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Cancer Discov. 2017 Oct;7(10):1154-1167. doi: 10.1158/2159-8290.CD-16-0850. Epub 2017 Jun 2.

Overcoming the Immunosuppressive Tumor Microenvironment of Hodgkin Lymphoma Using Chimeric Antigen Receptor T Cells.

Ruella M1,2,3, Klichinsky M1,3,4, Kenderian SS1,5, Shestova O1,2,3, Ziober A2,3, Kraft DO1, Feldman M2,3, Wasik MA2,3, June CH1,2,3,5, Gill S6,3,5.

Author information

1
Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
2
Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
3
Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
4
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
5
Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.
6
Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. saar.gill@uphs.upenn.edu.

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. Cancer Discov; 7(10); 1154-67. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 1047.

PMID:
28576927
PMCID:
PMC5628114
DOI:
10.1158/2159-8290.CD-16-0850
[Indexed for MEDLINE]
Free PMC Article

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