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Autoantibodies May Predict Immune-Related Toxicity: Results from a Phase I Study of Intralesional Bacillus Calmette–Guérin followed by Ipilimumab in Patients with Advanced Metastatic Melanoma

Published on Mar 2, 2018in Frontiers in Immunology4.72
· DOI :10.3389/fimmu.2018.00411
Jessica Duarte4
Estimated H-index: 4
(Ludwig Institute for Cancer Research),
Sagun Parakh8
Estimated H-index: 8
(Ludwig Institute for Cancer Research)
+ 7 AuthorsJonathan Cebon59
Estimated H-index: 59
(Ludwig Institute for Cancer Research)
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Abstract
Immune checkpoint inhibitors (ICI) have revolutionized the treatment of advanced melanoma. The first ICI to demonstrate clinical benefit, ipilimumab, targets cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), however long-term overall survival is just 22%. More than 40 years ago intralesional Bacillus Calmette-Guerin (BCG), a living attenuated strain of Mycobacterium bovis, was found to induce tumor regression by stimulating cell-mediated immunity following a localized and self-limiting infection. We evaluated these two immune stimulants in combination in melanoma with the aim of developing a more effective immunotherapy and to assess toxicity. In this phase I study patients with histologically confirmed stage III/IV metastatic melanoma received intralesional BCG injection followed by up to four cycles of intravenous ipilimumab (anti-CTLA-4) (ClinicalTrials.gov number NCT01838200). The trial was discontinued following treatment of the first five patients as the two patients receiving the escalation dose of BCG developed high-grade immune–related adverse events (irAEs) typical of ipilimumab monotherapy. These irAEs were characterized in both patients by profound increases in the repertoire of autoantibodies directed against both self- and cancer-antigens. Interestingly, the induced autoantibodies were detected at time points that preceded the development of symptomatic toxicity. There was no overlap in the antigen specificity between patients, and no evidence of clinical responses. Efforts to increase response rates through the use of novel immunotherapeutic combinations may be associated with higher rates of irAEs, thus the imperative to identify biomarkers of toxicity remains strong. While the small patient numbers in this trial do not allow for any conclusive evidence of predictive biomarkers, the observed changes warrant further examination of autoantibody repertoires in larger patient cohorts at risk of developing irAEs during their course of treatment. In summary: Dose escalation of intralesional BCG followed by ipilimumab therapy was not well tolerated in advanced melanoma patients and showed no evidence of clinical benefit. Measuring autoantibody responses may provide an early means for identifying patients at risk from developing severe irAEs during cancer immunotherapy.
  • References (40)
  • Citations (5)
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References40
Newest
Published on Sep 1, 2017in Cell36.22
Antoni Ribas94
Estimated H-index: 94
(UCLA: University of California, Los Angeles),
Reinhard Dummer94
Estimated H-index: 94
+ 17 AuthorsEugenio Fernandez4
Estimated H-index: 4
Summary Here we report a phase 1b clinical trial testing the impact of oncolytic virotherapy with talimogene laherparepvec on cytotoxic T cell infiltration and therapeutic efficacy of the anti-PD-1 antibody pembrolizumab. Twenty-one patients with advanced melanoma were treated with talimogene laherparepvec followed by combination therapy with pembrolizumab. Therapy was generally well tolerated, with fatigue, fevers, and chills as the most common adverse events. No dose-limiting toxicities occurr...
Published on Aug 1, 2017in Nature Reviews Clinical Oncology34.11
Jason J. Luke25
Estimated H-index: 25
,
Keith T. Flaherty89
Estimated H-index: 89
+ 1 AuthorsGeorgina V. Long66
Estimated H-index: 66
In less than a decade, the treatment landscape of metastatic melanoma has changed dramatically. Novel targeted agents and immunotherapies are revolutionizing patient outcomes, but the range of available drugs complicates clinical decision-making. Herein, the authors chart the therapeutic advances and review the current evidence that can be used to guide therapeutic decisions for individual patients with metastatic melanoma, highlighting knowledge gaps.
Published on Aug 1, 2017in Journal of Clinical Investigation12.28
Mark Ayers12
Estimated H-index: 12
(MSD: Merck & Co.),
Jared Lunceford21
Estimated H-index: 21
(MSD: Merck & Co.)
+ 12 AuthorsVeena Shankaran12
Estimated H-index: 12
(UW: University of Washington)
Abstract Programmed death-1-directed (PD-1-directed) immune checkpoint blockade results in durable antitumor activity in many advanced malignancies. Recent studies suggest that IFN-γ is a critical driver of programmed death ligand-1 (PD-L1) expression in cancer and host cells, and baseline intratumoral T cell infiltration may improve response likelihood to anti-PD-1 therapies, including pembrolizumab. However, whether quantifying T cell-inflamed microenvironment is a useful pan-tumor determinant...
Published on Jul 3, 2017in Expert Review of Proteomics2.96
Jessica Duarte4
Estimated H-index: 4
(La Trobe University),
Jonathan M. Blackburn20
Estimated H-index: 20
(UCT: University of Cape Town)
ABSTRACTIntroduction: High-content protein microarrays in principle enable the functional interrogation of the human proteome in a broad range of applications, including biomarker discovery, profiling of immune responses, identification of enzyme substrates, and quantifying protein-small molecule, protein-protein and protein-DNA/RNA interactions. As with other microarrays, the underlying proteomic platforms are under active technological development and a range of different protein microarrays a...
Published on May 1, 2017in Nature Medicine30.64
Carl H. June120
Estimated H-index: 120
,
Jeremy Warshauer5
Estimated H-index: 5
,
Jeffrey A. Bluestone132
Estimated H-index: 132
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.
Published on Sep 22, 2016in Journal of Clinical Oncology28.25
Jeffrey S. Weber81
Estimated H-index: 81
,
S. Targan1
Estimated H-index: 1
+ 5 AuthorsG. Nichol12
Estimated H-index: 12
9023 Background: Ipilimumab is a human anti-CTLA-4 antibody shown to have clinical activity in melanoma that is associated with immune-related adverse events (IrAEs). Methods: 50 HLA A*0201 positive patients with resected stages IIIC/IV melanoma received MART-1/gp100/tyrosinase peptides with adjuvant Montanide ISA 51 12 times subcutaneously with Ipilimumab at 3 or 10 mg/kg intravenously every 8 weeks for 12 months, and 25 HLA A *0201 negative patients received Ipilimumab alone at 10 mg/kg. Prima...
Published on Dec 1, 2016in Lancet Oncology35.39
Geoffrey T. Gibney21
Estimated H-index: 21
(MedStar Georgetown University Hospital),
Louis M Weiner1
Estimated H-index: 1
(MedStar Georgetown University Hospital),
Michael B. Atkins4
Estimated H-index: 4
(MedStar Georgetown University Hospital)
Summary The clinical development of checkpoint inhibitor-based immunotherapy has ushered in an exciting era of anticancer therapy. Durable responses can be seen in patients with melanoma and other malignancies. Although monotherapy with PD-1 or PD-L1 agents are typically well tolerated, the risk of immune-related adverse events increases with combination regimens. The development of predictive biomarkers is needed to optimise patient benefit, minimise risk of toxicities, and guide combination ap...
Published on May 1, 2016in Nature Reviews Cancer51.85
Suzanne L. Topalian82
Estimated H-index: 82
,
Janis M. Taube39
Estimated H-index: 39
+ 1 AuthorsDrew M. Pardoll113
Estimated H-index: 113
This Review assesses the mechanism-based biomarkers in use and in development for immune checkpoint inhibition, identifying cancer types and cancer phenotypes that are most likely to respond to immune checkpoint blockade, and considerations for future biomarkers of immune checkpoint response.
Published on May 1, 2016in Autoimmunity Reviews7.72
Pauline Zaenker2
Estimated H-index: 2
(ECU: Edith Cowan University),
Elin S. Gray29
Estimated H-index: 29
(ECU: Edith Cowan University),
Melanie Ziman24
Estimated H-index: 24
A link between autoimmune responses and cancer via autoantibodies was first described in the 1950s. Since, autoantibodies have been studied for their potential use as cancer biomarkers, however the exact causes of their production remain to be elucidated. This review summarizes current theories of the causes of autoantibody production in cancer, namely: 1) defects in tolerance and inflammation, 2) changes in protein expression levels, 3) altered protein structure, and 4) cellular death mechanism...
Published on Apr 21, 2016in PLOS ONE2.78
Gunasekaran Suwarnalata1
Estimated H-index: 1
,
Ai Huey Tan7
Estimated H-index: 7
+ 6 AuthorsJamuna Vadivelu24
Estimated H-index: 24
Parkinson's disease (PD) is the second most common chronic and progressive neurodegenerative disorder. Its etiology remains elusive and at present only symptomatic treatments exists. Helicobacter pylori chronically colonizes the gastric mucosa of more than half of the global human population. Interestingly, H. pylori positivity has been found to be associated with greater of PD motor severity. In order to investigate the underlying cause of this association, the Sengenics Immunome protein array,...
Cited By5
Newest
Published on Dec 1, 2019in Clinical Proteomics2.89
Milena Music (U of T: University of Toronto), Antoninus Soosaipillai35
Estimated H-index: 35
(MSH: Mount Sinai Hospital, Toronto)
+ 3 AuthorsEleftherios P. Diamandis97
Estimated H-index: 97
Background Autoantibodies are produced when tolerance to self-antigens is broken and they can be mediators of tissue injury and systemic inflammation. They are excellent biomarkers because they are minimally invasive to screen and are highly abundant in serum due to limited proteolysis and slow clearance. Conventionally used methods of identifying autoantibodies in patient sera include indirect immunofluorescence, enzyme-linked immunoabsorbent assays (ELISAs) and protein microarrays. Here we pre...
Published on Jun 11, 2019in Frontiers in Immunology4.72
Rachel Tanner12
Estimated H-index: 12
(University of Oxford),
Bernardo Villarreal-Ramos (Aberystwyth University)+ 1 AuthorsHelen McShane45
Estimated H-index: 45
(University of Oxford)
Bacillus Calmette Guerin (BCG) is the only currently available vaccine against tuberculosis (TB), but it confers incomplete and variable protection against pulmonary TB in humans and bovine TB (bTB) in cattle. Insights into the immune response induced by BCG offer an underexploited opportunity to gain knowledge that may inform the design of a more efficacious vaccine, which is urgently needed to control these major global epidemics. Humoral immunity in TB and bTB has been neglected, but recent s...
Published on May 13, 2019in Cells
Anne Largeot3
Estimated H-index: 3
,
Giulia Pagano + 2 AuthorsJerome Paggetti13
Estimated H-index: 13
Tumor-infiltrating lymphocytes are known to be critical in controlling tumor progression. While the role of T lymphocytes has been extensively studied, the function of B cells in this context is still ill-defined. In this review, we propose to explore the role of B cells in tumor immunity. First of all we define their dual role in promoting and inhibiting cancer progression depending on their phenotype. To continue, we describe the influence of different tumor microenvironment factors such as hy...
Published on Dec 12, 2018in Frontiers of Medicine in China
Jennifer A. Bridge3
Estimated H-index: 3
(UCSF: University of California, San Francisco),
James Lee12
Estimated H-index: 12
(UCSF: University of California, San Francisco)
+ 2 AuthorsJeffrey A. Bluestone132
Estimated H-index: 132
(UCSF: University of California, San Francisco)
Immunotherapy for skin malignancies has ushered in a new era for cancer treatments by demonstrating unprecedented durable responses in the setting of metastatic Melanoma. Consequently, checkpoint inhibitors are now the first-line treatment of metastatic melanoma and widely used as adjuvant therapy for stage III disease. With the observation that higher tumor mutational burden correlates with a better response, checkpoint inhibitors are tested in other skin cancer types of known high tumor mutati...
Published on Dec 1, 2018in Mammalian Genome2.34
Jessica Duarte4
Estimated H-index: 4
(La Trobe University),
Janique Peyper2
Estimated H-index: 2
(UCT: University of Cape Town),
Jonathan M. Blackburn20
Estimated H-index: 20
(UCT: University of Cape Town)
Recent developments in the immuno-oncology field strongly support a role for the immune system in both the prevention and progression of melanoma. Melanoma is a highly immunogenic cancer, including its ability to induce tumour antigen-specific B cell and antibody responses through largely unknown mechanisms. This review considers likely hypothetical mechanisms by which anti-tumour surveillance detects pre-cancerous cells and by which immune (including B cell and antibody) responses may be elicit...
Published on Dec 1, 2018in Mammalian Genome2.34
Jonathan Cebon59
Estimated H-index: 59
Current excitement about cancer immunotherapy is the result of unprecedented clinical impact from immune checkpoint inhibitors, particularly those that target programmed death (PD)-1 and PD-ligand (L)-1. Numerous other immunotherapeutics are also finding their way into the clinic either alone or in combination, and these have potential applications in many cancer types. Therapeutic cancer vaccines have been a major focus for many pioneers in the field yet have largely failed to live up to expect...
Published on Dec 1, 2018in Cancer immunology research8.62
Arabella Young2
Estimated H-index: 2
(UCSF: University of California, San Francisco),
Zoe Quandt4
Estimated H-index: 4
(UCSF: University of California, San Francisco),
Jeffrey A. Bluestone132
Estimated H-index: 132
(UCSF: University of California, San Francisco)
The explosion in novel cancer immunotherapies has resulted in extraordinary clinical successes in the treatment of multiple cancers. Checkpoint inhibitors (CPIs) that target negative regulatory molecules have become standard of care. However, with the growing use of CPIs, alone or in combination with chemotherapy, targeted therapies, or other immune modulators, a significant increase in immune-related adverse events (irAEs) has emerged. The wide-ranging and currently unpredictable spectrum of CP...
Published on Oct 1, 2018in Nature Reviews Rheumatology18.55
Leonard H. Calabrese9
Estimated H-index: 9
(Cleveland Clinic Lerner College of Medicine),
Cassandra Calabrese1
Estimated H-index: 1
(Cleveland Clinic Lerner College of Medicine),
Laura C. Cappelli6
Estimated H-index: 6
(Johns Hopkins University)
Immunotherapy has revolutionized the treatment of cancer, but a rapid rise in the use of the family of therapeutic agents known as checkpoint inhibitors (CPIs) is associated with a new group of immune-related adverse events (irAEs) in almost any organ system. Among these irAEs, rheumatic complications are common and seem to have features that are distinct from irAEs in other organ systems, including a highly variable time of clinical onset and the capacity to persist, possibly indefinitely, even...
View next paperPotential immune biomarkers of gastrointestinal toxicities and efficacy in patients with advanced melanoma treated with ipilimumab with or without prophylactic budesonide