Tadalafil Enhances Immune Signatures in Response to Neoadjuvant Nivolumab in Resectable Head and Neck Squamous Cell Carcinoma
Adam J Luginbuhl, Jennifer M Johnson, Larry A Harshyne, Alban J Linnenbach, Sanket K Shukla, Angela Alnemri, Gaurav Kumar, David M Cognetti, Joseph M Curry, Nikita Kotlov, Zoya Antysheva, Sandrine Degryse, Kyle Mannion, Michael K Gibson, James Netterville, Brandee Brown, Rita Axelrod, Ralph Zinner, Madalina Tuluc, Stacey Gargano, Benjamin E Leiby, Ayako Shimada, My G Mahoney, Ubaldo Martinez-Outschoorn, Ulrich Rodeck, Young J Kim, Andrew P South, Athanassios Argiris, Adam J Luginbuhl, Jennifer M Johnson, Larry A Harshyne, Alban J Linnenbach, Sanket K Shukla, Angela Alnemri, Gaurav Kumar, David M Cognetti, Joseph M Curry, Nikita Kotlov, Zoya Antysheva, Sandrine Degryse, Kyle Mannion, Michael K Gibson, James Netterville, Brandee Brown, Rita Axelrod, Ralph Zinner, Madalina Tuluc, Stacey Gargano, Benjamin E Leiby, Ayako Shimada, My G Mahoney, Ubaldo Martinez-Outschoorn, Ulrich Rodeck, Young J Kim, Andrew P South, Athanassios Argiris
Abstract
Purpose: We hypothesize that the addition of the phosphodiesterase-5 inhibitor tadalafil to the PD-1 inhibitor nivolumab, is safe and will augment immune-mediated antitumor responses in previously untreated squamous cell carcinoma of the head and neck (HNSCC).
Patients and methods: We conducted a two-arm multi-institutional neoadjuvant randomized trial in any-stage resectable HNSCC (NCT03238365). Patients were stratified at randomization by human papillomavirus (HPV) status. Patients in both arms received nivolumab 240 mg intravenously on days 1 and 15 followed by surgery on day 28. Those in the combination therapy arm also received tadalafil 10 mg orally once daily for 4 weeks. Imaging, blood, and tumor were obtained pretreatment and posttreatment for correlative analysis.
Results: Neoadjuvant therapy was well-tolerated with no grade 3 to 5 adverse events and no surgical delays. Twenty-five of 46 (54%) evaluable patients had a pathologic treatment response of ≥20%, including three (7%) patients with a complete pathologic response. Regardless of HPV status, tumor proliferation rate was a negative predictor of response. A strong pretreatment T-cell signature in the HPV-negative cohort was a predictor of response. Tadalafil altered the immune microenvironment, as evidenced by transcriptome data identifying enriched B- and natural killer cell gene sets in the tumor and augmented effector T cells in the periphery.
Conclusions: Preoperative nivolumab ± tadalafil is safe in HNSCC and results in more than 50% of the patients having a pathologic treatment response of at least 20% after 4 weeks of treatment. Pretreatment specimens identified HPV status-dependent signatures that predicted response to immunotherapy while posttreatment specimens showed augmentation of the immune microenvironment with the addition of tadalafil.
©2021 The Authors; Published by the American Association for Cancer Research.
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References
- Ferris RL, Blumenschein G, Fayette J, Guigay J, Colevas AD, Licitra L, et al. . Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 2016;375:1856–67.
- Seiwert TY, Burtness B, Mehra R, Weiss J, Berger R, Eder JP, et al. . Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol 2016;17:956–65.
- Cohen EEW, Soulières D, Tourneau CL, Dinis J, Ahn M-J, Soria A, et al. . Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet North Am Ed 2019;393:156–67.
- Schoenfeld JD, Hanna GJ, Jo VY, Rawal B, Chen Y-H, Catalano PS, et al. . Neoadjuvant Nivolumab or Nivolumab Plus Ipilimumab in untreated oral cavity squamous cell carcinoma: a phase 2 open-label randomized clinical trial. JAMA Oncol 2020;6:1563–70.
- Uppaluri R, Campbell KM, Egloff AM, Zolkind P, Skidmore ZL, Nussenbaum B, et al. . Neoadjuvant and adjuvant pembrolizumab in resectable locally advanced, human papillomavirus-unrelated head and neck cancer: a multicenter, phase 2 trial. Clin Cancer Res 2020;26:5140–52.
- Ferrarotto R, Bell D, Rubin ML, Hutcheson KA, Johnson JM, Goepfert RP, et al. . Impact of Neoadjuvant Durvalumab with or without Tremelimumab on CD8+ tumor lymphocyte density, safety, and efficacy in patients with oropharynx cancer: CIAO trial results. Clin Cancer Res 2020;26:3211–9.
- Burtness B, Harrington KJ, Greil R, Soulières D, Tahara M, de Castro G, et al. . Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet 2019;394:1915–28.
- Dos Santos LV, Abrahão CM, William WN Jr. Overcoming resistance to immune checkpoint inhibitors in head and neck squamous cell carcinomas. Front Oncol 2021;11:596290.
- Topalian SL, Taube JM, Pardoll DM. Neoadjuvant checkpoint blockade for cancer immunotherapy. Science 2020;367:eaax0182–11.
- Liu J, Blake SJ, Yong MCR, Harjunpää H, Ngiow SF, Takeda K, et al. . Improved efficacy of neoadjuvant compared to adjuvant immunotherapy to eradicate metastatic disease. Cancer Discov 2016;6:1382–99.
- Jia X-H, Xu H, Geng L-Y, Jiao M, Wang W-J, Jiang L-L, et al. . Efficacy and safety of neoadjuvant immunotherapy in resectable nonsmall cell lung cancer: a meta-analysis. Lung Cancer 2020;147:143–53.
- Chalabi M, Fanchi LF, Dijkstra KK, Van den Berg JG, Aalbers AG, Sikorska K, et al. . Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat Med 2020;26:566–76.
- Ferris RL, Spanos WC, Leidner R, Gonçalves A, Martens UM, Kyi C, et al. . Neoadjuvant nivolumab for patients with resectable HPV-positive and HPV-negative squamous cell carcinomas of the head and neck in the CheckMate 358 trial. J Immunother Cancer 2021;9:e002568.
- Uppaluri R, Chernock R, Mansour M, Jackson R, Rich J, Pipkorn P, et al. . Enhanced pathologic tumor response with two cycles of neoadjuvant pembrolizumab in surgically resectable, locally advanced HPV-negative head and neck squamous cell carcinoma (HNSCC). J Clin Oncol 2021;39:6008.
- Terrett NK, Bell AS, Brown D, Ellis P. Sildenafil (VIAGRATM), a potent and selective inhibitor of type 5 cGMP phosphodiesterase with utility for the treatment of male erectile dysfunction. Bioorg Med Chem Lett 1996;6:1819–24.
- Noonan KA, Ghosh N, Rudraraju L, Bui M, Borrello I. Targeting immune suppression with PDE5 inhibition in end-stage multiple myeloma. Cancer Immunol Res 2014;2:725–31.
- Califano JA, Khan Z, Noonan KA, Rudraraju L, Zhang Z, Wang H, et al. . Tadalafil augments tumor specific immunity in patients with head and neck squamous cell carcinoma. Clin Cancer Res. 2015;21:30–8.
- Weed DT, Vella JL, Reis IM, De la Fuente AC, Gomez C, Sargi Z, et al. . Tadalafil reduces myeloid-derived suppressor cells and regulatory T cells and promotes tumor immunity in patients with head and neck squamous cell carcinoma. Clin Cancer Res. 2015;21:39–48.
- Weed DT, Zilio S, Reis IM, Sargi Z, Abouyared M, Gomez-Fernandez CR, et al. . The reversal of immune exclusion mediated by tadalafil and an anti-tumor vaccine also induces PDL1 upregulation in recurrent head and neck squamous cell carcinoma: interim analysis of a phase I clinical trial. Front Immunol 2019;10:1206.
- Serafini P, Meckel K, Kelso M, Noonan K, Califano J, Koch W, et al. . Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. J Exp Med 2006;203:2691–702.
- Thall PF, Simon R. Practical Bayesian guidelines for phase IIB clinical trials. Biometrics 1994;50:337–49.
- Merlino DJ, Johnson JM, Tuluc M, Gargano S, Stapp R, Harshyne L, et al. . Discordant responses between primary head and neck tumors and nodal metastases treated with neoadjuvant nivolumab: correlation of radiographic and pathologic treatment effect. Front Oncol 2020;10:566315.
- Frelaut M, Tourneau CL, Borcoman E. Hyperprogression under immunotherapy. Int J Mol Sci 2019;20:2674.
- Bagaev A, Kotlov N, Nomie K, Svekolkin V, Gafurov A, Isaeva O, et al. . Conserved pan-cancer microenvironment subtypes predict response to immunotherapy. Cancer Cell 2021;39:845–65.
- Zaytcev A, Chelushkin M, Nuzhdina K, Bagaev A, Dyykanov D, Zyrin V, et al. . Abstract 853: Novel machine learning based deconvolution algorithm results in accurate description of tumor microenvironment from bulk RNAseq. Clin Res Exclud Clin Trials 2020;853.
- Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. . Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 2005;102:15545–50.
- Liberzon A, Birger C, Thorvaldsdóttir H, Ghandi M, Mesirov JP, Tamayo P. The molecular signatures database hallmark gene set collection. Cell Syst 2015;1:417–25.
- Aizarani N, Saviano A, Sagar, Mailly L, Durand S, Herman JS, et al. . A human liver cell atlas revealsng heterogeneity and epithelial progenitors. Nature 2019;572:199–204.
- Zhou X, Yao Z, Yang H, Liang N, Zhang X, Zhang F. Are immune-related adverse events associated with the efficacy of immune checkpoint inhibitors in patients with cancer? A systematic review and meta-analysis. Bmc Med 2020;18:87.
- Cortellini A, Chiari R, Ricciuti B, Metro G, Perrone F, Tiseo M, et al. . Correlations between the immune-related adverse events spectrum and efficacy of anti-PD1 immunotherapy in NSCLC patients. Clin Lung Cancer 2019;20:237–47.
- Foster CC, Kochanny S, Khattri A, Acharya R, Dekker A, Carol Tan Y-H, et al. . Association of immune-related adverse events (irAEs) with improved response, progression-free survival, and overall survival for patients with metastatic head and neck cancer receviing anti-PD-1 therapy. J Clin Oncol 36:15s, 2018(suppl; abstr 6014).
- Matsuo M, Yasumatsu R, Masuda M, Toh S, Wakasaki T, Hashimoto K, et al. . Relationship between immune-related adverse events and the long-term outcomes in recurrent/metastatic head and neck squamous cell carcinoma treated with nivolumab. Oral Oncol 2020;101:104525.
- Chen DS, Mellman I. Elements of cancer immunity and the cancer–immune set point. Nature 2017;541:321–30.
- Aggarwal C, Cohen RB, Morrow MP, Kraynak KA, Sylvester AJ, Knoblock DM, et al. . Immunotherapy targeting HPV16/18 generates potent immune responses in HPV-associated head and neck cancer. Clin Cancer Res 2019;25:110–24.
- Li W, Matakidou A, Ghazoui Z, Si H, Wildsmith S, Morsli N, et al. . Molecular biomarkers to identify patients (pts) who may benefit from durvalumab (D; anti-PD-L1) ± tremelimumab (T; anti-CTLA-4) in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) from HAWK and CONDOR studies. J Clin Oncol 2020;38:6548.
- Wang J, Sun H, Zeng Q, Guo X-J, Wang H, Liu H-H, et al. . HPV-positive status associated with inflamed immune microenvironment and improved response to anti-PD-1 therapy in head and neck squamous cell carcinoma. Sci Rep 2019;9:13404.
- Wise-Draper TM, Takiar V, Mierzwa ML, Casper K, Palackdharry S, Worden FP, et al. . Association of pathological response to neoadjuvant pembrolizumab with tumor PD-L1 expression and high disease-free survival (DFS) in patients with resectable, local-regionally advanced, head and neck squamous cell carcinoma (HNSCC). J Clin Oncol 2021;39:6006.
- Huang C, Chen L, Savage SR, Eguez RV, Dou Y, Li Y, et al. . Proteogenomic insights into the biology and treatment of HPV-negative head and neck squamous cell carcinoma. Cancer Cell 2021;20:1295.
- Schroeder JC, Puntigam L, Hofmann L, Jeske SS, Beccard IJ, Doescher J, et al. . Circulating exosomes inhibit B cell proliferation and activity. Cancers. 2020;12:2110.
- Harshyne LA, Nasca BJ, Kenyon LC, Andrews DW, Hooper DC. Serum exosomes and cytokines promote a T-helper cell type 2 environment in the peripheral blood of glioblastoma patients. Neuro-oncol 2015;nov107.
- Miyazaki T, Maiti M, Hennessy M, Chang T, Kuo P, Addepalli M, et al. . NKTR-255, a novel polymer-conjugated rhIL-15 with potent antitumor efficacy. J Immunother Cancer 2021;9:e002024.
- Hassel JC, Jiang H, Bender C, Winkler J, Sevko A, Shevchenko I, et al. . Tadalafil has biologic activity in human melanoma. Results of a pilot trial with Tadalafil in patients with metastatic Melanoma (TaMe). Oncoimmunology 2017;6:e1326440.
- Sutton SS, Magagnoli J, Cummings TH, Hardin JW. The association between phosphodiesterase-5 inhibitors and colorectal cancer in a national cohort of patients. Clin Transl Gastroenterol 2020;11:e00173.
Source: PubMed