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      Is autoimmunity the Achilles' heel of cancer immunotherapy?

      Author(s): , ,
      Publication date Created:
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      Journal: Nature Medicine
      Publisher: Springer Nature

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          Abstract

          In this Perspective, June, Bluestone and Warshauer discuss potential cellular and molecular explanations for the autoimmunity often associated with immunotherapy, and propose additional research and changes to reporting practices to aid efforts to understand and minimize these toxic side effects.

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          Most cited references47

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          Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade.

          Kristen E. Pauken, Morgan A. Sammons, Pamela M. Odorizzi … (2016)
          Blocking Programmed Death-1 (PD-1) can reinvigorate exhausted CD8 T cells (TEX) and improve control of chronic infections and cancer. However, whether blocking PD-1 can reprogram TEX into durable memory T cells (TMEM) is unclear. We found that reinvigoration of TEX in mice by PD-L1 blockade caused minimal memory development. After blockade, reinvigorated TEX became reexhausted if antigen concentration remained high and failed to become TMEM upon antigen clearance. TEX acquired an epigenetic profile distinct from that of effector T cells (TEFF) and TMEM cells that was minimally remodeled after PD-L1 blockade. This finding suggests that TEX are a distinct lineage of CD8 T cells. Nevertheless, PD-1 pathway blockade resulted in transcriptional rewiring and reengagement of effector circuitry in the TEX epigenetic landscape. These data indicate that epigenetic fate inflexibility may limit current immunotherapies.
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            Inducible apoptosis as a safety switch for adoptive cell therapy.

            Antonio Di Stasi, Siok-Keen Tey, Gianpietro Dotti … (2011)
            Cellular therapies could play a role in cancer treatment and regenerative medicine if it were possible to quickly eliminate the infused cells in case of adverse events. We devised an inducible T-cell safety switch that is based on the fusion of human caspase 9 to a modified human FK-binding protein, allowing conditional dimerization. When exposed to a synthetic dimerizing drug, the inducible caspase 9 (iCasp9) becomes activated and leads to the rapid death of cells expressing this construct. We tested the activity of our safety switch by introducing the gene into donor T cells given to enhance immune reconstitution in recipients of haploidentical stem-cell transplants. Patients received AP1903, an otherwise bioinert small-molecule dimerizing drug, if graft-versus-host disease (GVHD) developed. We measured the effects of AP1903 on GVHD and on the function and persistence of the cells containing the iCasp9 safety switch. Five patients between the ages of 3 and 17 years who had undergone stem-cell transplantation for relapsed acute leukemia were treated with the genetically modified T cells. The cells were detected in peripheral blood from all five patients and increased in number over time, despite their constitutive transgene expression. A single dose of dimerizing drug, given to four patients in whom GVHD developed, eliminated more than 90% of the modified T cells within 30 minutes after administration and ended the GVHD without recurrence. The iCasp9 cell-suicide system may increase the safety of cellular therapies and expand their clinical applications. (Funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute; ClinicalTrials.gov number, NCT00710892.).
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              IDO in the Tumor Microenvironment: Inflammation, Counter-Regulation, and Tolerance.

              David Munn, Andrew L Mellor (2016)
              Indoleamine 2,3-dioxygenase (IDO) has immunoregulatory roles associated with tryptophan metabolism. These include counter-regulation (controlling inflammation) and acquired tolerance in T cells. Recent findings reveal that IDO can be triggered by innate responses during tumorigenesis, and also by attempted T cell activation, either spontaneous or due to immunotherapy. Here we review the current understanding of mechanisms by which IDO participates in the control of inflammation and in peripheral tolerance. Focusing on the tumor microenvironment, we examine the role of IDO in response to apoptotic cells and the impact of IDO on Treg cell function. We discuss how the counter-regulatory and tolerogenic functions of IDO can be targeted for cancer immunotherapy and present an overview of the current clinical progress in this area.
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                Author and article information

                Journal
                Title: Nature Medicine
                Abbreviated Title: Nat Med
                Publisher: Springer Nature
                ISSN (Print): 1078-8956
                ISSN (Electronic): 1546-170X
                Publication date Created: May 5 2017
                Publication date (Print): May 5 2017
                Volume: 23
                Issue: 5
                Pages: 540-547
                Article
                DOI: 10.1038/nm.4321
                PubMed ID: 28475571
                SO-VID: 1e9aecd5-d669-4e5d-ba42-110e1d8a7839
                Copyright © © 2017
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