Development of Highly Effective Anti-Mesothelin hYP218 Chimeric Antigen Receptor T Cells With Increased Tumor Infiltration and Persistence for Treating Solid Tumors
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- Sakshi Tomar
- 1Thoracic and GI Malignancies Branch, CCR, NCI, NIH, Bethesda, Maryland.
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- Jingli Zhang
- 1Thoracic and GI Malignancies Branch, CCR, NCI, NIH, Bethesda, Maryland.
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- Manakamana Khanal
- 1Thoracic and GI Malignancies Branch, CCR, NCI, NIH, Bethesda, Maryland.
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- Jessica Hong
- 2Laboratory of Molecular Biology, CCR, NCI, NIH, Bethesda, Maryland.
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- Abhilash Venugopalan
- 1Thoracic and GI Malignancies Branch, CCR, NCI, NIH, Bethesda, Maryland.
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- Qun Jiang
- 1Thoracic and GI Malignancies Branch, CCR, NCI, NIH, Bethesda, Maryland.
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- Manjistha Sengupta
- 1Thoracic and GI Malignancies Branch, CCR, NCI, NIH, Bethesda, Maryland.
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- Markku Miettinen
- 3Laboratory of Pathology, CCR, NCI, NIH, Bethesda, Maryland.
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- Nan Li
- 2Laboratory of Molecular Biology, CCR, NCI, NIH, Bethesda, Maryland.
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- Ira Pastan
- 2Laboratory of Molecular Biology, CCR, NCI, NIH, Bethesda, Maryland.
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- Mitchell Ho
- 2Laboratory of Molecular Biology, CCR, NCI, NIH, Bethesda, Maryland.
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- Raffit Hassan
- 1Thoracic and GI Malignancies Branch, CCR, NCI, NIH, Bethesda, Maryland.
抄録
<jats:title>Abstract</jats:title> <jats:p>Mesothelin targeting CAR T cells have limited activity in patients. In this study, we sought to determine if efficacy of anti-mesothelin CAR T cells is dependent on the mesothelin epitopes that are recognized by them. To do so, we developed hYP218 (against membrane-proximal epitope) and SS1 (against membrane-distal epitope) CAR T cells. Their efficacy was assessed in vitro using mesothelin-positive tumor cell lines and in vivo in NSG mice with mesothelin-expressing ovarian cancer (OVCAR-8), pancreatic cancer (KLM-1), and mesothelioma patient-derived (NCI-Meso63) tumor xenografts. Persistence and tumor infiltration of CAR T cells was determined using flow cytometry. hYP218 CAR T cells killed cancer cells more efficiently than SS1 CAR T cells, with a two- to fourfold lower ET50 value (effector-to-target ratio for 50% killing of tumor cells). In mice with established tumors, single intravenous administration of hYP218 CAR T cells lead to improved tumor response and survival compared with SS1 CAR T cells, with complete regression of OVCAR-8 and NCI-Meso63 tumors. Compared with SS1 CAR T cells, there was increased peripheral blood expansion, persistence, and tumor infiltration of hYP218 CAR T cells in the KLM-1 tumor model. Persistence of hYP218 CAR T cells in treated mice led to antitumor immunity when rechallenged with KLM-1 tumor cells. Our results show that hYP218 CAR T cells, targeting mesothelin epitope close to cell membrane, are very effective against mesothelin-positive tumors and are associated with increased persistence and tumor infiltration. These results support its clinical development to treat patients with mesothelin-expressing cancers.</jats:p>
収録刊行物
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- Molecular Cancer Therapeutics
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Molecular Cancer Therapeutics 21 (7), 1195-1206, 2022-05-02
American Association for Cancer Research (AACR)