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

S Ninomiya, N Narala, L Huye, S Yagyu… - Blood, The Journal …, 2015 - ashpublications.org
S Ninomiya, N Narala, L Huye, S Yagyu, B Savoldo, G Dotti, HE Heslop, MK Brenner
Blood, The Journal of the American Society of Hematology, 2015ashpublications.org
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 …
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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