@article{28f76736a27f481b9060bbe4f9a2ecee,
title = "Overcoming the immunosuppressive tumor microenvironment of Hodgkin lymphoma using chimeric antigen receptor T cells",
abstract = "Patients with otherwise treatment-resistant Hodgkin lymphoma could benefit from chimeric antigen receptor T-cell (CART) therapy. However, Hodgkin lymphoma lacks CD19 and contains a highly immunosuppressive tumor microenvironment (TME). We hypothesized that in Hodgkin lymphoma, CART should target both malignant cells and the TME. We demonstrated CD123 on both Hodgkin lymphoma cells and TME, including tumor-associated macrophages (TAM). In vitro, Hodgkin lymphoma cells convert macrophages toward immunosuppressive TAMs that inhibit T-cell proliferation. In contrast, anti-CD123 CART recognized and killed TAMs, thus overcoming immunosuppression. Finally, we showed in immunodeficient mouse models that CART123 eradicated Hodgkin lymphoma and established long-term immune memory. A novel platform that targets malignant cells and the microenvironment may be needed to successfully treat malignancies with an immunosuppressive milieu. SIGNIFICANCE: Anti-CD123 chimeric antigen receptor T cells target both the malignant cells and TAMs in Hodgkin lymphoma, thereby eliminating an important immunosuppressive component of the tumor microenvironment.",
author = "Marco Ruella and Michael Klichinsky and Kenderian, {Saad S.} and Olga Shestova and Amy Ziober and Kraft, {Daniel O.} and Michael Feldman and Wasik, {Mariusz A.} and June, {Carl H.} and Saar Gill",
note = "Funding Information: This work was supported by grants from the University of Pennsylvania-Novartis Alliance (PI: C.H. June), the NIH5R01CA120409 grant (PI: C.H. June), the EMD-Serono Cancer Immunotherapy Clinical Fellowship by the Society for Immunotherapy of Cancer (SITC; PI: M. Ruella), the Bristol-Myers Squibb Oncology Fellowship in Clinical Cancer Research by the American Association for Cancer Research (AACR; PI: M. Ruella), the Gabrielle{\textquoteright}s Angel Foundation (PI: M. Ruella), the SIES-AIL fellowship by the Italian Society for Experimental Hematology and the Italian Leukemia Association (PI: M. Ruella), and an award from the National Cancer Institute (K12 CA090628; PI: S.S. Kenderian). Imaging was performed at the University of Pennsylvania Small Animal Imaging Facility (SAIF) Optical/Bioluminescence Core, supported by NIH grant CA016520. M. Klichinsky was funded by NIHT32-GM008076. Funding Information: M. Ruella reports receiving research support from Novartis as an inventor in patents. S.S. Kenderian has ownership interest (including patents) in Novartis. C.H. June reports receiving a commercial research grant from Novartis and has ownership interest in an IP licensed to Novartis by the University of Pennsylvania. S. Gill reports receiving research funding from Novartis Pharmaceuticals and has ownership interest in patents. No potential conflicts of interest were disclosed by the other authors. Publisher Copyright: {\textcopyright} 2017 American Association for Cancer Research.",
year = "2017",
month = oct,
doi = "10.1158/2159-8290.CD-16-0850",
language = "English (US)",
volume = "7",
pages = "1154--1167",
journal = "Cancer discovery",
issn = "2159-8274",
publisher = "American Association for Cancer Research Inc.",
number = "10",
}