Pan-T Booster Co-expressing MSLN CAR T Cell Therapy in Advanced/Metastatic Solid Tumors

Phase 2RecruitingNCT05693844

Chinese PLA General Hospital15 enrolled

Overview

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.

In this study, investigators have developed a novel CAR T cell system targeting mesothelin (MSLN) antigen, termed as Pan-T booster (harbouring CD40 agonist and one T cell costimulator agonist) co-expressing MSLN CAR T cell. Preclinical study demonstrated that this novel pan-T booster 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. The level of CAR-T cell expansion and the duration of expansion are important determining factors for subsequent dose escalation infusions (3×10\^6 cells/kg and 6×10\^6 cells/kg). Repeated infusion, immune checkpoint inhibitor (such as anti-PD1/PD-L1) or local therapy (radiotherapy) are allowed when patients achieve clinical benefit and the level of CAR-T cell expansion declines to low level. In the 3 patients receiving the first dose treatment, we observed high levels of expansion of both total T cells and CAR T cells in the PB after CAR T cell infusion (CAR T \> 300 per microliter, total T cells reaching 10 times the number of CAR T cells), one patient experienced a grade 2 pulmonary toxicity and transient liver dysfunction during the CAR T cell expansion period (infusion 14 days later), transient marked enlargement of the spleen, and required to be treated with glucocorticoids and ruxolitinib to control T cell toxicity. Efficacy monitoring showed that some target lesion clearance or reduction could be achieved within 2-4 weeks after CAR T infusion. Based on these observations, it was concluded that low-dose CAR T infusion (CAR+T cells 1×10\^6 cells/kg) could achieve the sufficient level of CAR T cell expansion, and the initially planned CAR T dose escalation was dispensable. Subsequent patients after May 10th, 2024, will all be treated using 1×10\^6 cells/kg dose.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

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

Time frame: 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.

Time frame: Up to 28 days since the initiation of MSLN targeted CAR T cell therapy

Secondary Outcomes

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.

Time frame: Up to 3 years

Objective response rate (ORR)

Objective response rate includes complete response and partial response defined by investigators according to RECIST 1.1or iRECIST criteria.

Time frame: Up to 3 years

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 frame: Up to 3 years

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.

Time frame: Up to 3 years

Duration of response (DOR)

Duration of response is defined as the time from objective response until documented tumor progression among responders.

Time frame: Up to 3 years

Overall Survival (OS)

Overall Survival is defined as the time from the initiation of MSLN targeted CAR T cell therapy to documented disease progression or death.

Time frame: Up to 3 years

Pan-T Booster Co-expressing MSLN CAR T Cell Therapy in Advanced/Metastatic Solid Tumors

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts