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Original Research

The multi-functionality of N-809, a novel fusion protein encompassing anti-PD-L1 and the IL-15 superagonist fusion complex

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Article: e1532764 | Received 23 Jul 2018, Accepted 26 Sep 2018, Published online: 27 Nov 2018

References

  • Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, Stankevich E, Pons A, Salay TM, McMiller TL, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 2010;28(19):3167–3175. doi:10.1200/jco.2009.26.7609
  • Conlon KC, Lugli E, Welles HC, Rosenberg SA, Fojo AT, Morris JC, Fleisher TA, Dubois SP, Perera LP, Stewart DM, et al. Redistribution, hyperproliferation, activation of natural killer cells and CD8 T cells, and cytokine production during first-in-human clinical trial of recombinant human Interleukin-15 in patients with cancer. J Clin Oncol 2015;33(1):74–82. doi:10.1200/JCO.2014.57.3329
  • Heery CR, O’Sullivan-Coyne G, Madan RA, Cordes L, Rajan A, Rauckhorst M, Lamping E, Oyelakin I, Marte JL, Lepone LM, et al. Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial. Lancet Oncol 2017;18(5):587–598. doi:10.1016/s1470-2045(17)30239-5
  • Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363(8):711–723. doi:10.1056/NEJMoa1003466
  • Rosenberg SAIL-2. the first effective immunotherapy for human cancer. J Immunol 2014;192(12):5451–5458. doi:10.4049/jimmunol.1490019
  • Callahan MK, Kluger H, Postow MA, Segal NH, Lesokhin A, Atkins MB, Kirkwood JM, Krishnan S, Bhore R, Horak C, et al. Nivolumab plus ipilimumab in patients with advanced melanoma: updated survival, response, and safety data in a phase I dose-escalation study. J Clin Oncol 2018;36(4):391–398.
  • Madan RA, Mohebtash M, Arlen PM, Vergati M, Rauckhorst M, Steinberg SM, Tsang KY, Poole DJ, Parnes HL, Wright JJ, et al. Ipilimumab and a poxviral vaccine targeting prostate-specific antigen in metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial. Lancet Oncol 2012;13(5):501–508. doi:10.1016/S1470-2045(12)70006-2
  • Zhang M, Yao Z, Dubois S, Ju W, Muller JR, Waldmann TA. Interleukin-15 combined with an anti-CD40 antibody provides enhanced therapeutic efficacy for murine models of colon cancer. Proc Natl Acad Sci U S A 2009;106(18):7513–7518. doi:10.1073/pnas.0902637106
  • Bibeau F, Lopez-Crapez E, Di Fiore F, Thezenas S, Ychou M, Blanchard F, Lamy A, Penault-Llorca F, Frebourg T, Michel P, et al. Impact of Fc{gamma}RIIa-Fc{gamma}RIIIa polymorphisms and KRAS mutations on the clinical outcome of patients with metastatic colorectal cancer treated with cetuximab plus irinotecan. J Clin Oncol 2009;27(7):1122–1129. doi:10.1200/jco.2008.18.0463
  • Cartron G, Dacheux L, Salles G, Solal-Celigny P, Bardos P, Colombat P, Watier H. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood 2002;99(3):754–758.
  • Zhang W, Gordon M, Schultheis AM, Yang DY, Nagashima F, Azuma M, Chang HM, Borucka E, Lurje G, Sherrod AE, et al. FCGR2A and FCGR3A polymorphisms associated with clinical outcome of epidermal growth factor receptor expressing metastatic colorectal cancer patients treated with single-agent cetuximab. J Clin Oncol 2007;25(24):3712–3718. doi:10.1200/jco.2006.08.8021
  • Apolo AB, Infante JR, Hamid O, Patel MR, Wang D, Kelly K, Mega AE, Britten CD, Ravaud A, Mita AC, et al. Avelumab (MSB0010718C; anti-PD-L1) in patients with metastatic urothelial carcinoma from the JAVELIN solid tumor phase 1b trial: analysis of safety, clinical activity, and PD-L1 expression. J Clin Oncol 2016;34(15_suppl):4514. doi:10.1200/JCO.2016.34.15_suppl.4514
  • Boyerinas B, Jochems C, Fantini M, Heery CR, Gulley JL, Tsang KY, Schlom J. Antibody-dependent cellular cytotoxicity (ADCC) activity of a novel anti-PD-L1 antibody avelumab (MSB0010718C) on human tumor cells. Cancer Immunol Res 2015;3(10):1148–1157. doi:10.1158/2326-6066.CIR-15-0059
  • Kaufman HL, Russell J, Hamid O, Bhatia S, Terheyden P, D’Angelo SP, Shih KC, Lebbé C, Linette GP, Milella M, et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol 2016;17(10):1374–1385. doi:10.1016/S1470-2045(16)30364-3
  • Khanna S, Thomas A, Abate-Daga D, Zhang J, Morrow B, Steinberg SM, Orlandi A, Ferroni P, Schlom J, Guadagni F, et al. Malignant mesothelioma effusions are infiltrated by CD3(+) T cells highly expressing PD-L1 and the PD-L1(+) tumor cells within these effusions are susceptible to ADCC by the anti-PD-L1 antibody avelumab. J Thorac Oncol 2016;11(11):1993–2005. doi:10.1016/j.jtho.2016.07.033
  • Donahue RN, Lepone LM, Grenga I, Jochems C, Fantini M, Madan RA, Heery CR, Gulley JL, Schlom J. Analyses of the peripheral immunome following multiple administrations of avelumab, a human IgG1 anti-PD-L1 monoclonal antibody. J Immunother Cancer 2017;5(1):20. doi:10.1186/s40425-017-0220-y
  • Apolo AB, Infante JR, Balmanoukian A, Patel MR, Wang D, Kelly K, Mega AE, Britten CD, Ravaud A, Mita AC, et al. Avelumab, an anti–programmed death-ligand 1 antibody, in patients with refractory metastatic urothelial carcinoma: results from a multicenter, phase ib study. J Clin Oncol 2017;35(19):2117–2124. doi:10.1200/jco.2016.71.6795
  • Gulley JL, Rajan A, Spigel DR, Iannotti N, Chandler J, Wong DJL, Leach J, Edenfield WJ, Wang D, Grote HJ, et al. Avelumab for patients with previously treated metastatic or recurrent non-small-cell lung cancer (JAVELIN Solid Tumor): dose-expansion cohort of a multicentre, open-label, phase 1b trial. Lancet Oncol 2017;18(5):599–610. doi:10.1016/s1470-2045(17)30240-1
  • Lipson EJ, Forde PM, Hammers H-J, Emens LA, Taube JM, Topalian SL. Antagonists of PD-1 and PD-L1 in cancer treatment. Semin Oncol 2015;42(4):587–600. doi:10.1053/j.seminoncol.2015.05.013
  • Marks-Konczalik J, Dubois S, Losi JM, Sabzevari H, Yamada N, Feigenbaum L, Waldmann TA, Tagaya Y. IL-2-induced activation-induced cell death is inhibited in IL-15 transgenic mice. Proc Natl Acad Sci U S A 2000;97(21):11445–11450. doi:10.1073/pnas.200363097
  • Tagaya Y, Bamford RN, DeFilippis AP, Waldmann TA. IL-15: a pleiotropic cytokine with diverse receptor/signaling pathways whose expression is controlled at multiple levels. Immunity 1996;4(4):329–336.
  • Waldmann TA. The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nat Rev Immunol 2006;6(8):595–601. doi:10.1038/nri1901
  • Kobayashi H, Carrasquillo JA, Paik CH, Waldmann TA, Tagaya Y. Differences of biodistribution, pharmacokinetics, and tumor targeting between interleukins 2 and 15. Cancer Res 2000;60(13):3577–3583.
  • Alter S, Rhode PR, Jeng EK, Wong HC. Targeted IL-15-based protein fusion complexes as cancer immunotherapy approaches. J Immunol Sci 2018;2(1):15–18. doi:10.29245/2578-3009/2018/1.1111
  • Rhode PR, Egan JO, Xu W, Hong H, Webb GM, Chen X, Liu B, Zhu X, Wen J, You L, et al. Comparison of the superagonist complex, ALT-803, to IL15 as cancer immunotherapeutics in animal models. Cancer Immunol Res 2016;4(1):49–60. doi:10.1158/2326-6066.cir-15-0093-t
  • Wong HC, Jeng EK, Rhode PR. The IL-15-based superagonist ALT-803 promotes the antigen-independent conversion of memory CD8(+) T cells into innate-like effector cells with antitumor activity. OncoImmunology 2013;2(11):e26442. doi:10.4161/onci.26442
  • Jochems C, Tritsch SR, Pellom ST, Su Z, Soon-Shiong P, Wong HC, Gulley JL, Schlom J. Analyses of functions of an anti-PD-L1/TGFβR2 bispecific fusion protein (M7824). Oncotarget 2017;8(43):75217–75231. doi:10.18632/oncotarget.20680
  • Rosario M, Liu B, Kong L, Collins LI, Schneider SE, Chen X, Han K, Jeng EK, Rhode PR, Leong JW, et al. The IL-15-based ALT-803 complex enhances FcgammaRIIIa-triggered NK cell responses and in vivo clearance of B cell lymphomas. Clin Cancer Res 2016;22(3):596–608. doi:10.1158/1078-0432.ccr-15-1419
  • Mathios D, Park CK, Marcus WD, Alter S, Rhode PR, Jeng EK, Wong HC, Pardoll DM, Lim M. Therapeutic administration of IL-15 superagonist complex ALT-803 leads to long-term survival and durable antitumor immune response in a murine glioblastoma model. Int J Cancer 2016;138(1):187–194. doi:10.1002/ijc.29686
  • Kim PS, Kwilas AR, Xu W, Alter S, Jeng EK, Wong HC, Schlom J, Hodge JW. IL-15 superagonist/IL-15RalphaSushi-Fc fusion complex (IL-15SA/IL-15RalphaSu-Fc; ALT-803) markedly enhances specific subpopulations of NK and memory CD8+ T cells, and mediates potent anti-tumor activity against murine breast and colon carcinomas. Oncotarget 2016;7(13):16130–16145. doi:10.18632/oncotarget.7470
  • Rosser CJ, Nix J, Ferguson L, Wong HC. Mp15-12 phase Ib trial of Alt-803, an Il-15 superagonist, plus Bacillus Calmette Guerin (Bcg) for the treatment of Bcg-naive patients with non-muscle-invasive bladder cancer (Nmibc). J Urol 197(4):e175. doi:10.1016/j.juro.2017.02.497
  • Sfakianos JP, Kim PH, Hakimi AA, Herr HW. The effect of restaging transurethral resection on recurrence and progression rates in patients with nonmuscle invasive bladder cancer treated with intravesical bacillus Calmette-Guerin. J Urol 2014;191(2):341–345. doi:10.1016/j.juro.2013.08.022
  • Romee R, Cooley S, Berrien-Elliott MM, Westervelt P, Verneris MR, Wagner JE, Weisdorf DJ, Blazar BR, Ustun C, DeFor TE, et al. First-in-human phase 1 clinical study of the IL-15 superagonist complex ALT-803 to treat relapse after transplantation. Blood 2018;131(23):2515–2527.
  • Yu P, Steel JC, Zhang M, Morris JC, Waitz R, Fasso M, Allison JP, Waldmann TA. Simultaneous inhibition of two regulatory T-cell subsets enhanced Interleukin-15 efficacy in a prostate tumor model. Proc Natl Acad Sci U S A 2012;109(16):6187–6192. doi:10.1073/pnas.1203479109
  • Yu P, Steel JC, Zhang M, Morris JC, Waldmann TA. Simultaneous blockade of multiple immune system inhibitory checkpoints enhances antitumor activity mediated by interleukin-15 in a murine metastatic colon carcinoma model. Clin Cancer Res 2010;16(24):6019–6028. doi:10.1158/1078-0432.CCR-10-1966
  • Wrangle JM, Velcheti V, Patel MR, Garrett-Mayer E, Hill EG, Ravenel JG, Miller JS, Farhad M, Anderton K, Lindsey K, et al. ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial. Lancet Oncol 2018;19(5):694–704. doi:10.1016/S1470-2045(18)30148-7
  • Jin BY, Campbell TE, Draper LM, Stevanovic S, Weissbrich B, Yu Z, Restifo NP, Rosenberg SA, Trimble CL, Hinrichs CS. Engineered T cells targeting E7 mediate regression of human papillomavirus cancers in a murine model. JCI Insight 2018;3:8. doi:10.1172/jci.insight.99488
  • Garcia-Foncillas J, Diaz-Rubio E. Progress in metastatic colorectal cancer: growing role of cetuximab to optimize clinical outcome. Clin Transl Oncol 2010;12(8):533–542. doi:10.1007/s12094-010-0551-3
  • Kies MS, Holsinger FC, Lee JJ, William WN Jr., Glisson BS, Lin HY, Lewin JS, Ginsberg LE, Gillaspy KA, Massarelli E, et al. Induction chemotherapy and cetuximab for locally advanced squamous cell carcinoma of the head and neck: results from a phase II prospective trial. J Clin Oncol 2010;28(1):8–14. doi:10.1200/JCO.2009.23.0425
  • Kol A, Terwisscha van Scheltinga A, Pool M, Gerdes C, de Vries E, de Jong S. ADCC responses and blocking of EGFR-mediated signaling and cell growth by combining the anti-EGFR antibodies imgatuzumab and cetuximab in NSCLC cells. Oncotarget 2017;8(28):45432–45446. doi:10.18632/oncotarget.17139
  • Jochems C, Hodge JW, Fantini M, Fujii R, Morillon YM 2nd, Greiner JW, Padget MR, Tritsch SR, Tsang KY, Campbell KS, et al. An NK cell line (haNK) expressing high levels of granzyme and engineered to express the high affinity CD16 allele. Oncotarget 2016;7(52):86359–86373. doi:10.18632/oncotarget.13411
  • Guo Y, Luan L, Rabacal W, Bohannon JK, Fensterheim BA, Hernandez A, Sherwood ER. IL-15 superagonist-mediated immunotoxicity: role of NK Cells and IFN-gamma. J Immunol 2015;195(5):2353–2364. doi:10.4049/jimmunol.1500300
  • Liu B, Kong L, Han K, Hong H, Marcus WD, Chen X, Jeng EK, Alter S, Zhu X, Rubinstein MP, et al. A novel fusion of ALT-803 (interleukin (IL)-15 superagonist) with an antibody demonstrates antigen-specific antitumor responses. J Biol Chem 2016;291(46):23869–23881. doi:10.1074/jbc.M116.733600
  • Karin N. Chemokines and cancer: new immune checkpoints for cancer therapy. Curr Opin Immunol 2018;51:140–145. doi:10.1016/j.coi.2018.03.004
  • Chacon JA, Wu RC, Sukhumalchandra P, Molldrem JJ, Sarnaik A, Pilon-Thomas S, Weber J, Hwu P, Radvanyi L. Co-stimulation through 4-1BB/CD137 improves the expansion and function of CD8(+) melanoma tumor-infiltrating lymphocytes for adoptive T-cell therapy. PLoS One 2013;8(4):e60031. doi:10.1371/journal.pone.0060031
  • Sierra JM, Raffo Iraolagoitia XL, Secchiari F, Ziblat A, Nuñez SY, Torres NI, Regge MV, Domaica CI, Zwirner NW, Fuertes MB. Tumor-experienced NK cells inhibit T cell proliferation and activation through PD-L1 (abstr 704). AACR Annual Meeting, April 14–18, 2018; Chicago, IL. Cancer Res 2018;78(Suppl 13):704. doi:10.1158/1538-7445.AM2018-704
  • Bi J, Tian Z. NK cell exhaustion. Front Immunol 2017;8:760. doi:10.3389/fimmu.2017.00760
  • Ndhlovu LC, Lopez-Verges S, Barbour JD, Jones RB, Jha AR, Long BR, Schoeffler EC, Fujita T, Nixon DF, Lanier LL. Tim-3 marks human natural killer cell maturation and suppresses cell-mediated cytotoxicity. Blood 2012;119(16):3734–3743. doi:10.1182/blood-2011-11-392951
  • Wang Z, Hong J, Sun W, Xu G, Li N, Chen X, Liu A, Xu L, Sun B, Zhang JZ. Role of IFN-gamma in induction of Foxp3 and conversion of CD4+ CD25- T cells to CD4+ Tregs. J Clin Invest 2006;116(9):2434–2441. doi:10.1172/JCI25826
  • Medina-Echeverz J, Haile LA, Zhao F, Gamrekelashvili J, Ma C, Metais JY, Dunbar CE, Kapoor V, Manns MP, Korangy F, et al. IFN-gamma regulates survival and function of tumor-induced CD11b+ Gr-1high myeloid derived suppressor cells by modulating the anti-apoptotic molecule Bcl2a1. Eur J Immunol 2014;44(8):2457–2467. doi:10.1002/eji.201444497
  • Liu B, Jones M, Kong L, Noel T, Jeng EK, Shi S, England CG, Alter S, Miller JS, Cai W, et al. Evaluation of the biological activities of the IL-15 superagonist complex, ALT-803, following intravenous versus subcutaneous administration in murine models. Cytokine 2018;107:105–112. doi:10.1016/j.cyto.2017.12.003
  • Felices M, Chu S, Kodal B, Bendzick L, Ryan C, Lenvik AJ, Boylan KLM, Wong HC, Skubitz APN, Miller JS, et al. IL-15 super-agonist (ALT-803) enhances natural killer (NK) cell function against ovarian cancer. Gynecol Oncol 2017;145(3):453–461. doi:10.1016/j.ygyno.2017.02.028
  • Zhu X, Marcus WD, Xu W, Lee HI, Han K, Egan JO, Yovandich JL, Rhode PR, Wong HC. Novel human interleukin-15 agonists. J Immunol 2009;183(6):3598–3607. doi:10.4049/jimmunol.0901244
  • Fallon JK, Vandeveer AJ, Schlom J, Greiner JW. Enhanced antitumor effects by combining an IL-12/anti-DNA fusion protein with avelumab, an anti-PD-L1 antibody. Oncotarget 2017;8(13):20558–20571. doi:10.18632/oncotarget.16137
  • Clarke P, Mann J, Simpson JF, Rickard-Dickson K, Primus FJ. Mice transgenic for human carcinoembryonic antigen as a model for immunotherapy. Cancer Res 1998;58(7):1469–1477.
  • Kass E, Schlom J, Thompson J, Guadagni F, Graziano P, Greiner JW. Induction of protective host immunity to carcinoembryonic antigen (CEA), a self-antigen in CEA transgenic mice, by immunizing with a recombinant vaccinia-CEA virus. Cancer Res 1999;59(3):676–683.