Anti-Mesothelin TNaive/SCM hYP218 (TNhYP218) CAR T Cells in Participants With Mesothelin-Expressing Solid Tumors Including Mesothelioma

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.

Background: * Mesothelin (MSLN), a cell surface glycoprotein, normally expressed on the mesothelial cells lining the pleura, peritoneum, and pericardium, is highly expressed in many cancers including mesothelioma, ovarian, lung, thymic, colorectal, pancreatic, and gastric cancers, making it an attractive target for immunotherapy. * Adoptive cell therapy using CAR T cells exploits the ability of these modified T cells to recognize and kill their target. Several mesothelin directed CAR T cell therapies have been evaluated in clinical trials, but thus far have not resulted in significant anti-tumor efficacy. * Many antibodies used to make anti-mesothelin CAR T cells bind to the immunogenic distal region of mesothelin, away from the cell membrane. * hYP218 CAR T cells target membrane-proximal region of mesothelin and in pre-clinical studies have shown increased tumor killing and persistence compared to CAR T cells binding to membrane distal region of mesothelin. * Naive/SCM T cells have stem cell like properties and have increased persistence and decreased exhaustion in tumors. * We hypothesize that TNaive/SCM anti-mesothelin, TNhYP218 CAR T cells will have enhanced anti-tumor activity and increased persistence in participants with mesothelioma and other mesothelin expressing cancers. Objectives: * Part 1- Dose escalation: Establish the recommended phase 2 dose (RP2D) of TNhYP218 CAR T cells based on dose-limiting toxicity (DLT) of defined adverse events (AEs). * Part 2- Dose expansion: Determine the preliminary objective response rate of TNhYP218 CAR T cells in a limited number of participants with mesothelioma treated at the RP2D. Eligibility: * Age 18 or older * Must have unresectable, histologically confirmed, recurrent, locally advanced, or metastatic mesothelioma, and other mesothelin expressing solid tumors. * Tumor must be positive for mesothelin in more than half of the cancer cells. * Participants must have an ECOG performance status of 0 or 1. * Participants must have adequate organ function. Design: * Phase 1 dose-escalation study of TNhYP218 CAR T cells, with a small expansion cohort. * Participants will undergo leukapheresis for cell manufacture, followed by lymphodepletion with chemotherapeutic drugs, followed by infusion of TNhYP218 CAR T cells. * Participants will be followed for safety for up to 15 years per FDA requirement.