Overview

This is a Phase 1, single-arm, single-center, open-label study to evaluate the safety and effectiveness of NKG2D/CLDN18.2-based CAR-T cells infusion in the treatment of advanced NKG2DL+/CLDN18.2+ solid tumors.

Eligibility

Inclusion Criteria:

1. Patients diagnosed as advanced solid tumors histopathologically or cytologically, such as gastric cancer and pancreatic cancer. 2. Patients fail standard treatment , or cannot tolerate standard treatment, or there is no standard treatment, the standard treatment recommendations refer to the latest version of the guidelines of the national comprehensive cancer network (NCCN) or the guidelines of the Chinese society of Clinical Oncology (CSCO);
2. Age 18-75 years; 4. ECOG score 0-1; 5. Expected survival ≥ 3 months; 6. Patients must meet coagulation parameters and have adequate peripheral venous access for apheresis, and must also have enough PBMC to manufacture CAR T cells; 7. NKG2DL/CLDN18.2 (according to the positive comprehensive score of 0-12 points, positive SCORE of NKG2DL and CLDN18.2 ≥5) positive confirmed by Immunohistochemistry. Biopsy tissue must be no more than 2 year, if not, must obtain new tissue material from a recent surgical or diagnostic biopsy; 8. Eligible organ and bone marrow functions defined as follows:
   1. Absolute neutrophil count ≥1.5×10^9/L, lymphocyte count ≥0.5×10^9/ L, platelet count ≥90×10^9/L, hemoglobin ≥90g/L (no blood transfusion or Erythropoietin within 7 days);
   2. Total bilirubin ≤1.5ULN; (Patients with Gilbert syndrome were diagnosed with total bilirubin ≤3mg/dL) Serum alanineamino transferase (ALT) or aspartate aminotransferase(AST)≤3ULN(ALT and AST in patients with liver metastases ≤5ULN);
   3. Creatinine ≤1.5ULN or eGFR≥60mL /min（Cockcroft and Gault）
   4. International normalized ratio (INR) ≤1.2;
   5. Lung function: ≤ grade 1 dyspnea(according to NCI-CTCAE V5.0), SaO2≥91%;
   6. Cardiac function:

        Cardiac ejection fraction (LVEF) detected by echocardiography or MUGA ≥50% 1 month before
        enrollment. 9. Patients must have measurable lesions as defined by RECIST 1.1; 10. If the
        patient is HBsAg positive or HBcAb positive, HBV-DNA should be < 2000IU/ml. HBsAg positive
        patients.Antiviral therapy must be received according to the Chronic Hepatitis B Prevention
        and Treatment Guidelines 2019.
        11.Patients fully understand the test and voluntarily sign the informed consent; 12.
        Patient agree to use approved contraceptive methods (e.g., birth control pills, barrier
        devices, iuds, contraindicated drugs) during the study and for at least 13 months after
        last cell infusion, until no CAR-T cells were detected by two consecutive PCR tests.
        Exclusion Criteria:
          1. Human immunodeficiency virus (HIV), Active hepatitis B (HBV DNA≥500IU/ml) or hepatitis
             c (anti-HCV positive and HCV RNA higher than the detection limit of analysis method)；
          2. Patients had received any gene therapy (including CAR-T cell therapy) or any T cell
             therapy；
          3. Patients had participated in other drug trials within 4 weeks prior to the study；
          4. Patients with history or CT examination revealed active tuberculosis infection within
             1 year before enrollment or patients diagnosed with active pulmonary tuberculosis 1
             year ago without regular treatment；
          5. Patients with sudden pulmonary disease, interstitial lung disease, pulmonary fibrosis,
             acute pulmonary disease, etc;
          6. Subjects with pre-existing or active autoimmune diseases, or those with potential for
             recurrence (e.g., Wolf erythematosus systemic) Sores, rheumatoid arthritis,
             inflammatory bowel disease, autoimmune thyroid disease, multiple sclerosis,
             vasculitis, kidneyGlomerulonephritis, etc.), or patients at high risk (such as those
             who have received organ transplants and require immunosuppressive therapy). But
             allowSubjects with the following diseases were enrolled:
        1)Type 1 diabetic patients with stable disease after a fixed dose of insulin; 2)Only
        autoimmune hypothyroidism on hormone replacement therapy 3)Skin conditions that do not
        require systemic treatment (e.g., eczema, a rash of up to 10% of the body surface, silver
        flakes without ophthalmic symptoms Disease,etc.); 4)The use of immunosuppressants, such as
        steroids, should be phased out before the study begins if the patient has adrenal glands.If
        they are not functional, corticosteroids can be continued to replace the physiological dose
        (dose equivalent to ≤10 mg prednisone/day) 7.A history of severe heart disease, including
        medically poorly controlled hypertension (systolic blood pressure >160mmHg and/or diastolic
        blood pressure) Pressure >90mmHg), and any of the following conditions occurring within the
        past 6 months: patients with QT prolongation syndrome, screening,Phase 12 lead ECG results
        QTc interval >470mSEC, congestive heart failure (New York Heart Association grade ≥Class
        Ⅲ), cardiac angioplasty and stenting, myocardial infarction, unstable angina pectoris,
        severe arrhythmia or the researcher assessed heart disease that was not eligible for
        enrollment.
        8. Clinically symptomatic brain metastases with the exception of patients with stable,
        asymptomatic brain metastases treated with radiotherapy or surgery for 14 days.
        9. Other central nervous system disorders judged by the investigators to be likely to
        affect the trial: such as epilepsy/seizures, cerebral ischemia/hemorrhage, Dementia,
        cerebellar disease or autoimmune disease affecting the central nervous system.
        10.Complicating hematologic malignancy or other primary malignant solid tumors, except in
        the following cases: 1) Patients with cervical or breast cancer accepted radical therapy
        without evidence of disease for more than 3 years; 2) The orthotopic tumor was successfully
        removed without definite resection patients with ≥5 years of evidence of disease.
        11.Prior to apheresis, he received the following antitumor treatments:
          1. Cytotoxic treatment within 14 days;
          2. have received small molecule targeted therapy within 14 days or at least 5 half-lives,
             whichever is shorter,Therapy or investigational drug therapy, or treatment with
             invasive investigational medical devices;
          3. Treatment with monoclonal antibodies within 21 days;
          4. Immunomodulator therapy within 7 days;
          5. Radiotherapy within 14 days. 12. Female subjects who are pregnant or breastfeeding
             during the screening period; 13. With a history of severe hypersensitivity to the
             primary therapeutic agents used in this study included fludarabine, cyclophosphamide,
             and PROPHYlaxis during pretreatment Tocilizumab and anti-infective drugs for CRS)
             14.Untreated brain metastases or symptoms of brain metastases. 15.Patients with heart
             disease or poorly controlled high blood pressure who need treatment.
        16.Patients with unstable or active peptic ulcers or gastrointestinal bleeding. 17.Patients
        who have a history of organ transplantation or are preparing for organ transplantation.
        18.Patients requiring anticoagulant therapy (e.g., warfarin or heparin). 19.Patients
        requiring long-term antiplatelet therapy (aspirin,dose>300mg/d;clopidogrel,dose>75mg/d)
        20.Patients had undergone major surgery or serious injury 4 weeks before the start of the
        study, or would undergo major surgery during the study.
        21.Toxicity > grade 1 from previous antineoplastic therapy before screening (except
        alopecia).
        22.Conditions that other researchers deemed inappropriate for inclusion