Allogeneic B7H3 CAR-γδT Cell Therapy for Advanced Solid Tumors

Early Phase 1

Not yet recruiting

• Conditions: Advanced Solid Tumors; Ovarian Cancers; Peritoneal (metastatic) Cancer
• Interventions: Drug: Fludarabine; Drug: Cyclophosphamide; Biological: B7H3 CAR-γδT cells

• Registration Number: NCT06825455
• Lead Sponsor: Peking University

Brief Summary

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.

Study Timeline

• Status Verified: 2024-10
• Study First Submitted: 2025-02-09
• Study First Submitted QC: 2025-02-09
• Last Update Submitted: 2025-02-09
• Study First Posted: 2025-02-13
• Last Update Posted: 2025-02-13
• Study Start: 2025-03-01
• Primary Completion: 2027-12-31
• Study Completion: 2027-12-31

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 18

Inclusion Criteria

1. Age ≥18 years old, gender is not limited;

2. Expected survival time ≥3 months;

3. ECOG score 0~1;

4. Patients who meet the clinical diagnostic criteria and have a clear pathological diagnosis of malignant solid tumors that have failed standard treatment;

5. Tumor tissue samples (specimens within one year are recommended) positive for B7H3 by immunohistochemical (IHC) staining or flow assay;

6. Presence of at least one evaluable lesion according to RECIST V1.1;

7. Tumors limited to peritoneal (metastatic) and ovarian cancer in patients in the laparotomy group;

8. 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.

9. 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;

10. Be able to understand the requirements and matters of the trial and be willing to participate in the clinical study as required;

11. Sign the trial informed consent form.

Exclusion Criteria

1. 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;
2. Patients who have been continuously using immunosuppressive drugs within 1 month prior to cell infusion;
3. Cerebrovascular accident or seizure within 6 months prior to signing the informed consent form;
4. Symptomatic brain metastases;
5. a known psychiatric or substance abuse disorder that would interfere with cooperation with the trial requirements;
6. 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;
7. 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;
8. Presence of active or uncontrolled infections requiring systemic therapy (except for mild genitourinary and upper respiratory tract infections);
9. 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);
10. have a confirmed diagnosis of an immunodeficiency
11. suffering from an active infection requiring systemic therapy;
12. 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;
13. Participation in a clinical study of another innovative drug within 1 month prior to screening;

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Intravenous infusion groups	Fludarabine	Patients with advanced solid tumor. A conditioning chemotherapy regimen of fludarabine and cyclophosphamide will be administered followed by investigational treatment, allogenic targeting B7H3 chimeric antigen receptor γδT cells.
Intravenous infusion groups	Cyclophosphamide	Patients with advanced solid tumor. A conditioning chemotherapy regimen of fludarabine and cyclophosphamide will be administered followed by investigational treatment, allogenic targeting B7H3 chimeric antigen receptor γδT cells.
Intravenous infusion groups	B7H3 CAR-γδT cells	Patients with advanced solid tumor. A conditioning chemotherapy regimen of fludarabine and cyclophosphamide will be administered followed by investigational treatment, allogenic targeting B7H3 chimeric antigen receptor γδT cells.
Abdominal infusion group	B7H3 CAR-γδT cells	Patients with ovarian cancer or peritoneal (metastatic) cancer.Before cell injection, for subjects with obvious ascites, the ascites should be pumped as clean as possible through peritoneal puncture, and then the abdomen should be rinsed with saline before the cell infusion is performed.

Primary Outcome Measures

Name	Time	Method
Incidence of Adverse Events (AEs)	12 months	AE is defined as any adverse medical event from the date of randomization to 12 months after B7H3 CAR-γδT cells infusion. Among them, cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome (ICANS) were graded according to American Society for Transplantation and Cellular Therapy (ASTCT) criteria, graft-versushost disease (GVHD) according to criteria defined by the Mount Sinai Acute GVHD International Consortium. Other AEs were graded according to common terminology criteria for adverse events (CTCAE) v5.0.

Secondary Outcome Measures

Name	Time	Method
Best objective Response Rate	12 months	The incidence of complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), or unevaluable (UE) as the best response to treatment assessed by investigators and based on the RECIST 1.1 criterion.
Progression Free Survival (PFS)	12 months	PFS is defined as the time from the B7H3 CAR-γδT cells infusion date to the date of disease progression assessed by investigators and based on the RECIST 1.1 criterion, or death any cause. Participants not meeting the criteria for progression by the analysis data cutoff date were censored at their last evaluable disease assessment date.
Overall Survival (OS)	12 months	OS is defined as the time from B7H3 CAR-γδT cells infusion to the date of death. Subjects who have not died by the analysis data cutoff date will be censored at their last contact date.
Duration of Response (DOR)	12 months	DOR is defined as the date of their first CR or PR (which is subsequently confirmed) to PD assessed by investigators and based on the RECIST 1.1 criterion, or death regardless of cause.
Immunogenicity: Proportion of subjects with anti drug antibody (ADA)	12 months	ADAs include anti-donor γδT antibody or anti-B7H3 CAR single-chain variable fragment antibody.
Pharmacodynamics	Up to 28 days after infusion	The cytokines mainly include interleukin-2 (IL-2 ), IL-6, IL-8, IL-10, tumor necrosis factor-α (TNF-α), C reactive protein (CRP), ferritin. Peak was defined as the maximum post-baseline level of the cytokine.
Pharmacokinetics	12 months	Persistence of B7H3 CAR-γδT cell assessed by number in peripheral blood and ascites

Trial Locations

Locations (1)

Beijing Cancer Hospital; 🇨🇳 Beijing, China