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

Phase

1/2

Condition

Neoplasms

Treatment

Cyclophosphamide

Fludarabine

Pan-T booster co-expressing MSLN CAR T cell

Clinical Study ID

NCT05693844

CHN-PLAGH-BT-077

Ages 18-75
All Genders

Study Summary

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.

Eligibility Criteria

Inclusion

Inclusion Criteria:

1. Age from 18 to 75 years with estimated life expectancy >3 months.
1. Histopathological confirmed advanced or metastatic solid tumors failed to at leastfirst-line treatment or initially diagnosed advanced/metastatic solid tumors that haveno NCCN guideline recommended standard first-line therapy. Mesothelin antigenexpression percentage >＝10%.
1. Have at least one measurable target lesion.
1. Fresh solid tumor samples or formalin-fixed paraffin embedded tumor archivalsamples within 6 months are necessary; Fresh tumor samples are preferred. Subjects arewilling to accept tumor rebiopsy in the process of this study.
1. Previous treatment must be completed for more than 4 weeks prior to the enrollmentof this study, and subjects have recovered to <= grade 1 toxicity.
1. Have an Eastern Cooperative Oncology Group performance status (ECOG) of 0 or 2 atthe time of enrollment.
1. Have adequate organ function, which should be confirmed within 2 weeks prior to thefirst dose of study drugs.
1. Previous treatment with anti-PD-1/PD-L1 antibodies are allowed.
1. Ability to understand and sign a written informed consent document.
1. Women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, and upto 90 days after the last dose of the drug.

Exclusion

Exclusion Criteria:

1. Active, known or suspected autoimmune diseases.
1. Known brain metastases or active central nervous system (CNS). Subjects with CNSmetastases who were treated with radiotherapy for at least 3 months prior toenrollment, have no central nervous symptoms and are off corticosteroids, are eligiblefor enrollment, but require a brain MRI screening.
1. Subjects are being treated with either corticosteroids (>10 mg daily prednisoneequivalent) or other immunosuppressive medications within 14 days of enrollment.
1. History of severe hypersensitive reactions to other monoclonal antibodies.
1. History of allergy or intolerance to study drug components.
1. Substance abuse, medical, psychological or social conditions that may interferewith the patient's participation in the study or evaluation of the study results.
1. History or concurrent condition of interstitial lung disease of any grade orseverely impaired pulmonary function.
1. 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 psychiatricillness/social situations and any other illness that would limit compliance with studyrequirements and jeopardize the safety of the patient.
1. History of human immunodeficiency virus (HIV) infection or acquiredimmunodeficiency syndrome (AIDS).
1. Pregnant or breast-feeding. Women of childbearing potential must have a pregnancytest performed within 7 days before the enrollment, and a negative result must bedocumented.
1. Previous or concurrent cancer within 3 years prior to treatment start EXCEPT forcuratively treated cervical cancer in situ, non-melanoma skin cancer, superficialbladder tumors [Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invadeslamina propria)].
1. Vaccination within 30 days of study enrollment.
1. Active bleeding or known hemorrhagic tendency.
1. Subjects with unhealed surgical wounds for more than 30 days.
1. Being participating any other trials or withdraw within 4 weeks.

Study Design

Cyclophosphamide

1/2

January 20, 2023

December 31, 2026

Study Description

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.

Connect with a study center

Kaichao Feng
Beijing, Beijing 100853
China
Active - Recruiting

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