Background:
Mesothelioma is an aggressive cancer that grows in the linings of the body; this can include the membranes that line the heart, lungs, and internal organs. Mesothelin (MSLN) is a protein that appears in high numbers in many tumors, including mesothelioma. Researchers are developing a new treatment that collects a person s own immune cells (T cells); the T cells are genetically modified to target and kill tumor cells with high levels of MSLN.
Objective:
To test a new treatment (TNhYP218 CAR T cells) in people with solid tumors including mesothelioma.
Eligibility:
People aged 18 and older with solid tumors including mesothelioma that returned or spread after standard treatment.
Design:
Participants will be screened. A small piece of tissue will be cut from a tumor (biopsy). The sample will be tested to see if it has enough MSLN.
Participants will undergo leukapheresis: Blood will be taken from their body through a vein. The blood will pass through a machine that separates out the T cells. The remaining blood will be returned to the body through a different vein.
Participant s T cells will be modified in a lab to produce TNhYP218 CAR T cells.
Participants will enter the hospital. For 7 days, they will receive drugs to prepare their bodies for the study treatment.
TNhYP218 CAR T cells will be administered into a vein. Participants will remain in the hospital for at least 7 more days.
After discharge, participants will have follow-up visits for 5 years. These visits may include imaging scans, blood and heart tests, and a new biopsy.
Long-term follow-up will continue another 10 years....
Participant must have unresectable, locally advanced, or metastatic, or recurrent mesothelioma and other mesothelin expressing solid tumors. For participants with mesothelioma only those with epithelioid or biphasic histology (with >80% epithelioid component) will be eligible. The diagnosis will be confirmed by the Laboratory of Pathology, CCR, NCI.
Participant must have progressed on at least one FDA-approved systemic therapy considered standard of care for their tumor type. There is no limit on the number of prior treatment regimens. Note: Given the aggressive nature of pancreatic cancer, otherwise eligible individuals with this cancer type can undergo leukapheresis before or while they are getting their frontline treatment as long as they meet all other inclusion criteria. However, TNhYP218 CAR T cells will only be administered after progression on first line standard of care therapy.
Participant must have at least 1 measurable lesion by RECIST version 1.1.
Tumor must have MSLN positivity of 2+ to 3+ in >= 50% cancer cells by immunohistochemistry on freshly collected biopsy or archival tissue.
Prior systemic therapy, an investigational therapy, radiation, and/or surgery within 14 days prior to leukapheresis and 21 days prior to lymphodepleting chemotherapy.
Prior administration of anti-PD-1 or anti-PD-L1 antibodies or other agents that in the opinion of the PI can stimulate immune activity and interfere with an infusion of CAR-T cells within 8 weeks prior to treatment initiation.
Participants with any form of primary immunodeficiency (e.g. severe combined immunodeficiency).
Participants with active or history of autoimmune or immune mediated disease such as multiple sclerosis, lupus, inflammatory bowel disease, rheumatoid arthritis, or small vessel vasculitis. NOTE: Participants with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible.
Sequential
cyclophosphamide
Drug600 mg/m\^2 IV infusion. Daily x 3 doses on Day -6, -5, -4
fludarabine
Drug30 mg/m\^2 IV infusion administered followed by cyclophosphamide on days both are given. Daily x 4 doses on Day -7, -6, -5 and -4
TNhYP218 CAR T Cells
Biological/VaccineVariable doses, administered intravenously on Day 0
mesothelin expression testing
DeviceAssay done at screening to determine mesothelin expression levels
Establish the recommended phase 2 dose (RP2D) of TNhYP218 CAR T cells based on dose-limiting toxicity (DLT) of defined adverse events (AEs).
The highest dose level below the maximum administered dose at which no more than 1 of 6 participants experience DLT from the initiation of CAR-T cell infusion (day 0) through day 28 after infusion (day 28).
Determine the preliminary objective response rate of TNhYP218 CAR T cells in a limited number of participants with mesothelioma treated at the recommended phase 2 dose.
The proportion of mesothelioma participants with partial response or complete response at the recommended phase 2 dose.
Near term safety of autologous genetically modified TNhYP218 CAR T cells in adult study participants with mesothelin expressing unresectable, metastatic, or recurrent mesothelioma and other mesothelin expressing solid tumors.
The near-term safety of the study therapy will be evaluated by reporting the grade and type of toxicity at each dose level.
Long term safety of autologous genetically modified TNhYP218 CAR T cells in adult study participants with mesothelin expressing unresectable, metastatic, or recurrent mesothelioma and other mesothelin expressing solid tumors.
The long-term safety will be assessed by the presence of RCL as well as clinical assessments.
Determine the objective response rate of TNhYP218 CAR T cells in participants with mesothelin expressing solid tumors treated at doses other than the RP2D
The proportion of participants with partial response or complete response at doses other than the recommended phase 2 dose.
Determine progression free survival in participants with mesothelin expressing solid tumors
The duration of time from start of treatment (lymphodepletion) to time of progression or death, whichever occurs first.
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