CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

1. Age 18-75 (inclusive).
2. ECOG performance status ≤2 and Estimated life expectancy of more than 3 months.
3. Histopathological confirmed advanced or metastatic solid tumors failed to at least first-line treatment or initially diagnosed advanced/metastatic solid tumors that have no NCCN guideline recommended standard first-line therapy. CD70 antigen expression level ≥ 30%.
4. At least one measurable lesion at baseline per RECIST version 1.1.
5. Fresh solid tumor samples or formalin-fixed paraffin embedded tumor archival samples within 6 months are necessary; Fresh tumor samples are preferred. Subjects are willing to accept tumor rebiopsy in the process of this study.
6. Adequate organ function as defined by the following criteria: ANC≥1.5x10\^9/L; Platelet count ≥75x10\^9/L; Hemoglobin ≥90 g/L;Serum AST and serum ALT, ≤3.0 x ULN (≤5 x ULN for patients with liver cancer or metastases); Total serum bilirubin ≤1.5 x ULN(≤3 x ULN for patients with liver cancer or metastases); Serum creatinine ≤1.5 xULN or creatinine clearance of ≥60 mL/min.
7. Pregnancy tests for women of childbearing age shall be negative; Both men and women agreed to use effective contraception during treatment and during the subsequent 1 year.
8. Ability to understand and sign a written informed consent documen.

Exclusion Criteria:

1. Subjects are being treated with either corticosteroids (\>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of enrollment.
2. Received cytotoxic chemicals, monoclonal antibodies, or immunotherapy within 4 weeks or 5 half-lives before enrollment;
3. Pregnant, lactating, or breastfeeding females;
4. Known positive test result for human immunodeficiency virus (HIV) oracquired immune deficiency syndrome (AIDS);Active infection of hepatitis B virus (HBV), or hepatitis C virus (HCV);
5. History of allergy or intolerance to study drug components;
6. Prior organ allograft transplantations or allogeneic hematopoietic stem cell transplantation;
7. Major surgery or trauma occurred within 28 days prior to enrollment, or major side effects have not been recovered.
8. Known brain metastases or active central nervous system (CNS).Subjects with CNS metastases who were treated with radiotherapy for at least 3 months prior to enrollment, have no central nervous symptoms and are off corticosteroids, are eligible for enrollment, but require a brain MRI screening.
9. Previous or concurrent cancer within 5 years prior to treatment start except for curatively treated cervical cancer in situ, non-melanoma skin cancer, superficial bladder tumors;
10. Any serious underlying medical (eg, pulmonary, renal, hepatic,gastrointestinal, or neurological) or psychiatric condition or any issue that would limit compliance with study requirements;
11. Vaccination within 30 days of study enrollment;
12. Previously received CD70-CAR T cell therapy;
13. Being participating any other trials or withdraw within 4 weeks;
14. Researchers believe that other reasons are not suitable for clinical trials.

主要终点：Incidence of treatment related adverse events · AE is defined as any adverse medical event from the date of randomization to 12 months after CD70-CAR-T cell infusion. Among them, CRS and ICANS were graded according to American Society for Transplantation and Cellular Therapy (ASTCT) criteria. Other AEs were graded according to common terminology criteria for adverse events (CTCAE) v5.0. · Up to 12 months since the initiation of CD70-CAR-T cell therapy.；Incidence of dose limiting toxicities (DLTs) · DLT was defined as CD70-CAR-T cells-related events with onset within first 28 days following infusion: The development of Grade (G) 3 or higher grade CRS lasting \> 2 weeks; All G4 non-hematologic toxicities. · Up to 28 days since the initiation of CD70-CAR-T cell therapy；Maximum tolerated dose (MTD) · MTD is defined as the highest dose level of less than or equal to 2 DLT among the 6 subjects finally determined. · Up to 28 days since the initiation of CD70-CAR-T cell therapy
次要终点：Number and copy number of CD70-CAR-T cells；Objective response rate (ORR)；Progression Free Survival (PFS)；Time to response (TTR)；Duration of response (DOR)；Overall Survival (OS)；Pharmacodynamics: Peak level of cytokines in serum

• CD70-targeting CAR-T cells · EXPERIMENTAL · Enrolled participants will be given a preconditioning regimen consisted of albumin-bound paclitaxel, cyclophosphamide and fludarabine before the infusion of CD70-CAR-T cells. Enrolled patients in this arm will be administered CD70-CAR-T cells in 3+3 based escalation manner.

In this single-center, single-arm,prospective, open-label, phase 1/2 study, the safety and efficacy of autologous CD70 targeted chimeric antigen receptor modified T (CAR-T) cell therapy will be evaluated in patients with CD70 antigen positive advanced/metastatic solid tumors . In this clinical trial, at least 12 eligible patients in dose escalation period will be enrolled to receive 3 doses of CD70-CAR cell therapy according to the "3+3" principle. In dose expansion period, additional at most 21 eligible patients will be enrolled to receive CD70-CAR-T cell therapy at dose of recommended phase 2 dose(RP2D).