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.
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Authors | Soranobu Ninomiya, Neeharika Narala, Leslie Huye, Shigeki Yagyu, Barbara Savoldo, Gianpietro Dotti, Helen E Heslop, Malcolm K Brenner, Cliona M Rooney, Carlos A Ramos |
Journal | Blood
(Blood)
Vol. 125
Issue 25
Pg. 3905-16
(Jun 18 2015)
ISSN: 1528-0020 [Electronic] United States |
PMID | 25940712
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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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
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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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