holds great promise for advancing immunotherapy in this field

Detailed description

This study is an open-label, dose-escalation exploratory clinical trial using γδ T cells derived from healthy donors, genetically engineered to express a chimeric antigen receptor (CAR) targeting B7H3 on their membrane. Preclinical in vitro and in vivo experiments demonstrated the modified CAR-γδ T cells possess specific cytotoxicity against B7H3-positive tumor cells.

According to the patients' disease conditions, they were divided into an intravenous infusion group and an intraperitoneal infusion group. Both groups underwent a dose-escalation study using the "3+3" design.

Interventions

• Drug Fludarabine
  Intravenous infusion group:30mg/m2 x 3 days (Day-4\~-2)
• Drug Cyclophosphamide
  Intravenous infusion group:500mg/m2 x 3 days (Day-4\~-2)
• Biological B7H3 CAR-γδT cells
  A single infusion of 6.0×107 CAR+ cells, 2.0×108CAR+ cells, and 6.0×108CAR+ cells

Primary outcome measures

• Incidence of Adverse Events (AEs) [Time frame: 12 months]

Secondary outcome measures (7)

• Best objective Response Rate [Time frame: 12 months]
• Duration of Response (DOR) [Time frame: 12 months]
• Progression Free Survival (PFS) [Time frame: 12 months]
• Overall Survival (OS) [Time frame: 12 months]
• Immunogenicity: Proportion of subjects with anti drug antibody (ADA) [Time frame: 12 months]
• Pharmacodynamics [Time frame: Up to 28 days after infusion]
• Pharmacokinetics [Time frame: 12 months]

Eligibility criteria

Inclusion criteria

• Age ≥18 years old, gender is not limited;
• Expected survival time ≥3 months;
• ECOG score 0\~1;
• Patients who meet the clinical diagnostic criteria and have a clear pathological diagnosis of malignant solid tumors that have failed standard treatment;
• Tumor tissue samples (specimens within one year are recommended) positive for B7H3 by immunohistochemical (IHC) staining or flow assay;
• Presence of at least one evaluable lesion according to RECIST V1.1;
• Tumors limited to peritoneal (metastatic) and ovarian cancer in patients in the laparotomy group;
• Substantially normal bone marrow reserve function and normal liver and renal function (laboratory tests need to be fulfilled before the first treatment with cell injection):

Blood: white blood cell count (WBC) ≥3E9/L, lymphocyte count (LY) ≥0.8E9/L, hemoglobin (Hb) ≥80g/L, platelet (PLT) ≥75E9/L; Liver: ALT ≤ 3 × ULN; AST ≤ 3 × ULN; total bilirubin ≤ 3.0 × ULN; Kidney: serum creatinine ≤ 1.5 × upper limit of normal range (ULN); Heart: left ventricular ejection fraction ≥50% on echocardiography; lung: normal oxygen saturation without oxygen.

• Pregnancy test should be negative for women of childbearing potential and both men and women agree to use effective contraception during treatment and for 1 year thereafter;
• Be able to understand the requirements and matters of the trial and be willing to participate in the clinical study as required;
• Sign the trial informed consent form.

Exclusion criteria

• Known hypersensitivity, allergy, intolerance, or contraindication to cell infusion or any of the drug components that may be used in the study, including fludarabine and cyclophosphamide;
• Patients who have been continuously using immunosuppressive drugs within 1 month prior to cell infusion;
• Cerebrovascular accident or seizure within 6 months prior to signing the informed consent form;
• Symptomatic brain metastases;
• a known psychiatric or substance abuse disorder that would interfere with cooperation with the trial requirements;
• Hepatitis B surface antigen (HBsAg) positivity or hepatitis B core antibody (HBcAb) positivity and a peripheral blood test for hepatitis B virus (HBV) DNA titer that is not within the normal reference range; hepatitis C virus (HCV) antibody positivity and peripheral blood hepatitis C virus (HCV) RNA positivity; human immunodeficiency virus (HIV) antibody positivity; syphilis Positive for syphilis;
• Serious cardiac disease: including, but not limited to, unstable angina pectoris, myocardial infarction (occurring within 6 months prior to screening), congestive heart failure (NYHA classification ≥ III), and severe arrhythmias;
• Presence of active or uncontrolled infections requiring systemic therapy (except for mild genitourinary and upper respiratory tract infections);
• has not recovered from acute toxic effects of prior therapy (prior therapy-induced hematologic or organ toxicity ≥ Grade 2, except for abnormalities related to study disease and medical history);
• have a confirmed diagnosis of an immunodeficiency
• suffering from an active infection requiring systemic therapy;
• a female subject of childbearing potential who plans to become pregnant within 2 years of cell infusion; or a male subject whose partner plans to become pregnant within 2 years of cell infusion;
• Participation in a clinical study of another innovative drug within 1 month prior to screening;

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Beijing Cancer Hospital — Beijing

Identifiers

NCT: NCT06825455 · QH10407-ST-01（0）

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗