CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

* 1\. Age from 18 to 75 years with estimated life expectancy \>3 months.
* 2\. 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. Mesothelin antigen expression percentage \>＝10%.
* 3\. Have at least one measurable target lesion.
* 4\. 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.
* 5\. 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.
* 6\. Have an Eastern Cooperative Oncology Group performance status (ECOG) of 0 or 2 at the time of enrollment.
* 7\. Have adequate organ function, which should be confirmed within 2 weeks prior to the first dose of study drugs.
* 8\. Previous treatment with anti-PD-1/PD-L1 antibodies are allowed.
* 9\. Ability to understand and sign a written informed consent document.
* 10\. Women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, and up to 90 days after the last dose of the drug.

Exclusion Criteria:

* 1\. Active, known or suspected autoimmune diseases.
* 2\. 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.
* 3\. Subjects are being treated with either corticosteroids (\>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of enrollment.
* 4\. History of severe hypersensitive reactions to other monoclonal antibodies.
* 5\. History of allergy or intolerance to study drug components.
* 6\. Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results.
* 7\. History or concurrent condition of interstitial lung disease of any grade or severely impaired pulmonary function.
* 8\. 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.
* 9\. History of human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS).
* 10\. Pregnant or breast-feeding. Women of childbearing potential must have a pregnancy test performed within 7 days before the enrollment, and a negative result must be documented.
* 11\. Previous or concurrent cancer within 3 years prior to treatment start EXCEPT for curatively treated cervical cancer in situ, non-melanoma skin cancer, superficial bladder tumors \[Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades lamina propria)\].
* 12\. Vaccination within 30 days of study enrollment.
* 13\. Active bleeding or known hemorrhagic tendency.
* 14\. Subjects with unhealed surgical wounds for more than 30 days.
* 15\. Being participating any other trials or withdraw within 4 weeks.

主要终点：Incidence of treatment related adverse events · Treatment related adverse events are defined as any medical events since the initiation of MSLN targeted CAR T cell therapy . CRS or CRES will be graded based on American Society for Transplantation and Cellular Therapy (ASTCT) criteria, and the others will be graded by CTCAE V5.0 · Up to 12 months since the initiation of MSLN targeted CAR T cell therapy；Incidence of dose limiting toxicities (DLTs) · Dose limiting toxicities are defined as MSLN targeted CAR T cell therapy related adverse events within the first 28 days that meet the following criteria: grade 3 or higher CRS or CRES, and any other grade 4 adverse events. · Up to 28 days since the initiation of MSLN targeted CAR T cell therapy
次要终点：Number and copy number of MSLN targeted CAR T cell；Objective response rate (ORR)；Progression Free Survival (PFS)；Time to response (TTR)；Duration of response (DOR)；Overall Survival (OS)

• Pan-T booster co-expressing MSLN CAR T cell · EXPERIMENTAL · Before the infusion of pan-T booster co-expressing MSLN CAR T cells, all enrolled patients need to undergo conditioning chemotherapy consisting of albumin-bound paclitaxel, cyclophosphamide, and fludarabine.

In preclinical study, investigators have demonstrated that the newly developed pan-T booster (harbouring CD40 agonist and one T cell costimulator agonist) co-expressing MSLN CAR T cell possess more powerful antitumor activity than previously reported MSLN-CAR T cells. In this clinical trial, enrolled patients receive an initial dose of pan-T booster co-expressing MSLN CAR T cells at 1×10\^6 cells/kg based on the basic principle of dose escalation design, in order to evaluate the safety, feasibility, pharmacokinetics/pharmacodynamics, and efficacy of pan-T booster co-expressing MSLN CAR T cell in vivo.