Allogeneic B7H3 CAR-γδT Cell Therapy for Advanced Solid Tumors

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

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

Study Overview

• Status: Not yet recruiting
• Conditions: Advanced Solid Tumors; Ovarian Cancers; Peritoneal (metastatic) Cancer
• Intervention / Treatment: Drug: Fludarabine; Drug: Cyclophosphamide; Biological: B7H3 CAR-γδT cells

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 Type: Interventional
• Enrollment (Estimated): 18
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Changsong Qi; Phone Number: 010-88196561; Email: xiwangpku@126.com
• Study Contact Backup: Name: Lin Shen; Phone Number: 010-88196561; Email: doctorshenlin@sina.cn

Study Locations

• China
  • Beijing, China
    • Beijing Cancer Hospital
    • Contact: Changsong Qi, Ph.D; Phone Number: +86-13811394004; Email: xiwangpku@126.com

Participation Criteria

Eligibility Criteria

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

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intravenous infusion groups; 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.	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
Experimental: Abdominal infusion group; 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.	Biological: B7H3 CAR-γδT cells; A single infusion of 6.0×107 CAR+ cells, 2.0×108CAR+ cells, and 6.0×108CAR+ cells

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Adverse Events (AEs)	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.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best objective Response Rate	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.	12 months
Duration of Response (DOR)	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.	12 months
Progression Free Survival (PFS)	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.	12 months
Overall Survival (OS)	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.	12 months
Immunogenicity: Proportion of subjects with anti drug antibody (ADA)	ADAs include anti-donor γδT antibody or anti-B7H3 CAR single-chain variable fragment antibody.	12 months
Pharmacodynamics	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.	Up to 28 days after infusion
Pharmacokinetics	Persistence of B7H3 CAR-γδT cell assessed by number in peripheral blood and ascites	12 months

Collaborators and Investigators

• Sponsor: Peking University

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2025
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: February 9, 2025
• First Submitted That Met QC Criteria: February 9, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 9, 2025
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: CAR-T; cell therapy; γδT
• Additional Relevant MeSH Terms: Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide; Fludarabine
• Other Study ID Numbers: QH10407-ST-01（0）

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
• product manufactured in and exported from the U.S.: No