Tumor indoleamine 2,3-dioxygenase (IDO) inhibits CD19-CAR T cells and is downregulated by lymphodepleting drugs.
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.
Center for Cell and Gene Therapy, Houston Methodist Hospital, Texas Children's Hospital, and Baylor College of Medicine, Houston, TX; and.
Soranobu
S
Ninomiya
Center for Cell and Gene Therapy, Houston Methodist Hospital, Texas Children's Hospital, and Baylor College of Medicine, Houston, TX; and.
Neeharika
N
Narala
Center for Cell and Gene Therapy, Houston Methodist Hospital, Texas Children's Hospital, and Baylor College of Medicine, Houston, TX; and.
Leslie
L
Huye
Center for Cell and Gene Therapy, Houston Methodist Hospital, Texas Children's Hospital, and Baylor College of Medicine, Houston, TX; and.
Shigeki
S
Yagyu
Center for Cell and Gene Therapy, Houston Methodist Hospital, Texas Children's Hospital, and Baylor College of Medicine, Houston, TX; and Departments of Pediatrics.
Barbara
B
Savoldo
Center for Cell and Gene Therapy, Houston Methodist Hospital, Texas Children's Hospital, and Baylor College of Medicine, Houston, TX; and Medicine, and.
Gianpietro
G
Dotti
Center for Cell and Gene Therapy, Houston Methodist Hospital, Texas Children's Hospital, and Baylor College of Medicine, Houston, TX; and Departments of Pediatrics, Medicine, and.
Helen E
HE
Heslop
Center for Cell and Gene Therapy, Houston Methodist Hospital, Texas Children's Hospital, and Baylor College of Medicine, Houston, TX; and Departments of Pediatrics, Medicine, and.
Malcolm K
MK
Brenner
Center for Cell and Gene Therapy, Houston Methodist Hospital, Texas Children's Hospital, and Baylor College of Medicine, Houston, TX; and Departments of Pediatrics, Pathology and Immunology, and Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX.
Cliona M
CM
Rooney
Center for Cell and Gene Therapy, Houston Methodist Hospital, Texas Children's Hospital, and Baylor College of Medicine, Houston, TX; and Medicine, and.
Carlos A
CA
Ramos
D000818:Animals; D018941:Antigens, CD19 / Q000276:immunology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D003520:Cyclophosphamide / Q000494:pharmacology; D004195:Disease Models, Animal; D015536:Down-Regulation; D005434:Flow Cytometry; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000187:drug effects / Q000378:metabolism*; D008223:Lymphoma / Q000201:enzymology* / Q000276:immunology*; D051379:Mice; D016513:Mice, SCID; D060888:Real-Time Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D011993:Recombinant Fusion Proteins; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D018941:Antigens, CD19; D000970:Antineoplastic Agents; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine