Immunological Correlates of Response to Immune Checkpoint Inhibitors in Metastatic Urothelial Carcinoma

Overview

Journal Target Oncol

Specialty Oncology

Date 2018 Sep 30

PMID 30267200

Citations 16

Authors

Alice Tzeng

C Marcela Diaz-Montero

Patricia A Rayman

Jin S Kim

Paul G Pavicic Jr

James H Finke

Pedro C Barata

Marcelo Lamenza

Sarah Devonshire

Kim Schach

Hamid Emamekhoo

Marc S Ernstoff

Christopher J Hoimes

Brian I Rini

Jorge A Garcia

Timothy D Gilligan

Moshe C Ornstein

Petros Grivas

Affiliations

Soon will be listed here.

Abstract

Background: The identification of prognostic and/or predictive biomarkers for response to immune checkpoint inhibitors (ICI) could help guide treatment decisions.

Objective: We assessed changes in programmed cell death-1 (PD1)/PD1 ligand (PDL1) expression in key immunomodulatory cell subsets (myeloid-derived suppressor cells [MDSC]; cytotoxic T lymphocytes [CTL]) following ICI therapy and investigated whether these changes correlated with outcomes in patients with metastatic urothelial carcinoma (mUC).

Patients And Methods: Serial peripheral blood samples were collected from ICI-treated mUC patients. Flow cytometry was used to quantify PD1/PDL1 expression on MDSC (CD33HLADR) and CTL (CD8CD4) from peripheral blood mononuclear cells. MDSC were grouped into monocytic (M)-MDSC (CD14CD15), polymorphonuclear (PMN)-MDSC (CD14CD15), and immature (I)-MDSC (CD14CD15). Mixed-model regression and Wilcoxon signed-rank or rank-sum tests were performed to assess post-ICI changes in immune biomarker expression and identify correlations between PD1/PDL1 expression and objective response to ICI.

Results: Of 41 ICI-treated patients, 26 received anti-PDL1 (23 atezolizumab/3 avelumab) and 15 received anti-PD1 (pembrolizumab) therapy. Based on available data, 27.5% had prior intravesical Bacillus Calmette-Guérin therapy, 42% had prior neoadjuvant chemotherapy, and 70% had prior cystectomy or nephroureterectomy. Successive doses of anti-PDL1 correlated with decreased percentage of PDL1 (%PDL1) M-MDSC, while doses of anti-PD1 correlated with decreased %PD1 M- and I-MDSC. Although pre-treatment %PD1 CTL did not predict response, a greater %PD1 CTL within 9 weeks after ICI initiation correlated with objective response.

Conclusions: Treatment with ICI correlated with distinct changes in PD1/PDL1-expressing peripheral immune cell subsets, which may predict objective response to ICI. Further studies are required to validate immune molecular expression as a prognostic and/or predictive biomarker for long-term outcomes in mUC.

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References

Diaz-Montero C, Salem M, Nishimura M, Garrett-Mayer E, Cole D, Montero A . Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol Immunother. 2008; 58(1):49-59. PMC: 3401888. DOI: 10.1007/s00262-008-0523-4. View

Powles T, ODonnell P, Massard C, Arkenau H, Friedlander T, Hoimes C . Efficacy and Safety of Durvalumab in Locally Advanced or Metastatic Urothelial Carcinoma: Updated Results From a Phase 1/2 Open-label Study. JAMA Oncol. 2017; 3(9):e172411. PMC: 5824288. DOI: 10.1001/jamaoncol.2017.2411. View

Balar A, Galsky M, Rosenberg J, Powles T, Petrylak D, Bellmunt J . Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2016; 389(10064):67-76. PMC: 5568632. DOI: 10.1016/S0140-6736(16)32455-2. View

Rosenberg J, Hoffman-Censits J, Powles T, van der Heijden M, Balar A, Necchi A . Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016; 387(10031):1909-20. PMC: 5480242. DOI: 10.1016/S0140-6736(16)00561-4. View

Gabitass R, Annels N, Stocken D, Pandha H, Middleton G . Elevated myeloid-derived suppressor cells in pancreatic, esophageal and gastric cancer are an independent prognostic factor and are associated with significant elevation of the Th2 cytokine interleukin-13. Cancer Immunol Immunother. 2011; 60(10):1419-30. PMC: 3176406. DOI: 10.1007/s00262-011-1028-0. View

Maleki Vareki S, Garrigos C, Duran I . Biomarkers of response to PD-1/PD-L1 inhibition. Crit Rev Oncol Hematol. 2017; 116:116-124. DOI: 10.1016/j.critrevonc.2017.06.001. View

Chen P, Roh W, Reuben A, Cooper Z, Spencer C, Prieto P . Analysis of Immune Signatures in Longitudinal Tumor Samples Yields Insight into Biomarkers of Response and Mechanisms of Resistance to Immune Checkpoint Blockade. Cancer Discov. 2016; 6(8):827-37. PMC: 5082984. DOI: 10.1158/2159-8290.CD-15-1545. View

Agarwal N, Pal S, Hahn A, Nussenzveig R, Pond G, Gupta S . Characterization of metastatic urothelial carcinoma via comprehensive genomic profiling of circulating tumor DNA. Cancer. 2018; 124(10):2115-2124. PMC: 6857169. DOI: 10.1002/cncr.31314. View

Ridder K, Sevko A, Heide J, Dams M, Rupp A, Macas J . Extracellular vesicle-mediated transfer of functional RNA in the tumor microenvironment. Oncoimmunology. 2015; 4(6):e1008371. PMC: 4485784. DOI: 10.1080/2162402X.2015.1008371. View

10.

Kuklinski L, Yan S, Li Z, Fisher J, Cheng C, Noelle R . VISTA expression on tumor-infiltrating inflammatory cells in primary cutaneous melanoma correlates with poor disease-specific survival. Cancer Immunol Immunother. 2018; 67(7):1113-1121. PMC: 11028124. DOI: 10.1007/s00262-018-2169-1. View

11.

Siegel R, Miller K, Jemal A . Cancer Statistics, 2017. CA Cancer J Clin. 2017; 67(1):7-30. DOI: 10.3322/caac.21387. View

12.

Wei T, Zhang J, Qin Y, Wu Y, Zhu L, Lu L . Increased expression of immunosuppressive molecules on intratumoral and circulating regulatory T cells in non-small-cell lung cancer patients. Am J Cancer Res. 2015; 5(7):2190-201. PMC: 4548330. View

13.

Routy B, Le Chatelier E, Derosa L, Duong C, Alou M, Daillere R . Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2017; 359(6371):91-97. DOI: 10.1126/science.aan3706. View

14.

Carballido E, Rosenberg J . Optimal treatment for metastatic bladder cancer. Curr Oncol Rep. 2014; 16(9):404. DOI: 10.1007/s11912-014-0404-2. View

15.

Gopalakrishnan V, Spencer C, Nezi L, Reuben A, Andrews M, Karpinets T . Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2017; 359(6371):97-103. PMC: 5827966. DOI: 10.1126/science.aan4236. View

16.

Le D, Durham J, Smith K, Wang H, Bartlett B, Aulakh L . Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017; 357(6349):409-413. PMC: 5576142. DOI: 10.1126/science.aan6733. View

17.

Milowsky M, Rumble R, Booth C, Gilligan T, Eapen L, Hauke R . Guideline on Muscle-Invasive and Metastatic Bladder Cancer (European Association of Urology Guideline): American Society of Clinical Oncology Clinical Practice Guideline Endorsement. J Clin Oncol. 2016; 34(16):1945-52. DOI: 10.1200/JCO.2015.65.9797. View

18.

Ornstein M, Diaz-Montero C, Rayman P, Elson P, Haywood S, Finke J . Myeloid-derived suppressors cells (MDSC) correlate with clinicopathologic factors and pathologic complete response (pCR) in patients with urothelial carcinoma (UC) undergoing cystectomy. Urol Oncol. 2018; 36(9):405-412. DOI: 10.1016/j.urolonc.2018.02.018. View

19.

Sivan A, Corrales L, Hubert N, Williams J, Aquino-Michaels K, Earley Z . Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science. 2015; 350(6264):1084-9. PMC: 4873287. DOI: 10.1126/science.aac4255. View

20.

Wong-You-Cheong J, Woodward P, Manning M, Sesterhenn I . From the Archives of the AFIP: neoplasms of the urinary bladder: radiologic-pathologic correlation. Radiographics. 2006; 26(2):553-80. DOI: 10.1148/rg.262055172. View