Association of CTLA-4 Polymorphisms with Improved Overall Survival in Melanoma Patients Treated with CTLA-4 Blockade: A Pilot Study

Queirolo, Paola; Morabito, Anna; Laurent, Stefania; Lastraioli, Sonia; Piccioli, Patrizia; Ascierto, Paolo A.; Gentilcore, Giusy; Serra, Martina; Marasco, Antonella; Tornari, Elena; Dozin, Béatrice; Pistillo, Maria Pia

doi:10.3109/07357907.2013.793699

Cited by 53 publications

(43 citation statements)

References 44 publications

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“…Moreover, there were 30 studies with 9675 cases and 9623 controls for rs3087243 [12-15, 17, 23-25, 27-29, 31, 32, 35, 37, 40, 41, 44, 45, 47, 53, 54, 61, 63, 65, 66, 73-75]. Additionally, rs4553808 was in 17 studies [12, 14, 15, 23, 28, 29, 31, 37, 41, 44, 47, 49, 51, 52, 62, 73, 76], rs5742909 was in 32 studies [12, 14, 15, 20, 24, 25, 28-30, 32, 34, 35, 39-41, 45, 47, 52-54, 56, 57, 59, 62, 63, 65, 66, 70, 73, 76, 77], rs733618 was in 14 studies [13, 23, 28, 37, 44, 47, 51, 52, 62, 73-76, 78], and they were analysed. Of the 67 studies, 9 presented a significant deviation from HWE (5 studies on rs231775 [11, 13, 34, 51, 66], 4 studies on rs4553808 [51, 62…”

Section: Resultsmentioning

confidence: 99%

Association of Five Snps in Cytotoxic T-Lymphocyte Antigen 4 and Cancer Susceptibility: Evidence from 67 Studies

Fang

Huang

et al. 2018

Cell Physiol Biochem

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Background/Aims: CTLA-4 polymorphisms are associated with susceptibility to various cancers, but the results are often conflicting. Hence, we performed a comprehensive meta-analysis to quantitatively investigate the association between CTLA-4 polymorphisms (rs231775, rs4553808，rs5742909, rs3087243 or rs733618) and cancer risk. Methods: Data were collected from PubMed and Web of Science. A total of 67 case-control studies were selected for quantitative analysis. Stata (Version 12) software was used to calculate the odds ratio (OR) and 95% confidence interval (CI) to evaluate the strength of the associations. Subgroup meta-analysis was conducted based on ethnicity and cancer type. Heterogeneity tests, sensitivity analysis, and publication bias assessments were also performed. Results: rs231775, rs4553808 and rs5742909 but not rs3087243 and rs733618 were significantly related to cancer risk. In analyses stratified by ethnicity, both rs231775 and rs4553808 were significant susceptibility polymorphisms in an Asian population but not in a Caucasian population. Moreover, there were stronger associations between the rs231775 polymorphism and increased risk of bone, breast, liver, head and neck and pancreatic cancers. Additionally, rs4553808 was associated with significantly increased susceptibility to breast cancer and head and neck cancer. Conclusion: rs231775, rs4553808 and rs5742909 may be used as predictive genetic biomarkers for cancer predisposition. Combined detection of CTLA-4 SNPs could be a useful tool for prediction of cancer susceptibility in clinical practice.

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Section: Resultsmentioning

confidence: 99%

Association of Five Snps in Cytotoxic T-Lymphocyte Antigen 4 and Cancer Susceptibility: Evidence from 67 Studies

Fang

Huang

et al. 2018

Cell Physiol Biochem

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“…Genetic analysis of 64 ipilimumab-treated melanoma patients uncovered a correlation between mutational load and clinical benefit and identified a neo-antigen landscape specific to tumors that are highly responsive to treatment 220 . Some specific genetic mutations 221 and the presence of particular single-nucleotide polymorphisms 222 have also been shown to predict clinical response. Interestingly, the single-nucleotide polymorphisms (SNPs) that correlated with beneficial clinical response did not show any correlation with the occurrence or severity of adverse events 222 , suggesting that the mechanisms underlying efficacy and toxicity do not overlap entirely and can thus be differentially targeted when designing future immunomodulatory mAbs for greater therapeutic index.…”

Section: Expert Opinion: Is It Possible To Selectively Increase Samentioning

confidence: 99%

“…Some specific genetic mutations 221 and the presence of particular single-nucleotide polymorphisms 222 have also been shown to predict clinical response. Interestingly, the single-nucleotide polymorphisms (SNPs) that correlated with beneficial clinical response did not show any correlation with the occurrence or severity of adverse events 222 , suggesting that the mechanisms underlying efficacy and toxicity do not overlap entirely and can thus be differentially targeted when designing future immunomodulatory mAbs for greater therapeutic index. This study also supports an earlier hypothesis that some mutations considered silent passengers should instead be classified as immune determinants 223 that collectively define immunogenicity and susceptibility to antitumor effector mechanisms employed by the immune system.…”

Section: Expert Opinion: Is It Possible To Selectively Increase Samentioning

confidence: 99%

Enhancing the safety of antibody-based immunomodulatory cancer therapy without compromising therapeutic benefit: Can we have our cake and eat it too?

Ryan

Wasser

Adler

et al. 2016

Expert Opinion on Biological Therapy

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Introduction Monoclonal antibodies (mAbs) targeting checkpoint inhibitors have demonstrated clinical benefit in treating patients with cancer and have paved the way for additional immune-modulating mAbs such as those targeting costimulatory receptors. The full clinical utility of these agents, however, is hampered by immune-related adverse events (irAEs) that can occur during therapy. Areas covered We first provide a general overview of tumor immunity, followed by a review of the two major classes of immunomodulatory mAbs being developed as cancer therapeutics: checkpoint inhibitors and costimulatory receptor agonists. We then discuss therapy-associated adverse events. Finally, we describe in detail the mechanisms driving their therapeutic activity, with an emphasis on interactions between antibody fragment crystallizable (Fc) domains and Fc receptors (FcR). Expert Opinion Given that Fc-FcR interactions appear critical in facilitating the ability of immunomodulatory mAbs to elicit both therapeutically useful as well as adverse effects, the engineering of mAbs that can effectively engage their targets while limiting interaction with FcRs might represent a promising future avenue for developing the next generation of immune-enhancing tumoricidal agents with increased safety and retention of efficacy.

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“…After analyzing 6 CTLA-4 single nucleotide polymorphisms (SNPs) (−1661A>G, −1577G>A, −658C>T, −319C>T, +49A>G, and CT60G>A) in malignant melanoma patients, a recent study found that the −1577G/A and CT60G/A genotypes had better overall survival and response to ipilimumab treatment (104). Different SNPs alter CTLA-4 expression, so response to ipilimumab can differ depending on the genotype.…”

Section: Future Directionsmentioning

confidence: 99%

Immune-mediated adverse events of anticytotoxic T lymphocyte–associated antigen 4 antibody therapy in metastatic melanoma

Quirk

Shure

Agrawal

2015

Translational Research

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Ipilimumab, an antibody that blocks cytotoxic T lymphocyte-associated antigen-4 (CTLA-4; CD152), was approved by the Food and Drug Administration (FDA) in 2011 for the treatment of unresectable stage III or IV malignant melanoma. Although the addition of this particular immunotherapy has broadened treatment options, immune-related adverse events (irAEs) are associated with ipilimumab therapy, including dermatologic effects, colitis and diarrhea, endocrine effects, hepatotoxicity, ocular effects, renal effects, neurologic effects, and others. In this article, a critical evaluation of the underlying mechanisms of irAEs associated with anti-CTLA-4 therapy is presented. Additionally, potentially beneficial effects of combinational therapies to alleviate ipilimumab-induced irAEs in malignant melanoma are discussed. Future research is warranted to elucidate the efficacy of such combination therapies as well as specific biomarkers that would help to predict a clinical response to ipilimumab in patients with malignant melanoma.

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Association of CTLA-4 Polymorphisms with Improved Overall Survival in Melanoma Patients Treated with CTLA-4 Blockade: A Pilot Study

Cited by 53 publications

References 44 publications

Association of Five Snps in Cytotoxic T-Lymphocyte Antigen 4 and Cancer Susceptibility: Evidence from 67 Studies

Association of Five Snps in Cytotoxic T-Lymphocyte Antigen 4 and Cancer Susceptibility: Evidence from 67 Studies

Enhancing the safety of antibody-based immunomodulatory cancer therapy without compromising therapeutic benefit: Can we have our cake and eat it too?

Immune-mediated adverse events of anticytotoxic T lymphocyte–associated antigen 4 antibody therapy in metastatic melanoma

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