CELL INTELLIGENCE · 肿瘤细胞治疗研究

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;

主要终点：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
次要终点：Best objective Response Rate；Duration of Response (DOR)；Progression Free Survival (PFS)；Overall Survival (OS)；Immunogenicity: Proportion of subjects with anti drug antibody (ADA)；Pharmacodynamics；Pharmacokinetics

• Intravenous infusion groups · EXPERIMENTAL · 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 · EXPERIMENTAL · 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.

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