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.
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.
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.
Single group
Pan-T booster co-expressing MSLN CAR T cell
Biological/VaccineStarting Dose: 1×10\^6 cells/kg
Albumin-bound paclitaxel
DrugAdministered intravenously at dose of 100-200mg/m2 on day -5
Cyclophosphamide
DrugAdministered intravenously at a total dose of 15-30mg/kg on day -3 and day -2
Fludarabine
DrugAdministered intravenously at dose of 30mg/m2/d on day -3 and day -2
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
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.
Number and copy number of MSLN targeted CAR T cell
Number and copy number of MSLN targeted CAR T cell are evaluated by number in peripheral blood and tumor tissue.
Objective response rate (ORR)
Objective response rate includes complete response and partial response defined by investigators according to RECIST 1.1or iRECIST criteria.
Progression Free Survival (PFS)
Progression Free Survival is defined as the time from the initiation of MSLN targeted CAR T cell therapy to documented disease progression or death.
Time to response (TTR)
TTR is defined as the time from the initiation of MSLN targeted CAR T cell therapy to first assessed CR or PR by investigators according to RECIST 1.1or iRECIST criteria.
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Chinese PLA General Hospital
Lead sponsor
UTC Therapeutics Inc.
Collaborator
