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Inducing Immunogenic Cell Death By
Orchestrating the Innate (NK) and Adaptive
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ONCOLOGY – Selected References

MODALITY 1: ANKTIVA (N-803)
CLINICAL

  • Romee R, Cooley S, Berrien-Elliott MM, et al. First-in-human phase 1 clinical study of the IL-15 superagonist complex ALT-803 to treat relapse after transplantation. Blood. Jun 7 2018;131(23):2515-2527. doi:10.1182/blood-2017-12-823757
  • Wrangle JM, Velcheti V, Patel MR, 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. May 2018;19(5):694-704. doi:10.1016/s1470-2045(18)30148-7
  • Margolin K, Morishima C, Velcheti V, et al. Phase I Trial of ALT-803, A Novel Recombinant IL15 Complex, in Patients with Advanced Solid Tumors. Clin Cancer Res. Nov 15 2018;24(22):5552-5561. doi:10.1158/1078-0432.ccr-18-0945

PRECLINICAL

  • Xu W, Jones M, Liu B, et al. Efficacy and mechanism-of-action of a novel superagonist interleukin-15: interleukin-15 receptor αSu/Fc fusion complex in syngeneic murine models of multiple myeloma. Cancer Res. May 15 2013;73(10):3075-86. doi:10.1158/0008-5472.can-12-2357
  • Gomes-Giacoia E, Miyake M, Goodison S, et al. Intravesical ALT-803 and BCG treatment reduces tumor burden in a carcinogen induced bladder cancer rat model; a role for cytokine production and NK cell expansion. PLoS One. 2014;9(6):e96705. doi:10.1371/journal.pone.0096705
  • Jones RB, Mueller S, O’Connor R, et al. A Subset of Latency-Reversing Agents Expose HIV-Infected Resting CD4+ T-Cells to Recognition by Cytotoxic T-Lymphocytes. PLoS Pathog. Apr 2016;12(4):e1005545. doi:10.1371/journal.ppat.1005545
  • Kim PS, Kwilas AR, Xu W, et al. IL-15 superagonist/IL-15RαSushi-Fc fusion complex (IL-15SA/IL-15RαSu-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. Mar 29 2016;7(13):16130-45. doi:10.18632/oncotarget.7470
  • Mathios D, Park CK, Marcus WD, et al. 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. Jan 1 2016;138(1):187-94. doi:10.1002/ijc.29686
  • Rhode PR, Egan JO, Xu W, et al. Comparison of the Superagonist Complex, ALT-803, to IL15 as Cancer Immunotherapeutics in Animal Models. Cancer Immunol Res. Jan 2016;4(1):49-60. doi:10.1158/2326-6066.cir-15-0093-t
  • Rosario M, Liu B, Kong L, et al. The IL-15-Based ALT-803 Complex Enhances FcγRIIIa-Triggered NK Cell Responses and In Vivo Clearance of B Cell Lymphomas. Clin Cancer Res. Feb 1 2016;22(3):596-608. doi:10.1158/1078-0432.ccr-15-1419
  • Wagner JA, Rosario M, Romee R, et al. CD56bright NK cells exhibit potent antitumor responses following IL-15 priming. J Clin Invest. Nov 1 2017;127(11):4042-4058. doi:10.1172/jci90387
  • Felices M, Chu S, Kodal B, et al. IL-15 super-agonist (ALT-803) enhances natural killer (NK) cell function against ovarian cancer. Gynecol Oncol. Jun 2017;145(3):453-461. doi:10.1016/j.ygyno.2017.02.028
  • Webb GM, Li S, Mwakalundwa G, et al. The human IL-15 superagonist ALT-803 directs SIV-specific CD8(+) T cells into B-cell follicles. Blood Adv. Jan 23 2018;2(2):76-84. doi:10.1182/bloodadvances.2017012971
  • Ellis-Connell AL, Balgeman AJ, Zarbock KR, et al. ALT-803 Transiently Reduces Simian Immunodeficiency Virus Replication in the Absence of Antiretroviral Treatment. J Virol. Feb 1 2018;92(3) doi:10.1128/jvi.01748-17
  • Jochems C, Tritsch SR, Pellom ST, et al. Analyses of functions of an anti-PD-L1/TGFβR2 bispecific fusion protein (M7824). Oncotarget. Sep 26 2017;8(43):75217-75231. doi:10.18632/oncotarget.20680
  • Knudson KM, Hicks KC, Alter S, Schlom J, Gameiro SR. Mechanisms involved in IL-15 superagonist enhancement of anti-PD-L1 therapy. J Immunother Cancer. Mar 21 2019;7(1):82. doi:10.1186/s40425-019-0551-y
  • Lee KL, Benz SC, Hicks KC, et al. Efficient Tumor Clearance and Diversified Immunity through Neoepitope Vaccines and Combinatorial Immunotherapy. Cancer Immunol Res. 08 2019;7(8):1359-1370. doi:10.1158/2326-6066.CIR-18-0620
  • Hicks KC, Knudson KM, Lee KL, et al. Cooperative Immune-Mediated Mechanisms of the HDAC Inhibitor Entinostat, an IL15 Superagonist, and a Cancer Vaccine Effectively Synergize as a Novel Cancer Therapy. Clin Cancer Res. Feb 1 2020;26(3):704-716. doi:10.1158/1078-0432.ccr-19-0727
MODALITY 1: N-809
  • Jochems C, Tritsch SR, Knudson KM, et al. The multi-functionality of N-809, a novel fusion protein encompassing anti-PD-L1 and the IL-15 superagonist fusion complex. Oncoimmunology. 2019;8(2):e1532764. doi:10.1080/2162402x.2018.1532764
  • Knudson KM, Hicks KC, Ozawa Y, Schlom J, Gameiro SR. Functional and mechanistic advantage of the use of a bifunctional anti-PD-L1/IL-15 superagonist. J Immunother Cancer. Apr 2020;8(1)doi:10.1136/jitc-2019-000493
MODALITY 1: N-820
  • Liu B, Kong L, Han K, et al. A Novel Fusion of ALT-803 (Interleukin (IL)-15 Superagonist) with an Antibody Demonstrates Antigen-specific Antitumor Responses. J Biol Chem. Nov 11 2016;291(46):23869-23881. doi:10.1074/jbc.M116.733600
MODALITY 1: N-830
  • Chen S, Yu L, Jiang C, et al. Pivotal study of iodine-131-labeled chimeric tumor necrosis treatment radioimmunotherapy in patients with advanced lung cancer. J Clin Oncol. Mar 2005;23(7):1538-47. doi:10.1200/JCO.2005.06.108.
  • Yu L, Ju DW, Chen W, et al. 131I-chTNT radioimmunotherapy of 43 patients with advanced lung cancer. Cancer Biother Radiopharm. Feb 2006;21(1):5-14. doi:10.1089/cbr.2006.21.5
  • Chen S, Yu L, Jiang C, et al. Pivotal study of iodine-131-labeled chimeric tumor necrosis treatment radioimmunotherapy in patients with advanced lung cancer. J Clin Oncol. Mar 2005;23(7):1538-47. doi:10.1200/JCO.2005.06.108.
    MODALITY 2: ALDOXORUBICIN

     CLINICAL

    • Unger C, Häring B, Medinger M, et al. Phase I and pharmacokinetic study of the (6-maleimidocaproyl)hydrazone derivative of doxorubicin. Clin Cancer Res. Aug 15 2007;13(16):4858-66. doi:10.1158/1078-0432.ccr-06-2776
    • Chawla SP, Chua VS, Hendifar AF, et al. A phase 1B/2 study of aldoxorubicin in patients with soft tissue sarcoma. Cancer. Feb 15 2015;121(4):570-9. doi:10.1002/cncr.29081
    • Chawla SP, Papai Z, Mukhametshina G, et al. First-Line Aldoxorubicin vs Doxorubicin in Metastatic or Locally Advanced Unresectable Soft-Tissue Sarcoma: A Phase 2b Randomized Clinical Trial. JAMA Oncol. Dec 2015;1(9):1272-80. doi:10.1001/jamaoncol.2015.3101
    • Mita MM, Natale RB, Wolin EM, et al. Pharmacokinetic study of aldoxorubicin in patients with solid tumors. Invest New Drugs. Apr 2015;33(2):341-8. doi:10.1007/s10637-014-0183-5

     PRECLINICAL

    • Di Stefano G, Lanza M, Kratz F, Merina L, Fiume L. A novel method for coupling doxorubicin to lactosaminated human albumin by an acid sensitive hydrazone bond: synthesis, characterization and preliminary biological properties of the conjugate. Eur J Pharm Sci. Dec 2004;23(4-5):393-7. doi:10.1016/j.ejps.2004.09.005
    • Lebrecht D, Geist A, Ketelsen UP, et al. The 6-maleimidocaproyl hydrazone derivative of doxorubicin (DOXO-EMCH) is superior to free doxorubicin with respect to cardiotoxicity and mitochondrial damage. Int J Cancer. Feb 15 2007;120(4):927-34. doi:10.1002/ijc.22409
    • Kratz F, Fichtner I, Graeser R. Combination therapy with the albumin-binding prodrug of doxorubicin (INNO-206) and doxorubicin achieves complete remissions and improves tolerability in an ovarian A2780 xenograft model. Invest New Drugs. Aug 2012;30(4):1743-9. doi:10.1007/s10637-011-9686-5
    • Marrero L, Wyczechowska D, Musto AE, et al. Therapeutic efficacy of aldoxorubicin in an intracranial xenograft mouse model of human glioblastoma. Neoplasia. Oct 2014;16(10):874-82. doi:10.1016/j.neo.2014.08.015
    MODALITY 3: hAd5, 2nd Gen Human Adenovirus Type 5
    CLINICAL

    • Morse MA, Chaudhry A, Gabitzsch ES, et al. Novel adenoviral vector induces T-cell responses despite anti-adenoviral neutralizing antibodies in colorectal cancer patients. Cancer Immunol Immunother. Aug 2013;62(8):1293-301. doi:10.1007/s00262-013-1400-3
    • Balint JP, Gabitzsch ES, Rice A, et al. Extended evaluation of a phase 1/2 trial on dosing, safety, immunogenicity, and overall survival after immunizations with an advanced-generation Ad5 [E1-, E2b-]-CEA(6D) vaccine in late-stage colorectal cancer. Cancer Immunol Immunother. Aug 2015;64(8):977-87. doi:10.1007/s00262-015-1706-4
    • Gatti-Mays ME, Redman JM, Donahue RN, et al. A Phase I Trial Using a Multitargeted Recombinant Adenovirus 5 (CEA/MUC1/Brachyury)-Based Immunotherapy Vaccine Regimen in Patients with Advanced Cancer. Oncologist. Jun 2020;25(6):479-e899. doi:10.1634/theoncologist.2019-0608

     PRECLINICAL

    • Gabitzsch ES, Xu Y, Yoshida LH, Balint J, Amalfitano A, Jones FR. Novel Adenovirus type 5 vaccine platform induces cellular immunity against HIV-1 Gag, Pol, Nef despite the presence of Ad5 immunity. Vaccine. Oct 30 2009;27(46):6394-8. doi:10.1016/j.vaccine.2009.06.028
    • Gabitzsch ES, Xu Y, Balint JP, Jr., Hartman ZC, Lyerly HK, Jones FR. Anti-tumor immunotherapy despite immunity to adenovirus using a novel adenoviral vector Ad5 [E1-, E2b-]-CEA. Cancer Immunol Immunother. Jul 2010;59(7):1131-5. doi:10.1007/s00262-010-0847-8
    • Jones FR, Gabitzsch ES, Xu Y, et al. Prevention of influenza virus shedding and protection from lethal H1N1 challenge using a consensus 2009 H1N1 HA and NA adenovirus vector vaccine. Vaccine. Sep 16 2011;29(40):7020-6. doi:10.1016/j.vaccine.2011.07.073
    • Wieking BG, Vermeer DW, Spanos WC, et al. A non-oncogenic HPV 16 E6/E7 vaccine enhances treatment of HPV expressing tumors. Cancer Gene Ther. Oct 2012;19(10):667-74. doi:10.1038/cgt.2012.55
    • Gabitzsch ES, Balint-Junior JP, Xu Y, et al. Control of SIV infection and subsequent induction of pandemic H1N1 immunity in rhesus macaques using an Ad5 [E1-, E2b-] vector platform. Vaccine. Nov 26 2012;30(50):7265-70. doi:10.1016/j.vaccine.2012.09.058
    • Rice AE, Latchman YE, Balint JP, Lee JH, Gabitzsch ES, Jones FR. An HPV-E6/E7 immunotherapy plus PD-1 checkpoint inhibition results in tumor regression and reduction in PD-L1 expression. Cancer Gene Ther. Sep 2015;22(9):454-62. doi:10.1038/cgt.2015.40
    • Maruyama J, Mateer EJ, Manning JT, et al. Adenoviral vector-based vaccine is fully protective against lethal Lassa fever challenge in Hartley guinea pigs. Vaccine. Oct 23 2019;37(45):6824-6831. doi:10.1016/j.vaccine.2019.09.030
    • Rice A, Verma M, Shin A et al. A Next Generation Bivalent Human Ad5 COVID-19 Vaccine Delivering Both Spike and Nucleocapsid Antigens Elicits Th1 Dominant CD4+, CD8+ T-cell and Neutralizing Antibody Responses. bioRxic 2020.07.29.227575; doi: https://doi.org/10.1101/2020.07.29.227595 doi: https://doi.org/10.1101/2020.07.29.227595 (*not peer-reviewed)
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