allogeneic b7h3 car-γδt cell therapy for advanced solid tumors

Conditions: Advanced Solid Tumors; Ovarian Cancers; Peritoneal (metastatic) Cancer

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

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.

Eligibility criteria:
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;

Keywords: cell therapy γδt car-t