Tumor indoleamine 2,3-dioxygenase (IDO) inhibits CD19-CAR T cells and is
downregulated by lymphodepleting drugs
#MMPMID25940712
Ninomiya S
; Narala N
; Huye L
; Yagyu S
; Savoldo B
; Dotti G
; Heslop HE
; Brenner MK
; Rooney CM
; Ramos CA
Blood
2015[Jun]; 125
(25
): 3905-16
PMID25940712
show ga
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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