Is autoimmunity the Achilles' heel of cancer immunotherapy?

Published on May 1, 2017in Nature Medicine30.641
· DOI :10.1038/nm.4321
Carl H. June124
Estimated H-index: 124
Jeremy T. Warshauer5
Estimated H-index: 5
Jeffrey A. Bluestone137
Estimated H-index: 137
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.
Figures & Tables
  • References (104)
  • Citations (98)
📖 Papers frequently viewed together
3,027 Citations
8,044 Citations
396 Citations
78% of Scinapse members use related papers. After signing in, all features are FREE.
#1Jiangtao Ren (UPenn: University of Pennsylvania)H-Index: 4
#2Xiaojun Liu (UPenn: University of Pennsylvania)H-Index: 13
Last. Yangbing Zhao (UPenn: University of Pennsylvania)H-Index: 34
view all 6 authors...
Purpose: Using gene-disrupted allogeneic T cells as universal effector cells provides an alternative and potentially improves current chimeric antigen receptor (CAR) T-cell therapy against cancers and infectious diseases. Experimental Design: The CRISPR/Cas9 system has recently emerged as a simple and efficient way for multiplex genome engineering. By combining lentiviral delivery of CAR and electro-transfer of Cas9 mRNA and gRNAs targeting endogenous TCR, β-2 microglobulin (B2M) and PD1 simulta...
196 CitationsSource
#1Arnab Ghosh (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 13
#2Melody Smith (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 6
Last. M.R.M. van den Brink (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 61
view all 26 authors...
Allogeneic chimeric antigen receptor (CAR) T cells are capable of inducing graft-versus-host disease (GVHD) in recipients, yet this is not commonly seen in the clinic. Marcel van den Brink, Michel Sadelain and colleagues show that alloreactive CAR T cells have reduced effector function due to signaling through the CAR and T cell receptor, resulting in reduced GVHD, while the graft-versus-leukemia effect is maintained by non-alloreactive CAR T cells.
65 CitationsSource
#1David Y. Oh (UCSF: University of California, San Francisco)H-Index: 7
#2Jason Cham (UCSF: University of California, San Francisco)H-Index: 3
Last. Lawrence Fong (UCSF: University of California, San Francisco)H-Index: 41
view all 8 authors...
Immune checkpoint inhibitors can induce clinical responses with many cancers but also immune-related adverse events (IRAEs). Mechanisms driving IRAEs are unknown. Because CTLA-4 blockade leads to proliferation of circulating T cells, we examined whether ipilimumab leads to clonal expansion of tissue-reactive T cells. Rather than narrowing the T cell repertoire to a limited number of clones, ipilimumab induced greater repertoire diversification in IRAE patients compared to patients without IRAEs,...
36 CitationsSource
#1Jared R. Lowe (Duke University)H-Index: 2
#2Daniel J. Perry (UF: University of Florida)H-Index: 12
Last. Brent A. Hanks (Duke University)H-Index: 14
view all 6 authors...
Background Checkpoint inhibitor immunotherapy is becoming an effective treatment modality for an increasing number of malignancies. As a result, autoinflammatory side-effects are also being observed more commonly in the clinic. We are currently unable to predict which patients will develop more severe toxicities associated with these treatment regimens.
29 CitationsSource
#1Kristen E. Pauken (UPenn: University of Pennsylvania)H-Index: 20
#2Morgan A. Sammons (UPenn: University of Pennsylvania)H-Index: 11
Last. E. J. Wherry (UPenn: University of Pennsylvania)H-Index: 2
view all 19 authors...
Blocking Programmed Death–1 (PD-1) can reinvigorate exhausted CD8 T cells (T EX ) and improve control of chronic infections and cancer. However, whether blocking PD-1 can reprogram T EX into durable memory T cells (T MEM ) is unclear. We found that reinvigoration of T EX in mice by PD-L1 blockade caused minimal memory development. After blockade, reinvigorated T EX became reexhausted if antigen concentration remained high and failed to become T MEM upon antigen clearance. T EX acquired an epigen...
250 CitationsSource
#1Debattama R. Sen (Harvard University)H-Index: 7
#2Jim Kaminski (University of California, Berkeley)H-Index: 2
Last. W. Nicholas Haining (MIT: Massachusetts Institute of Technology)H-Index: 34
view all 19 authors...
Exhausted T cells in cancer and chronic viral infection express distinctive patterns of genes, including sustained expression of programmed cell death protein 1 (PD-1). However, the regulation of gene expression in exhausted T cells is poorly understood. Here, we define the accessible chromatin landscape in exhausted CD8+ T cells and show that it is distinct from functional memory CD8+ T cells. Exhausted CD8+ T cells in humans and a mouse model of chronic viral infection acquire a state-specific...
209 CitationsSource
#1Pranshu Bansal (UNM: University of New Mexico)H-Index: 5
#2Diaa Osman (UNM: University of New Mexico)H-Index: 2
Last. Yanis Boumber (UNM: University of New Mexico)H-Index: 15
view all 5 authors...
Non-small cell lung cancer (NSCLC) is one of most common malignancies and the leading cause of cancer deaths worldwide. Despite advances in targeted therapies, majority of NSCLC patients do not have targetable genomic alterations. Nevertheless, recent discovery that NSCLC is an immunogenic tumor type, and several breakthroughs in immunotherapies have led to rapid expansion of this new treatment modality in NSCLC with recent FDA approvals of PD-1 inhibitors, nivolumab and pembrolizumab. Here, we ...
11 CitationsSource
Immune checkpoint inhibitors have improved clinical outcomes associated with numerous cancers, but high-grade, immune-related adverse events can occur, particularly with combination immunotherapy. We report the cases of two patients with melanoma in whom fatal myocarditis developed after treatment with ipilimumab and nivolumab. In both patients, there was development of myositis with rhabdomyolysis, early progressive and refractory cardiac electrical instability, and myocarditis with a robust pr...
396 CitationsSource
#1Jeroen de Filette (Vrije Universiteit Brussel)H-Index: 3
#2Yanina Jansen (Vrije Universiteit Brussel)H-Index: 7
Last. Bert Bravenboer (Vrije Universiteit Brussel)H-Index: 30
view all 7 authors...
Context: Immune checkpoint blockade is associated with endocrine-related adverse events. Thyroid dysfunction during pembrolizumab therapy, an anti-programmed cell death 1 (PD-1) receptor monoclonal antibody, remains to be fully characterized. Objective: To assess the incidence and characteristics of pembrolizumab-associated thyroid dysfunction. Design and Setting: Thyroid function was monitored prospectively in melanoma patients who initiated pembrolizumab within an expanded access program at a ...
51 CitationsSource
#1Aude G. Chapuis (UW: University of Washington)H-Index: 11
#2Ilana M. Roberts (UW: University of Washington)H-Index: 2
Last. Cassian YeeH-Index: 33
view all 15 authors...
PurposePeripheral blood–derived antigen-specific cytotoxic T cells (CTLs) provide a readily available source of effector cells that can be administered with minimal toxicity in an outpatient setting. In metastatic melanoma, this approach results in measurable albeit modest clinical responses in patients resistant to conventional therapy. We reasoned that concurrent cytotoxic T-cell lymphocyte antigen-4 (CTLA-4) checkpoint blockade might enhance the antitumor activity of adoptively transferred CT...
29 CitationsSource
Cited By98
#1Prabhakaran Kumar (UIC: University of Illinois at Chicago)H-Index: 7
#2Shikha Saini (UIC: University of Illinois at Chicago)H-Index: 9
Last. Bellur Prabahakar (UIC: University of Illinois at Chicago)H-Index: 46
view all 3 authors...
Abstract Regulatory T-cells (Tregs) can facilitate immune evasion by tumor cells by dampening anti-tumor immunity. Reduced Teff/Treg ratio and enhanced Treg functional activity have been observed in patients suffering from different types of cancers, and attenuated Treg numbers/functions can serve as prognostic indicators. Normally, Tregs play an essential role in the maintenance of immune tolerance and prevention of autoimmunity. The most common immune checkpoint blockers (ICB) targeting co-inh...
12 CitationsSource
#1Chuan HuH-Index: 9
view all 11 authors...
Abstract To achieve safe and effective antitumor immunity, we constructed the M1-macrophage-membrane-coated nanoparticles [(C/I)BP@B-A(D)&M1m] having laser-responsive, size-changeable, on-demand drug release and prolonged circulation retention properties. (C/I)BP@B-A(D)&M1m delayed clearance by the phagocytic system and homed to tumor efficiently. Upon 650 nm laser irradiation, the hydrophobic core of the PEGylated bilirubin nanoparticles (BP) got disrupted, releasing small-sized deep-penetratin...
#1Uma Thanarajasingam (Mayo Clinic)H-Index: 10
Last. Noha Abdel-Wahab (Assiut University)H-Index: 8
view all 2 authors...
#1Zia Khan (Genentech)H-Index: 2
#2Flavia Di Nucci (Genentech)H-Index: 1
Last. Ellie Guardino (Genentech)H-Index: 13
view all 18 authors...
PD-1 and PD-L1 act to restrict T cell responses in cancer and contribute to self-tolerance. Consistent with this role, PD-1 checkpoint inhibitors have been associated with immune-related adverse events (irAEs), immune toxicities thought to be autoimmune in origin. Analyses of dermatological irAEs have identified an association with improved overall survival (OS) following anti–PD-(L)1 therapy, but the factors that contribute to this relationship are poorly understood. We collected germline whole...
1 CitationsSource
#1Mitchell S. von Itzstein (UTSW: University of Texas Southwestern Medical Center)
#2Shaheen Khan (UTSW: University of Texas Southwestern Medical Center)H-Index: 17
Last. David E. Gerber (UTSW: University of Texas Southwestern Medical Center)H-Index: 31
view all 3 authors...
BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of multiple cancers. However, these promising therapies may also cause immune-related adverse events (irAEs) in a substantial proportion of patients. These autoimmune phenomena may affect almost any organ system and may occur at almost any point in therapy. In some instances, these toxicities are life-threatening and potentially permanent. Diverse clinical presentation and unpredictable timing further complicate th...
3 CitationsSource
#1Elisa Gremese (UCSC: Catholic University of the Sacred Heart)H-Index: 27
#2Stefano Alivernini (UCSC: Catholic University of the Sacred Heart)H-Index: 17
Last. Gianfranco Ferraccioli (UCSC: Catholic University of the Sacred Heart)H-Index: 59
view all 4 authors...
Abstract Immune related adverse events (irAEs) have been observed with all checkpoint inhibitors and are very frequent. The evidences coming from experimental models of congenital or acquired deficiency of CTLA-4 or from PD-1 knock-out mice, provided all the informations to interpret the organ or systemic manifestations (endocrine, or systemic autoimmune chronic inflammatory diseases-ACIDs) observed in trials as well as in registries of cohorts treated with anti-CTLA-4 or anti-PD-1/PD-L1 inhibit...
#1Maria V. Deligiorgi (UoA: National and Kapodistrian University of Athens)
#2Mihalis I. Panayiotidis (Northumbria University)H-Index: 9
Last. Dimitrios T. Trafalis (UoA: National and Kapodistrian University of Athens)H-Index: 8
view all 3 authors...
Designated as scientific breakthrough of current decade, immune checkpoint inhibitors attenuate the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death 1 (PD-1)/ligand 1 (PD-L1) pathways, depriving cancer cells of a key strategy of evasion from immunosurveillance. The reinvigoration of immune response translates into clinical success, inevitably entwined with a novel constellation of immune-related adverse events. The present review dissects the endocrine immune-re...
: Immune checkpoint inhibitor (ICI)-related inflammatory diseases, including polymyositis (PM) and dermatomyositis (DM), in patients suffering from neoplastic disorders represent a medical challenge. The treatment of these conditions has taken on new urgency due to the successful and broad development of cancer-directed immunological-based therapeutic strategies. While primary and secondary PM/DM phenotypes have been pathophysiologically characterized, a rational, stepwise approach to the treatm...
2 CitationsSource
#1Michael D. Richter (UW: University of Washington)
#2Grant C. Hughes (UW: University of Washington)H-Index: 7
Last. John A. Thompson (Seattle Cancer Care Alliance)H-Index: 61
view all 6 authors...
Abstract The growth of cancer immunotherapy has led to an urgent need for a multispecialty approach to treating patients with advanced malignancies. Checkpoint inhibitor therapies cause a wide range of toxicities termed immune-related adverse events (irAEs) that can affect any organ system. Similar to the anti-tumor responses induced by these medications, irAEs represent an interruption of self-tolerance that results in T cell-driven cytotoxicity, the exact mechanisms of which are likely heterog...
#1Khashayar Esfahani (McGill University)H-Index: 4
#2Arielle Elkrief (McGill University)H-Index: 2
Last. Leonard H. Calabrese (Cleveland Clinic)H-Index: 59
view all 8 authors...
The enhancement of immune responses upon treatment with immune checkpoint inhibitors can have the desired outcome of reinvigorating antitumour immune surveillance, but often at the expense of immune-related adverse events (irAEs). This novel disease entity often prompts comparisons with, and extrapolation of treatment approaches from, primary autoimmune disorders. Accordingly, current treatment guidelines for irAEs make generic recommendations adapted from the literature describing primary autoi...
3 CitationsSource