Mécanismes de résistance au BCG des cancers de la vessie

Le cancer de la vessie est le 9ème cancer le plus fréquent avec 435 000 nouveaux cas diagnostiqués chaque année et 165 000 décès par an dans le monde. Au diagnostic, 70-80% des cancers de la vessie sont tumeurs superficielles n’infiltrant pas le muscle vésical (TVNIM). Depuis près de 40 ans, les instillations intra-vésicales de bacille de Calmette-Guérin (BCG) sont le traitement de référence des TVNIM ayant un risque élevé de progression (T1, carcinome in situ, Ta haut grade). Malgré un traitement bien conduit, le taux de récidive est d'environ 50%, et la progression vers une tumeur infiltrant le muscle est estimé à 20%-30% dans les 5 ans. Jusqu’à 15% des patients développent des métastases de leur carcinome urothélial. Aujourd’hui, aucun biomarqueur ne permet de prédire la réponse au BCG, ni l’évolution métastatique de la maladie. La cystectomie totale reste le traitement de référence en cas de non-réponse au BCG. Plusieurs essais cliniques évaluent des traitements immuno-modulateurs ciblant les points de contrôle immunitaires PD1, PD-L1 en 2° ligne de traitement après échec du BCG. Les instillations endo-vésicales d’adénovirus recombinant, de virus oncolytique ou d'agoniste de la voie STING sont des stratégies thérapeutiques en cours d'évaluation. L'objectif de ce travail était d'étudier les mécanismes de résistance intrinsèques des cellules tumorales exposées au BCG afin d'identifier de nouvelles cibles thérapeutiques.Bladder cancer is a heterogeneous disease that displays invasive and non-invasive histological features, and a wide spectrum of molecular alterations and subtypes. Treatment of non-invasive tumors with high-risk features (carcinoma in situ, high-grade Ta, T1) includes trans-urethral resection of the tumor, followed by intravesical instillations of bacillus Calmette-Guérin (BCG). Despite a multitude of evidence for anti-tumor efficacy, 50% of patients with high-risk NMIBC develop tumor recurrence and 20-30% disease progression. Ultimately, 10-15% of patients die of metastatic disease. New therapeutic strategies are currently in clinical development to treat BCG-unresponsive tumors including antagonistic antibodies directed against the T-cell immune checkpoints PD-1, PD-L1 and CTLA-4, but also recombinant adenovirus interferon α (Ad-IFNα/Syn3), oncolytic virus and STING agonists. Although recent studies have identified potential immune parameters that could impact clinical response, mechanisms of tumor resistance to BCG immunotherapy remain poorly understood. Additionally, tumor heterogeneity and plasticity of cancer cells undermine our attempts to precise dynamics of immune escape under selective pressure. How cancer cells evade to the anti-tumor immune response, and whether cancer cells acquire intrinsic undesirable characteristics upon BCG exposure remain unknown. Altogether, this highlights the crucial need to better understand the mechanisms of tumor resistance that occur during BCG immunotherapy in order to identify new targetable pathways and treatment strategies

Comment to: Relationship between the expression of PD-1/PD-L1 and 18 F-FDG uptake in bladder cancer

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Essais de phase I évaluant des thérapies moléculaires ciblées? (quelle place accorder à la sexualité des patients?)

L'avènement des thérapies moléculaires ciblées (TMC) a ouvert une nouvelle ère thérapeutique en cancérologie. Ces. nouveaux traitements posent cependant de nombreuses questions pour I'avenir, en particulier celle de la gestion des toxicités aiguës et tardives. Si certains profils de toxicité sont bien connus, d'autres effets secondaires, comme le retentissement sur la fonction sexuelle ont été peu étudiés. Objectifs: Evaluer la qualité de vie sexuelle des patients inclus dans un essai thérapeutique de phase I et étudier l'impact des TMC sur la survenue des troubles sexuels. Matériel et Méthode: Tout patient inclus dans un essai de phase I à l'Institut Gustave Roussy entre le 09/05/2011 et le 12/07/2011 a été sollicité lors de son inclusion et après un mois de traitement pour évaluer sa qualité de vie (questionnaire SF-12), son seuil de dépression (questionnaire BDI-H) et sa fonction sexuelle (questionnaires FSFI pour les femmes, HEF pour les hommes). Résultats: Cette étude est la première évaluation de la qualité de vie sexuelle de patients traités dans un essai de phase I. Soixante-trois patients ont été évalués à l'inclusion. Le taux de réponse était de 75% pour les questionnaires FSFI et HEF. Pour 57% des femmes et 71 % des hommes, la qualité de vie sexuelle actuelle était un sujet d'intérêt. Après un mois de traitement, les troubles sexuels étaient majorés chez les femmes, notamment au niveau de la lubrification et des douleurs, sans facteur significatif associé; chez les hommes les thérapies anti- angiogéniques étaient associées de manière significative à l'altération de leur fonction sexuelle globale, en analyse univariée (p=0,04). Conclusion: L'effet des thérapies moléculaires ciblées sur la fonction sexuelle, notamment des thérapies anti-angiogéniques, devrait être mieux évalué en raison de leur impact probable sur la fonction érectile chez l 'homme et la lubrification vaginale chez la femme.PARIS13-BU Serge Lebovici (930082101) / SudocSudocFranceF

PD-L1 testing in urothelial bladder cancer: essentials of clinical practice

International audiencePurpose: While immunotherapy has become an increasingly attractive strategy in patients with urothelial bladder cancer, the need for a biomarker to identify patients whose cancer is the most likely to respond has never been more crucial. This review systematically evaluates evidence regarding PD-L1 as a predictive biomarker of response to anti-PD(L)1 monoclonal antibodies in patients with urothelial bladder carcinoma, and discusses its current limits in routine clinical practice. Methods: We performed a critical review of PubMed/Medline according to the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) statement. Prospective clinical trials evaluating anti-PD(L)1 monoclonal antibodies in urothelial bladder carcinoma together with retrospective studies evaluating PD-L1 expression in patients with bladder cancer were included. Results: Evidence data related to PD-L1 as a predictive biomarker of response to immune checkpoint blockade monotherapy across clinical trials are detailed in this review. The different companion diagnostic assays, and the methods for PD-L1 scoring in urothelial bladder carcinoma are reported. Additionally, the issues related to the implementation of PD-L1 testing in clinical practice are discussed. Conclusions: PD-(L)1 monoclonal antibodies atezolizumab and pembrolizumab are restricted to patients with PD-L1 positive status in the first-line setting in patients with advanced or metastatic urothelial bladder carcinoma who are ineligible to cisplatin-based chemotherapy. Importantly, the use of anti-PD(L)1 mAb in the other clinical settings is not based on PD-L1 status, but rather on patients’ clinical characteristics. Further identification of biomarkers with high negative predictive value will also be of utmost importance to identify patients who may not respond to such immunotherapies

Future role of [18F]-FDG PET/CT in patients with bladder cancer in the new era of neoadjuvant immunotherapy?

International audienceComment on: [18F]Fluoro-Deoxy-Glucose positron emission tomography to evaluate lymph node involvement in patients with muscle-invasive bladder cancer receiving neoadjuvant pembrolizumab. Marandino L, Capozza A, Bandini M, Raggi D, Farè E, Pederzoli F, Gallina A, Capitanio U, Bianchi M, Gandaglia G, Fossati N, Colecchia M, Giannatempo P, Serafini G, Padovano B, Salonia A, Briganti A, Montorsi F, Alessi A, Necchi A. Urol Oncol. 2021 Apr;39(4):235.e15-235.e21. doi: 10.1016/j.urolonc.2020.09.035. Epub 2020 Oct 16. PMID: 3307110

Utility of Routine Preoperative F-18-Fluorodeoxyglucose Positron Emission Tomography/Computerized Tomography in Identifying Pathological Lymph Node Metastases at Radical Cystectomy. Letter

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Efficacy of triptorelin pamoate 11.25 mg administered subcutaneously for achieving medical castration levels of testosterone in patients with locally advanced or metastatic prostate cancer

Objectives: Gonadotropin-releasing hormone agonists are widely used as androgen deprivation therapy in many men with locally advanced or metastatic prostate cancer. Gonadotropin-releasing hormone agonists are delivered by intramuscular injection every 1, 3 or 6 months, but in some patients subcutaneous injection may be more appropriate. This study assessed the efficacy and safety profile of the gonadotropin-releasing hormone agonist, triptorelin pamoate, when administered by the subcutaneous route. Methods: In this multicentre, open-label, single-arm study, androgen deprivation therapy-naïve men with locally advanced or metastatic prostate cancer received the gonadotropin-releasing hormone agonist triptorelin pamoate 11.25 mg (3-month formulation) by the subcutaneous route twice (at baseline and 13 weeks later). The co-primary efficacy endpoints were the proportion of patients with a castration level of serum testosterone (<50 ng/dl) after 4 weeks, and of these, those still castrated after 26 weeks. Results: Of the 126 treated patients, 123 [97.6%; 95% confidence interval (CI): 93.2–99.5)] were castrated 4 weeks after the first subcutaneous injection, and 115/119 patients (96.6%; 95% CI: 91.6–99.1) castrated at 4 weeks maintained castration at 26 weeks. Median prostate-specific antigen levels were reduced by 64.2 and 96.0% at 4 and 26 weeks, respectively. The probability of maintaining a testosterone level <20 ng/dl up to 26 weeks was 90.0% (95% CI: 85.0–95.0). The most frequently occurring treatment-related adverse events were typical of gonadotropin-releasing hormone agonist treatment (hot flushes, increased weight, erectile dysfunction and hyperhidrosis). Conclusions: This study demonstrates that triptorelin pamoate 11.25 mg administered by the subcutaneous route every 3 months is as efficacious and well tolerated as administration via the intramuscular route in men with locally advanced or metastatic prostate cancer

Development of immunotherapy in bladder cancer: present and future on targeting PD(L)1 and CTLA-4 pathways

International audiencePURPOSE:Over the past 3 decades, no major treatment breakthrough has been reported for advanced bladder cancer. Recent Food and Drug Administration (FDA) approval of five immune checkpoint inhibitors in the management of advanced bladder cancer represent new therapeutic opportunities. This review examines the available data of the clinical trials leading to the approval of ICIs in the management of metastatic bladder cancer and the ongoing trials in advanced and localized settings.METHODS:A literature search was performed on PubMed and ClinicalTrials.gov combining the MeSH terms: 'urothelial carcinoma' OR 'bladder cancer', and 'immunotherapy' OR 'CTLA-4' OR 'PD-1' OR 'PD-L1' OR 'atezolizumab' OR 'nivolumab' OR 'ipilimumab' OR 'pembrolizumab' OR 'avelumab' OR 'durvalumab' OR 'tremelimumab'. Prospectives studies evaluating anti-PD(L)1 and anti-CTLA-4 monoclonal antibodies were included.RESULTS:Evidence-data related to early phase and phase III trials evaluating the 5 ICIs in the advanced urothelial carcinoma are detailed in this review. Anti-tumour activity of the 5 ICIs supporting the FDA approval in the second-line setting are reported. The activity of PD(L)1 inhibitors in the first-line setting in cisplatin-ineligible patients are also presented. Ongoing trials in earlier disease-states including non-muscle-invasive and muscle-invasive bladder cancer are discussed.CONCLUSIONS:Blocking the PD-1 negative immune receptor or its ligand, PD-L1, results in unprecedented rates of anti-tumour activity in patients with metastatic urothelial cancer. However, a large majority of patients do not respond to anti-PD(L)1 drugs monotherapy. Investigations exploring the potential value of predictive biomarkers, optimal combination and sequences are ongoing to improve such treatment strategies

Targeting the DNA damage response in immuno-oncology: developments and opportunities

International audienceImmunotherapy has revolutionized cancer treatment and substantially improved patient outcome with regard to multiple tumour types. However, most patients still do not benefit from such therapies, notably because of the absence of pre-existing T cell infiltration. DNA damage response (DDR) deficiency has recently emerged as an important determinant of tumour immunogenicity. A growing body of evidence now supports the concept that DDR-targeted therapies can increase the antitumour immune response by (1) promoting antigenicity through increased mutability and genomic instability, (2) enhancing adjuvanticity through the activation of cytosolic immunity and immunogenic cell death and (3) favouring reactogenicity through the modulation of factors that control the tumour–immune cell synapse. In this Review, we discuss the interplay between the DDR and anticancer immunity and highlight how this dynamic interaction contributes to shaping tumour immunogenicity. We also review the most innovative preclinical approaches that could be used to investigate such effects, including recently developed ex vivo systems. Finally, we highlight the therapeutic opportunities presented by the exploitation of the DDR–anticancer immunity interplay, with a focus on those in early-phase clinical development