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Validation and implementation of prognostic immunological factors for clinical responses to imiquimod therapy in patients with cervical high grade squamous intraepithelial lesions

Projectomschrijving

Op weg naar een gepersonaliseerde behandeling van voorstadia van baarmoederhalskanker

In de behandeling van voorstadia van baarmoederhalskanker wordt een behandeling met crème in plaats van een kleine operatie onderzocht. De crème werkt niet bij iedereen, daarom bestuderen de onderzoekers afweercellen die vooraf kunnen voorspellen wie er wel en wie er niet reageert om de behandeling effectiever in te kunnen zetten.

Towards personalized therapy in premalignant cervical dysplasia

In the treatment of premalignant cervical dysplasia, therapy with a topical cream instead of a surgical procedure is being investigated. The cream is not effective to everyone. The researchers will analyze the importance of pre-existent immune cells in order to predict patients responsiveness and increase treatment efficacy.

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Titel: Importance of the Immune Microenvironment in the Spontaneous Regression of Cervical Squamous Intraepithelial Lesions (cSIL) and Implications for Immunotherapy
Auteur: Caroline L P Muntinga 1 2, Peggy J de Vos van Steenwijk 2 3, Ruud L M Bekkers 1 2, Edith M G van Esch 1
Magazine: Journal of Clinical Medicine
Link: https://pubmed.ncbi.nlm.nih.gov/35268523/
Titel: Immune-based biomarker accurately predicts response to imiquimod immunotherapy in cervical high-grade squamous intraepithelial lesions
Auteur: Ziena Abdulrahman 1 2, Natasja Hendriks 3, Arnold J Kruse 3, Antonios Somarakis 1, Anna J M van de Sande 4, Heleen J van Beekhuizen 4, Jurgen M J Piek 5, Noel F C C de Miranda 1, Loes F S Kooreman 3, Brigitte F M Slangen 3, Sjoerd H van der Burg # 1 2, Peggy J de Vos van Steenwijk # 3, Edith M G van Esch
Magazine: journal for Immunotherapy of Cancer
Titel: IMMUNE-BASED BIOMARKER ACCURATELY PREDICTS RESPONSE TO IMIQUIMOD IMMUNOTHERAPY IN CERVICAL HIGH-GRADE SQUAMOUS INTRAEPITHELIAL LESIONS
Auteur: Ziena Abdulrahman1, Natasja Hendriks2, Arnold J. Kruse2, Antonios Somarakis3, Anna J.M. van de Sande4, Heleen J. van Beekhuizen4, Jurgen M.J. Piek5, Noel F.C.C. de Miranda6, Loes F.S. Kooreman7, Brigitte F.M. Slangen2, Sjoerd H. van der Burg1*, Peggy J. de Vos van Steenwijk2*, Edith M.G. van Esch5*
Titel: Inflammatory immune microenvironment in cervical high-grade squamous intraepithelial lesions predicts response to topical imiquimod immunotherapy
Auteur: Ziena Abdulrahman1, Natasja Hendriks2, Arnold Kruse2, Meike van de Sande3, Heleen van Beekhuizen3, Jurgen Piek4, Loes Kooreman2, Brigitte Slangen2, Sjoerd H. van der Burg1, Peggy J. de Vos van Steenwijk2*, Edith M.G. van Esch4*
Titel: Biomarker for predicting response to TLR 7-agonist immunotherapy of squamous intraepithelial lesions and therapeutic use thereof
Auteur: SH van der Burg, Z. Abdulrahman, PJ de Vos van Steenwijk, EMG van Esch

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Samenvatting van de aanvraag

Cervical high grade squamous intraepithelial lesions (cervical HSIL), are a common premalignant condition caused by a persistent infection with a high risk human papilloma virus (hrHPV). Cervical HSIL has a high incidence in mainly young women and is treated by a large loop excision of the transformation zone (LLETZ). LLETZ therapy is effective in the treatment of cervical HSIL whereas it is associated with recurrence rates of approximately 10-15% and potential complications such as hemorrhage, infection and an increased pre-term birth risk in subsequent pregnancies. Alternative therapy is therefore warranted especially in this young patient group with a subsequent wish to conceive children. In the last decades topical immune modifier imiquimod has been used to treat hrHPV induced anogenital neoplasia’s, as vulvar HSIL and cervical HSIL. The clinical response rates are promising approaching lesion regression in 50% of patients. A notable number of patients fails to respond to these therapies and long-term effectiveness remains to be established. Moreover the side effects of imiquimod therapy during a sixteen weeks treatment regimen are extensive and may result in reduction of patient compliance or dose reduction. Prediction of treatment responses to imiquimod therapy would aid in patient selection and counselling. Our previous exploratory research in vulvar HSIL patients showed a correlation between the presence of a pro-inflammatory microenvironment and a favorable course of the disease with less recurrences. An immune environment which is however characterized by immune tolerant intraepithelial infiltration of macrophages and regulatory T-cells as well as the absence of IFNy producing activated T cells is related to recurrences and disease progression into carcinoma. In vulvar HSIL responses to immunotherapy, in terms of therapeutic vaccination or imiquimod, are associated with a pre-existing ‘hot’ pro-inflammatory tumor microenvironment rich of pro-inflammatory T cells and inflammatory macrophages. Non-responsiveness to immunotherapy on the other hand is associated with a ‘cold’ tumor microenvironment which lack pro-inflammatory immune cells. Importantly neither therapeutic vaccination or imiquimod is able to change the ‘cold’ tumor microenvironment. A coordinated inflammatory response with an influx of both effector T cells as well as myeloid cells is necessary to establish complete clinical responses. Cervical HSIL, as vulvar HSIL, is induced by a persistent hrHPV infection and imiquimod is used to induce local inflammation and clinical responses in cervical HSIL as well. We hypothesize that the type of local immune response present in pre-therapy biopsies of cervical HSIL, comparable to vulvar HSIL, can predict the potential of a lesion to regress upon imiquimod. Preliminary data in a cohort of cervical HSIL patients treated with imiquimod, confirm our data in vulvar HSIL. A pre-existent abundant pro-inflammatory immune cell infiltrate, reflected by CD3+ and CD8+ T cells and type 1 macrophages is associated with clinical responses to imiquimod. Moreover responses to imiquimod therapy are associated with the induction of an effector T cell response during therapy marked by TIM3 expression. In this study proposal we aim to identify a potential predictive immune biomarker for therapy responses to imiquimod and to determine a cut-off value. We aim to develop a pathological scoring system which can be used in validation and implementation of this potential prospective immune biomarker. Moreover we will evaluate E2 methylation status to predict patients responsiveness since the E2 methylation state was prior related to responses to cidofovir 1% gel, an anti-viral topical crème, and imiquimod in vulvar HSIL. Nanostring ® technology IO360 pathway analyses provides extensive and detailed information about the pre-existing immune status based on RNA expression. We will assess if this new technique - which can be used under GMP conditions - forms an alternative or an additional assay to predict which patients will respond to imiquimod therapy. In depth analysis of the pre-existent immune status based on RNA expression will provide more knowledge in mechanisms involved in responsiveness. Subsequently we aim to perform a validation study of the predictive biomarker(s)/diagnostic scoring system for allocation to imiquimod or LLETZ therapy based on immune infiltrates in pre-therapy biopsies. After validation we intend to start a nationwide non-inferiority trial where we allocate cervical HSIL patients to either imiquimod or LLETZ therapy based on infiltrates in their pre-therapy biopsies. This innovative translational research design preludes the start of personalized medicine in the treatment of HPV induced cervical HSIL preventing unnecessary exposure and side effects by either one of therapies.

Onderwerpen

Kenmerken

Projectnummer:
90719023
Looptijd: 91%
Looptijd: 91 %
2021
2024
Gerelateerde subsidieronde:
Projectleider en penvoerder:
dr. E.M.G van Esch MD PhD
Verantwoordelijke organisatie:
Catharina Ziekenhuis