Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity

作者：Prasad S. Adusumilli, Leonid Cherkassky, Jonathan Villena‐Vargas, Christos Colovos, Elliot L. Servais, Jason Plotkin, David R. Jones, Michel Sadelain · 发表于：Science Translational Medicine · 年份：2014 · DOI：10.1126/scitranslmed.3010162 · 被引用次数：574 · 研究领域：CAR-T cell therapy research、Virus-based gene therapy research、Immune Cell Function and Interaction

Translating the recent success of chimeric antigen receptor (CAR) T cell therapy for hematological malignancies to solid tumors will necessitate overcoming several obstacles, including inefficient T cell tumor infiltration and insufficient functional persistence. Taking advantage of an orthotopic model that faithfully mimics human pleural malignancy, we evaluated two routes of administration of mesothelin-targeted T cells using the M28z CAR. We found that intrapleurally administered CAR T cells vastly outperformed systemically infused T cells, requiring 30-fold fewer M28z T cells to induce long-term complete remissions. After intrapleural T cell administration, prompt in vivo antigen-induced T cell activation allowed robust CAR T cell expansion and effector differentiation, resulting in enhanced antitumor efficacy and functional T cell persistence for 200 days. Regional T cell administration also promoted efficient elimination of extrathoracic tumor sites. This therapeutic efficacy was dependent on early CD4(+) T cell activation associated with a higher intratumoral CD4/CD8 cell ratios and CD28-dependent CD4(+) T cell-mediated cytotoxicity. In contrast, intravenously delivered CAR T cells, even when accumulated at equivalent numbers in the pleural tumor, did not achieve comparable activation, tumor eradication, or persistence. The ability of intrapleurally administered T cells to circulate and persist supports the concept of delivering optimal CAR T cell therapy through "regi...