pan-t booster co-expressing msln car t cell therapy in advanced/metastatic solid tumors

Conditions: Advanced or Metastatic Solid Tumors

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.

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 criteria:
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.