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Tumor indoleamine 2,3-dioxygenase (IDO) inhibits CD19-CAR T cells and is downregulated by lymphodepleting drugs.

Abstract
Although T cells expressing CD19-specific chimeric antigen receptors (CARs) are a promising new therapy for B-cell malignancies, objective responses are observed at lower frequencies in patients with lymphoma than in those with acute B-cell leukemia. We postulated that the tumor microenvironment suppresses CAR-expressing T cells (CARTs) through the activity of indoleamine 2,3-dioxygenase (IDO), an intracellular enzyme that converts tryptophan into metabolites that inhibit T -: cell activity. To investigate the effects of tumor IDO on CD19-CART therapy, we used a xenograft lymphoma model expressing IDO as a transgene. CD19-CARTs inhibited IDO-negative tumor growth but had no effect on IDO-positive tumors. An IDO inhibitor (1-methyl-tryptophan) restored IDO-positive tumor control. Moreover, tryptophan metabolites inhibited interleukin (IL)-2-, IL-7-, and IL-15-dependent expansion of CARTs; diminished their proliferation, cytotoxicity, and cytokine secretion in vitro in response to CD19 recognition; and increased their apoptosis. Inhibition of CD19-CARTs was not mitigated by the incorporation of costimulatory domains, such as 4-1BB, into the CD19-CAR. Finally, we found that fludarabine and cyclophosphamide, frequently used before CART administration, downregulated IDO expression in lymphoma cells and improved the antitumor activity of CD19-CART in vivo. Because tumor IDO inhibits CD19-CARTs, antagonizing this enzyme may benefit CD19-CART therapy.
AuthorsSoranobu Ninomiya, Neeharika Narala, Leslie Huye, Shigeki Yagyu, Barbara Savoldo, Gianpietro Dotti, Helen E Heslop, Malcolm K Brenner, Cliona M Rooney, Carlos A Ramos
JournalBlood (Blood) Vol. 125 Issue 25 Pg. 3905-16 (Jun 18 2015) ISSN: 1528-0020 [Electronic] United States
PMID25940712 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Copyright© 2015 by The American Society of Hematology.
Chemical References
  • Antigens, CD19
  • Antineoplastic Agents
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Receptors, Antigen, T-Cell
  • Recombinant Fusion Proteins
  • Cyclophosphamide
  • Vidarabine
  • fludarabine
Topics
  • Animals
  • Antigens, CD19 (immunology)
  • Antineoplastic Agents (pharmacology)
  • Blotting, Western
  • Cell Line, Tumor
  • Chromatography, High Pressure Liquid
  • Cyclophosphamide (pharmacology)
  • Disease Models, Animal
  • Down-Regulation
  • Flow Cytometry
  • Humans
  • Immunotherapy (methods)
  • Indoleamine-Pyrrole 2,3,-Dioxygenase (drug effects, metabolism)
  • Lymphoma (enzymology, immunology)
  • Mice
  • Mice, SCID
  • Real-Time Polymerase Chain Reaction
  • Receptors, Antigen, T-Cell (immunology)
  • Recombinant Fusion Proteins
  • T-Lymphocytes (drug effects, immunology)
  • Vidarabine (analogs & derivatives, pharmacology)
  • Xenograft Model Antitumor Assays

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