CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

* Age ≥ 1 year (including cut-off value), gender is not limited
* Expected survival time ≥ 3 months
* Karnofsky score (\> 16 years) or Lansky score (≤ 16 years) \> 60 points
* Meet the clinical diagnostic criteria and be diagnosed as recurrent / refractory neuroblastoma. For first-line standard treatment, please refer to the consensus of experts in the diagnosis and treatment of Pediatric Neuroblastoma (Chinese Journal of Pediatric surgery, Volume 36, No. 1, 2015), the guidelines for the diagnosis and treatment of Pediatric Neuroblastoma of 2019 by the Health Commission, and the consensus of experts in the diagnosis and treatment of Pediatric Neuroblastoma (CCCG-NB-2021 Program) (Chinese Journal of Pediatric surgery, Volume 43, No. 7, 2022)

  1. Recurrence is defined as the determination of recurrence after remission after at least first-line standard treatment.
  2. Refractory is defined as a person who is not in remission after at least 4 cycles of chemotherapy (≥ 2 chemotherapeutic drugs, including alkylating agents and platinum)
* The tumor tissue samples of the subjects were stained by immunohistochemistry (IHC) to show that the expression intensity of B7-H3 on the surface of tumor cell membranes was 1+ or above, and the proportion of positive staining of tumor cell membranes was ≥1%
* At least one measurable lesion defined by RECISTv1.1 criteria, and at least one lesion that can be irradiated (except bone marrow)
* Subjects with lesions only in the bone marrow may also be enrolled (without irradiation)
* Liver and kidney function, cardiopulmonary function must meet the following requirements:

  1. Total bilirubin ≤ 3 × ULN;ALT and AST ≤ 5 × ULN
  2. Creatinine≤2 ULN
  3. Left ventricular ejection fraction ≥ 50%
  4. Blood oxygen saturation ≥ 92%
* Patients and/or their guardians understand the trial and have signed informed consent

Exclusion Criteria:

* Patients who were judged by the investigator to require long-term immunosuppressive therapy at the time of screening
* Cerebrovascular accident or seizure occurred within 6 months before signing the informed consent
* Malignant tumors other than neuroblastoma, excluding carcinoma in situ
* Hepatitis B surface antigen (HBsAg) positive; hepatitis B core antibody (HBcAb) positive and peripheral blood hepatitis B virus (HBV) DNA titer detection not within the normal reference range; hepatitis C virus (HCV) antibody positive and peripheral blood type C Hepatitis virus (HCV) RNA positive; human immunodeficiency virus (HIV) antibody positive; cytomegalovirus (CMV) DNA positive; syphilis positive
* Serious cardiac disease: including but not limited to unstable angina, myocardial infarction (within 6 months prior to screening), congestive heart failure (New York Heart Association \[NYHA\] classification ≥ grade III), severe arrhythmia
* Unstable systemic disease as judged by the investigator: including but not limited to severe liver, kidney or metabolic disease requiring drug therapy
* Presence of chronic progressive neurological disease
* Patients who have not recovered from acute toxic effects of prior treatment
* Active or uncontrolled infection requiring systemic treatment (except mild urogenital and upper respiratory tract infections)
* Pregnancy-capable female subjects who plan to become pregnant within 2 years of cell reinfusion; or male subjects whose partners plan to become pregnant within 2 years of cell reinfusion
* Those who have received CAR-T therapy or other gene-modified cell therapy before screening
* Participated in other clinical studies within 1 month before screening
* Subjects screened for evidence of central nervous system involvement
* For patients with liver metastases, the distribution of liver metastases exceeds 1/2 of the liver
* According to the judgment of the investigators, it does not meet the situation of cell preparation
* Other circumstances deemed inappropriate by investigators

主要终点：MTD · Maximum tolerated dose of TAA06 Injection in subjects with relapsed/refractory neuroblastoma · about 3 years；RP2D · Phase 2 recommended dose of TAA06 Injection in subjects with relapsed/refractory · about 3 years；Assessment of the safety after B7-H3-targeted chimeric antigen receptor T cells infusion (Safety) · Treatment Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) ,(according to the evaluation criteria for common adverse events, NCICTCAE version 5.0) · about 3 years
次要终点：Assessment of pharmacokinetic (about Cmax)；Assessment of pharmacokinetic (about Tmax)；Assessment of pharmacokinetic (about AUC0-28d)；Assessment of pharmacokinetic (about AUC0-90d)；Objective Response Rate (ORR)；Disease Control Rate（DCR）；Duration of Response（DOR）；Progression-free Survival（PFS）

• T cell injection targeting TAA06 chimeric antigen receptor · EXPERIMENTAL · The subjects, who sign the informed consent forms and been screened by inclusion/exclusion criteria, will be assigned into 2.0 × 10\^6, 4.0 × 10\^6 and 8.0 × 10\^6 CAR-T/kg groups in order of sequence.

Phase I clinical trials are designed as open-label, dose-escalation and dose-expansion clinical studies, the main purpose of which is to explore the tolerability, safety, cytokinetic characteristics and RP2D and preliminary observation of the efficacy of the study drug in subjects with B7-H3-positive relapsed/refractory neuroblastoma.