Mini-Review Article

PD1 and PD-L1 Inhibitors for the Treatment of Kidney Cancer: The Role of PD-L1 Assay

Author(s): Alessia Cimadamore*, Francesco Massari , Matteo Santoni, Antonio Lopez-Beltran , Liang Cheng , Marina Scarpelli, Rodolfo Montironi and Holger Moch

Volume 21, Issue 16, 2020

Page: [1664 - 1671] Pages: 8

DOI: 10.2174/1389450121666200324151056

Price: $65


Background: Immune checkpoint inhibitors targeting the programmed death receptor ligand 1 (PD-L1)/programmed death receptor 1 (PD-1) pathway represent a drastic change in the treatment landscape of RCC resulting in a dynamic and evolving scenario. There is an urgent need for predictive biomarkers of response to provide a personalized therapeutic strategy for individual patients.

Objective: In this review, we focused on trials that investigated the administration of a PD-1 and PDL1 inhibitor alone or in combination with another agent and compared the different assays applied in each trial to evaluate the role of PD-L1 as a prognostic and predictive biomarker.

Conclusion: So far, the use of PD-L1 expression alone is not sufficient to predict treatment response and present many limitations: the lack of consensus between different methodologies on biomarker assessment, the heterogeneity of PD-L1 between primary tumors and metastatic sites, different criteria of response to therapy (RECIST vs. irRECIST), the complex interplay with inflammatory components, previous treatments, administration of antibiotic therapy. Combinations of different biomarkers and biological features, such as gene expression associated with angiogenesis, immune response and myeloid inflammation are promising biological variables that need to be validated in the context of prospective clinical trials.

Keywords: Immune-checkpoint inhibitors, immunotherapy, ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, renal cell carcinoma, PD-L1 immunohistochemistry.

Graphical Abstract
Cancer Stat Facts SEER. Kidney and renal pelvis cancer
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin 2019; 69(1): 7-34.
[ ] [PMID: 30620402]
Moch H, Cubilla AL, Humphrey PA, Reuter VE. Ulbright tm. the 2016 who classification of tumours of the urinary system and male genital organs-part a: renal, penile, and testicular tumours. Eur Urol 2016; 70(1): 93-105.
[ ] [PMID: 26935559]
Cimadamore A, Massari F, Santoni M, et al. Molecular characterization and diagnostic criteria of renal cell carcinoma with emphasis on liquid biopsies. Expert Rev Mol Diagn 2019; 20(2): 1-10.
[PMID: 31498685]
Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015; 373(19): 1803-13.
[ ] [PMID: 26406148]
Choueiri TK, Fishman MN, Escudier B, et al. Immunomodulatory activity of nivolumab in metastatic renal cell carcinoma (mRCC). Clin Cancer Res 2016; 22(22): 5461-71.
[ ] [PMID: 27169994]
Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 2018; 378(14): 1277-90.
[ ] [PMID: 29562145]
Choueiri TK, Apolo AB, Powles T, et al. A phase 3, randomized, open-label study of nivolumab combined with cabozantinib vs sunitinib in patients with previously untreated advanced or metastatic renal cell carcinoma (RCC; CheckMate 9ER). Journal of Clinical Oncology 2018; 36(15_suppl).TPS4598-8
Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019; 380(12): 1116-27.
[ ] [PMID: 30779529]
McDermott DF, Lee JL, Szczylik C, et al. Pembrolizumab monotherapy as first-line therapy in advanced clear cell renal cell carcinoma (accRCC): Results from cohort A of KEYNOTE-427. J Clin Oncol 2018; 15(Suppl.): 4500.
McDermott DF, Lee JL, Ziobro M, et al. First-line pembrolizumab (pembro) monotherapy for advanced non-clear cell renal cell carcinoma (nccRCC): Results from KEYNOTE-427 cohort B. Journal of Clinical Oncology 2019; 37(7_suppl): 546-6.
Atkins MB, McDermott DF, Powles T, et al. IMmotion150: a phase II trial in untreated metastatic renal cell carcinoma (mRCC) patients (pts) of atezolizumab (atezo) and bevacizumab (bev) vs and following atezo or sunitinib (sun). J Clin Oncol 2017; 35: 4505.
Rini BI, Powles T, Atkins MB, et al. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet 2019; 393(10189): 2404-15.
[ ] [PMID: 31079938]
McGregor BA, McKay RR, Braun DA, et al. Results of a multicenter phase ii study of atezolizumab and bevacizumab for patients with metastatic renal cell carcinoma with variant histology and/or sarcomatoid features. J Clin Oncol 2019; •••JCO1901882
[PMID: 31721643]
Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019; 380(12): 1103-15.
[ ] [PMID: 30779531]
Yentz SE, Reimers MA, Joshi M, et al. Single-arm phase ib/II study of durvalumab and guadecitabine in advanced kidney cancer (NCT03308396). Journal of Clinical Oncology 2018; 36(6_suppl).TPS711-1
Nagarsheth N, Wicha MS, Zou W. Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat Rev Immunol 2017; 17(9): 559-72.
[ ] [PMID: 28555670]
Powles T, Larkin JMG, Patel P, et al. A phase II study investigating the safety and efficacy of savolitinib and durvalumab in metastatic papillary renal cancer (CALYPSO). Journal of Clinical Oncology 2019; 37(7_suppl): 545-.
Callea M, Albiges L, Gupta M, et al. Differential expression of pd-l1 between primary and metastatic sites in clear-cell renal cell carcinoma. Cancer Immunol Res 2015; 3(10): 1158-64.
[ ] [PMID: 26014095]
Basu A, Yearley JH, Annamalai L, Pryzbycin C, Rini B. Association of pd-l1, pd-l2, and immune response markers in matched renal clear cell carcinoma primary and metastatic tissue specimens. Am J Clin Pathol 2019; 151(2): 217-25.
[ ] [PMID: 30346474]
Yuan C, Liu Z, Yu Q, et al. Expression of PD-1/PD-L1 in primary breast tumours and metastatic axillary lymph nodes and its correlation with clinicopathological parameters. Sci Rep 2019; 9(1): 14356.
[ ] [PMID: 31591439]
Baine MK, Turcu G, Zito CR, et al. Characterization of tumor infiltrating lymphocytes in paired primary and metastatic renal cell carcinoma specimens. Oncotarget 2015; 6(28): 24990-5002.
[ ] [PMID: 26317902]
Corrò C, Healy ME, Engler S, et al. IL-8 and CXCR1 expression is associated with cancer stem cell-like properties of clear cell renal cancer. J Pathol 2019; 248(3): 377-89.
[ ] [PMID: 30883740]
Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab for metastatic renal cell carcinoma: results of a randomized phase ii trial. J Clin Oncol 2015; 33(13): 1430-7.
[ ] [PMID: 25452452]
Pignon JC, Jegede O, Shukla SA, et al. irRECIST for the evaluation of candidate biomarkers of response to nivolumab in metastatic clear cell renal cell carcinoma: analysis of a phase ii prospective clinical trial. Clin Cancer Res 2019; 25(7): 2174-84.
[ ] [PMID: 30670497]
Seymour L, Bogaerts J, Perrone A, et al. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol 2017; 18(3): e143-52.
[ ] [PMID: 28271869]
Iacovelli R, Nolè F, Verri E, et al. Prognostic role of PD-L1 expression in renal cell carcinoma. A systematic review and meta-analysis. Target Oncol 2016; 11(2): 143-8.
[ ] [PMID: 26429561]
Thompson RH, Kuntz SM, Leibovich BC, et al. Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term follow-up. Cancer Res 2006; 66(7): 3381-5.
[ ] [PMID: 16585157]
Tykodi SS. PD-1 as an emerging therapeutic target in renal cell carcinoma: current evidence. OncoTargets Ther 2014; 7: 1349-59.
[ ] [PMID: 25114573]
Choueiri TK, Figueroa DJ, Fay AP, et al. Correlation of PD-L1 tumor expression and treatment outcomes in patients with renal cell carcinoma receiving sunitinib or pazopanib: results from COMPARZ, a randomized controlled trial. Clin Cancer Res 2015; 21(5): 1071-7.
[ ] [PMID: 25538263]
Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol 2016; 17(7): 917-27.
[ ] [PMID: 27279544]
George DJ, Hessel C, Halabi S, et al. Cabozantinib versus sunitinib for untreated patients with advanced renal cell carcinoma of intermediate or poor risk: subgroup analysis of the alliance a031203 cabosun trial. Oncologist 2019; 24(11): 1497-501.
[ ] [PMID: 31399500]
Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med 2015; 373(19): 1814-23.
[ ] [PMID: 26406150]
Flaifel A, Xie W, Braun DA, et al. PD-L1 Expression and clinical outcomes to cabozantinib, everolimus, and sunitinib in patients with metastatic renal cell carcinoma: Analysis of the Randomized Clinical Trials METEOR and CABOSUN. Clin Cancer Res 2019; 25(20): 6080-8.
[ ] [PMID: 31371341]
Wallin JJ, Bendell JC, Funke R, et al. Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nat Commun 2016; 7: 12624.
[ ] [PMID: 27571927]
Powles T, Chowdhury S, Bower M, et al. The effect of sunitinib on immune subsets in metastatic clear cell renal cancer. Urol Int 2011; 86(1): 53-9.
[ ] [PMID: 20975250]
Adotevi O, Pere H, Ravel P, et al. A decrease of regulatory T cells correlates with overall survival after sunitinib-based antiangiogenic therapy in metastatic renal cancer patients. J Immunother 2010; 33(9): 991-8.
[ ] [PMID: 20948437]
Atkins MB, McDermott DF, Powles T, et al. IMmotion150: A phase II trial in untreated metastatic renal cell carcinoma patients of atezolizumab and bevacizumab vs and following atezolizumab or sunitinib. J Clin Oncol 2017; 45(15): 4505.
Brauer MJ, Zhuang G, Schmidt M, et al. Identification and analysis of in vivo VEGF downstream markers link VEGF pathway activity with efficacy of anti-VEGF therapies. Clin Cancer Res 2013; 19(13): 3681-92.
[ ] [PMID: 23685835]
McDermott DF, Huseni MA, Atkins MB, et al. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat Med 2018; 24(6): 749-57.
[ ] [PMID: 29867230]
Ruf M, Moch H, Schraml P. PD-L1 expression is regulated by hypoxia inducible factor in clear cell renal cell carcinoma. Int J Cancer 2016; 139(2): 396-403.
[ ] [PMID: 26945902]
Chevrier S, Levine JH, Zanotelli VRT, et al. An Immune Atlas of Clear Cell Renal Cell Carcinoma. Cell 2017; 169(4): 736-749.e18.
[ ] [PMID: 28475899]
Schraml P, Athelogou M, Hermanns T, Huss R, Moch H. Specific immune cell and lymphatic vessel signatures identified by image analysis in renal cancer. Mod Pathol 2019; 32(7): 1042-52.
[ ] [PMID: 30737470]
Zajac AJ, Blattman JN, Murali-Krishna K, et al. Viral immune evasion due to persistence of activated T cells without effector function. J Exp Med 1998; 188(12): 2205-13.
[ ] [PMID: 9858507]
Hashimoto M, Kamphorst AO, Im SJ, et al. CD8 T cell exhaustion in chronic infection and cancer: Opportunities for interventions. Annu Rev Med 2018; 69: 301-18.
[ ] [PMID: 29414259]
Pauken KE, Wherry EJ. Overcoming T cell exhaustion in infection and cancer. Trends Immunol 2015; 36(4): 265-76.
[ ] [PMID: 25797516]
Blackburn SD, Shin H, Haining WN, et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol 2009; 10(1): 29-37.
[ ] [PMID: 19043418]
Kamphorst AO, Ahmed R. Manipulating the PD-1 pathway to improve immunity. Curr Opin Immunol 2013; 25(3): 381-8.
[ ] [PMID: 23582509]
Hargadon KM, Johnson CE, Williams CJ. Immune checkpoint blockade therapy for cancer: An overview of FDA-approved immune checkpoint inhibitors. Int Immunopharmacol 2018; 62: 29-39.
[ ] [PMID: 29990692]
Im SJ, Hashimoto M, Gerner MY, et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature 2016; 537(7620): 417-21.
[ ] [PMID: 27501248]
Wu T, Ji Y, Moseman EA, et al. The TCF1-Bcl6 axis counteracts type I interferon to repress exhaustion and maintain T cell stemness. Sci Immunol 2016; 1(6): 8593.
[ ] [PMID: 28018990]
Sade-Feldman M, Yizhak K, Bjorgaard SL, et al. Defining T cell states associated with response to checkpoint immunotherapy in melanoma. Cell 2019; 176(1-2): 404.
[ ] [PMID: 30633907]
Siddiqui I, Schaeuble K, Chennupati V, et al. Intratumoral Tcf1(+)PD-1(+)CD8(+) T cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy. Immunity 2019; 50(1): 195-211.e10.
[ ] [PMID: 30635237]
Miller BC, Sen DR, Al Abosy R, et al. Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade. Nat Immunol 2019; 20(3): 326-36.
[ ] [PMID: 30778252]
Jansen CS, Prokhnevska N, Master VA, et al. An intra-tumoral niche maintains and differentiates stem-like CD8 T cells. Nature 2019; 576(7787): 465-70.
[ ] [PMID: 31827286]
Wang S, He Z, Wang X, Li H, Liu XS. Antigen presentation and tumor immunogenicity in cancer immunotherapy response prediction. eLife 2019.8e49020
[] [PMID: 31767055]
Şenbabaoğlu Y, Gejman RS, Winer AG, et al. Tumor immune microenvironment characterization in clear cell renal cell carcinoma identifies prognostic and immunotherapeutically relevant messenger RNA signatures. Genome Biol 2016; 17(1): 231.
[ ] [PMID: 27855702]
Strauss L, Mahmoud MAA, Weaver JD, et al. Targeted deletion of PD-1 in myeloid cells induces antitumor immunity. Sci Immunol 2020; 5(43): 1863.
[ ] [PMID: 31901074]
Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018; 359(6371): 91-7.
[ ] [PMID: 29097494]
Cimadamore A, Santoni M, Massari F, et al. Microbiome and cancers, with focus on genitourinary tumors. Front Oncol 2019; 9: 178.
[ ] [PMID: 30972292]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy