Overcoming the immunosuppressive tumor microenvironment of Hodgkin lymphoma using chimeric antigen receptor T cells

Marco Ruella, Michael Klichinsky, Saad S. Kenderian, Olga Shestova, Amy Ziober, Daniel O. Kraft, Michael Feldman, Mariusz A. Wasik, Carl H. June, Saar Gill

Research output: Contribution to journalArticle

55 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1154-1167
Number of pages14
JournalCancer discovery
Volume7
Issue number10
DOIs
StatePublished - Oct 2017

ASJC Scopus subject areas

  • Oncology

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    Ruella, M., Klichinsky, M., Kenderian, S. S., Shestova, O., Ziober, A., Kraft, D. O., Feldman, M., Wasik, M. A., June, C. H., & Gill, S. (2017). Overcoming the immunosuppressive tumor microenvironment of Hodgkin lymphoma using chimeric antigen receptor T cells. Cancer discovery, 7(10), 1154-1167. https://doi.org/10.1158/2159-8290.CD-16-0850