CTLA-4 gene variant -1661A&gt;G may predict the onset of endocrine adverse events in metastatic melanoma patients treated with ipilimumab

Queirolo, Paola; Dozin, Béatrice; Morabito, Anna; Banelli, Barbara; Carosio, Roberta; Fontana, Vincenzo; Ferrucci, Pier Francesco; Martinoli, Chiara; Cocorocchio, Emilia; Ascierto, Paolo A.; Madonna, Gabriele; Simeone, Ester; Galitiis, Federica De; Cappellini, Gian Carlo Antonini; Marchetti, Paolo; Guida, Michele; Tommasi, Stefania; Ghilardi, Laura; Merelli, Barbara; Fava, Paolo; Osella‐Abate, Simona; Giusti, Massimo; Romani, Massimo; Ferone, Diego; Spagnolo, Francesco; Pistillo, Maria Pia; Intergroup, Italian Melanoma

doi:10.1016/j.ejca.2018.04.005

Cited by 22 publications

(14 citation statements)

References 6 publications

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“…A smaller study of acute onset type 1 diabetes due to anti-PD-1 therapy showed four out of five patients had HLA subgroups DRB01* 03 or 04, which are associated with type 1 diabetes risk in the general population [16]. Another study of patients with metastatic melanoma treated with ipilimumab suggests that having CTLA-4 gene variant 1661A>G may predispose patients to developing endocrine irAEs [17]. These data evaluated with the present study suggest that a patient's immunogenetic framework may increase the risk for developing irAEs like inflammatory arthritis due to ICI therapy.…”

Section: Discussionmentioning

confidence: 99%

Association of HLA-DRB1 shared epitope alleles and immune checkpoint inhibitor-induced inflammatory arthritis

et al. 2018

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Objective To evaluate the frequency of HLA class I and II alleles associated with traditional forms of inflammatory arthritis in patients with immune checkpoint inhibitor (ICI)-induced inflammatory arthritis as compared with population controls. Methods High-resolution HLA typing was performed on 27 patients with ICI-induced inflammatory arthritis and 726 healthy controls. Genotyping at the shared epitope (SE) locus (HLA DRB1) was performed on 220 RA cases. Allele-positivity rates and frequency of having at least one SE allele were compared using Fisher’s exact test between ICI-induced inflammatory arthritis and healthy controls. Frequency of having at least one SE allele was also compared between ICI-induced inflammatory arthritis and RA cases. Results Twenty-six patients with ICI-induced inflammatory arthritis were of European descent, and one was African American. In those 26 patients, 16 (61.5%) had at least one SE allele, significantly different from healthy controls of European descent, in whom 299 (41.2%) had at least one SE allele (odds ratio 2.3, P = 0.04). The allele-positivity rate of DRB1*04: 05 was also higher in the ICI-induced inflammatory arthritis group. The ICI-induced inflammatory arthritis population and RA patients of European descent did not differ in frequency of having at least one SE allele, but ICI-induced inflammatory arthritis patients were more likely to be autoantibody-negative for RF and anti-CCP antibodies. Conclusion Patients with ICI-induced inflammatory arthritis of European descent were more likely to have at least one SE allele than healthy controls. Further studies are needed to validate these findings and investigate whether a unique immunogenetic framework increases risk for different immune-related adverse events.

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Section: Discussionmentioning

confidence: 99%

Association of HLA-DRB1 shared epitope alleles and immune checkpoint inhibitor-induced inflammatory arthritis

et al. 2018

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“…Cappelli et al recently evaluated immunogenetics in patients with ICI-induced IA and found that patients of European descent were more likely to be positive for HLA-DRB1 shared epitope alleles than population controls (98). Furthermore, patients with CTLA-4 gene variant 1661A>G may predispose melanoma patients to the development of endocrine irAEs (99). In addition, the JHH group have recently demonstrated that in NSCLC, tumor histologic type may be a risk factor for CIP development and that the development of CIP worsens survival in patients receiving immunotherapy (58, 59).…”

Section: Discussionmentioning

confidence: 99%

Immune-Related Adverse Events: A Case-Based Approach

2019

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Immunotherapy has heralded the advent of a new era in oncology. Immune checkpoint inhibitors (ICIs) enhance anti-tumor immunity, thereby reinvigorating a patient's immune system to fight cancer. While therapy with this class of agents has resulted in improved clinical outcomes for patients with multiple tumor types, a broad spectrum of immune-related adverse events (irAEs) may affect any organ system, with variable clinical presentations. Prompt recognition and management of irAEs are associated with improved irAE outcomes, and represents an important new clinical challenge for practicing oncologists. Herein, we provide a comprehensive case-based review of the most common and clinically-important irAEs, focussing on epidemiology, clinical manifestations, and management. We also examine future strategies that may provide meaningful insights into the prevention and management of irAEs.

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“…Years ago, it was shown that SNVs in CTLA-4 may affect the transcriptional activity of the gene as well as the interaction with CD80 and influence immune response in autoimmune diseases ( 39 , 40 ). SNV of CTLA- 4 are implicated in clinical response and survival in melanoma patients ( 41 , 42 ) and, more recently, SNV-1577G > A and SNV CT60G > A were linked to a better response to Ipilimumab in a 173-patients cohort ( 43 ) and SNV-1661A > G to the onset of endocrine adverse events ( 44 ).…”

Section: Genetic and Epigenetic Factors Determine The Functionality Omentioning

confidence: 99%

Immune Checkpoints and Innovative Therapies in Glioblastoma

et al. 2018

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Targeting the Immune Checkpoint molecules (ICs; CTLA-4, PD-1, PD-L1/2, and others) which provide inhibitory signals to T cells, dramatically improves survival in hard-to-treat tumors. The establishment of an immunosuppressive environment prevents endogenous immune response in glioblastoma; therefore, manipulating the host immune system seems a reasonable strategy also for this tumor. In glioma patients the accumulation of CD4+/CD8+ T cells and Treg expressing high levels of CTLA-4 and PD-1, or the high expression of PD-L1 in glioma cells correlates with WHO high grade and short survival. Few clinical studies with IC inhibitors (ICis) were completed so far. Notably, the first large-scale randomized trial (NCT 02017717) that compared PD-1 blockade and anti-VEGF, did not show an OS increase in the patients treated with anti-PD-1. Several factors could have contributed to the failure of this trial and must be considered to design further clinical studies. In particular the possibility of targeting at the same time different ICs was pre-clinically tested in an animal model were inhibitors against IDO, CTLA-4 and PD-L1 were combined and showed persistent and significant antitumor effects in glioma-bearing mice. It is reasonable to hypothesize that the immunological characterization of the tumor in terms of type and level of expressed IC molecules on the tumor and TIL may be useful to design the optimal ICi combination for a given subset of tumor to overcome the immunosuppressive milieu of glioblastoma and to efficiently target a tumor with such high cellular complexity.

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CTLA-4 gene variant -1661A>G may predict the onset of endocrine adverse events in metastatic melanoma patients treated with ipilimumab

Cited by 22 publications

References 6 publications

Association of HLA-DRB1 shared epitope alleles and immune checkpoint inhibitor-induced inflammatory arthritis

Association of HLA-DRB1 shared epitope alleles and immune checkpoint inhibitor-induced inflammatory arthritis

Immune-Related Adverse Events: A Case-Based Approach

Immune Checkpoints and Innovative Therapies in Glioblastoma

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