CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

1. Age 18-75 (inclusive).
2. The Eastern Cooperative Oncology Group (ECOG) score ≤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 National Comprehensive Cancer Network (NCCN) guideline recommended standard firstline therapy. Tumor types include but are not limited to:biliary malignancies, pancreatic cancer, lung cancer, breast cancer, head and neck malignancies, gynecological tumors, etc.
4. The expression of CD73 or AXL antigen is≥50%.
5. At least one measurable lesion at baseline per RECIST version 1.1.
6. 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.
7. Adequate organ function as defined by the following criteria:

   * Absolute neutrophil count (ANC) ≥ 1 x 10\^9/L, Platelet count ≥75 x 10\^9/ L, hemoglobin (Hgb) ≥ 90g/L ;
   * Serum creatinine≤1.5 upper limit of normal (ULN) or creatinine clearance (as estimated by Cockcroft Gault) ≥60 mL/min;
   * Serum aspartate amino transferase (AST) and alanine aminotransferase (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);
   * Cardiac ejection fraction ≥ 50%, no evidence of pericardial effusion as determined by an echocardiogram (ECHO), and no clinically significant electrocardiogram (ECG) findings;
   * International Normalized Ratio (INR) ≤ 1.5 times the upper limit of normal (ULN), and Activated Partial Thromboplastin Time (APTT) ≤ 1.5 times ULN;
   * Baseline oxygen saturation \>91% on room air.
8. Previous treatment must be completed for more than 4 weeks prior to the enrollment of this study, and subjects have recovered to \<= grade 1 toxicity (except for hematological toxicities and clinically non-significant toxicities such as alopecia).
9. 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.
10. Ability to understand and sign a written informed consent document.

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, immunotherapy, targeted therapy or other anti-tumor therapy 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) or acquired 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. Uncontrolled intercurrent illness, including ongoing or active systemic infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia (excluding insignificant sinus bradycardia and sinus tachycardia) or psychiatric illness/social situations and any other illness that would limit compliance with study requirements and jeopardize the safety of the patient.
11. Active bleeding or known hemorrhagic tendency.
12. Vaccination within 30 days of study enrollment.
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：Phase 1: Incidence of treatment related adverse events (TRAEs). · TRAEs are defined as any medical events since the initiation of CD73/AXL.HypoSti.CAR-T cell therapy . Cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome (ICANS) will be evaluated according to the standards released by American Society for Transplantation and Cellular Therapy (ASTCT) criteria in 2019, and the others will be graded by common terminology criteria for adverse events (CTCAE) V5.0. · Up to 12 months；Phase 1:Incidence of dose limiting toxicities (DLTs). · DLTs are defined as CD73/AXL.HypoSti.CAR-T cell therapy related adverse events within the first 28 days that meet the following criteria: * Grade 4 CRS or grade 3 CRS that is not resolved to grade 2 or lower within 2 weeks; * Grade 3 ICANS lasting for ≥7 days or Grade 4 ICANS; * Any other Grade ≥4 and Grade 3 AEs related to the CD73/AXL.HypoSti.CAR-T infusion that lasts for ≥14 days, except hematology toxicity. · Up to 28 days after infusion.；Phase 1: RP2D · The recommended dose for phase 2 was determined through phase 1 study. · Up to 12 months.；Phase 2: Objective response rate (ORR) . · ORR includes complete response(CR) and partial response (PR), as defined by investigators according to investigators Response Evaluation Criteria in Solid Tumours 1.1 (RECIST 1.1) or Immune Response Evaluation Criteria in Solid Tumours (iRECIST) criteria. · Up to 3 years.
次要终点：Phase 1 and phase 2: Pharmacokinetics:Number and copy number of CD73/AXL.HypoSti.CAR-T cells .；Phase 1 and phase 2: Pharmacodynamics: Peak level of cytokines in serum.；Phase 2:Progression Free Survival (PFS)；Phase 2:Time to response (TTR).；Phase 2:Duration of response (DOR) .；Phase 2:Overall Survival (OS)

• CD73/AXL.HypoSti.CAR-T cells · EXPERIMENTAL · Enrolled participants will be given a preconditioning regimen consisted of albumin-bound paclitaxel, cyclophosphamide and fludarabine before the infusion of CD73/AXL.HypoSti.CAR-T cells. Enrolled patients in this arm will be administered CD73/AXL.HypoSti.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 novel autologous hypoxia-activated CAR-T cell therapy targeting CD73 and AXL ( CD73/AXL.HypoSti.CAR-T) will be evaluated in patients with CD73/AXL 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 CD73/AXL.HypoSti.CAR-T cell therapy according to the "3+3" principle. In dose expansion period, additional at most 21 eligible patients will be enrolled to receive CD73/AXL.HypoSti.CAR-T cell therapy at dose of recommended phase 2 dose(RP2D).