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Tumor indoleamine 2,3-dioxygenase (IDO) inhibits CD19-CAR T cells and is downregulated by lymphodepleting drugs
| Content Provider | Scilit |
|---|---|
| Author | Ninomiya, Soranobu Narala, Neeharika Huye, Leslie Yagyu, Shigeki Savoldo, Barbara Dotti, Gianpietro Heslop, Helen E. Brenner, Malcolm K. Rooney, Cliona M. Ramos, Carlos A. |
| Copyright Year | 2015 |
| Description | 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. |
| Related Links | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4473118/pdf |
| Ending Page | 3916 |
| Page Count | 12 |
| Starting Page | 3905 |
| DOI | 10.1182/blood-2015-01-621474 |
| Journal | Blood |
| Issue Number | 25 |
| Volume Number | 125 |
| Language | English |
| Publisher | American Society of Hematology |
| Publisher Date | 2015-06-18 |
| Access Restriction | Open |
| Subject Keyword | Immunology Cd19 Ido Apoptosis Antigen Lymphoma Tumor Carts Model Tryptophan Journal: Blood (Vol- 2012, Issue- 25) |
| Content Type | Text |
| Resource Type | Article |
