NK-Cell-Mediated Targeting of Various Solid Tumors Using a B7-H3 Tri-Specific Killer Engager In Vitro and In Vivo
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Construction of cam1615B7H3 TriKEs
2.2. Purification of Protein from Inclusion Bodies
2.3. Cancer Cell Lines and Antibody
2.4. Cell Products
2.5. NK Cell Expansion via IL-15 Stimulation
2.6. Evaluation of Cytotoxicity and NK Cell Activation
2.7. Real-Time Tumor-Killing Assay
2.8. Mass Cytometry (CyTOF)
2.9. In Vivo Mouse Study and Imaging
2.10. Statistical Analysis
3. Results
3.1. Creation and Purification of a B7-H3 Targeting TriKE
3.2. cam1615B7H3 TriKE Induces Potent and Specific NK Cell Proliferation
3.3. cam1615B7H3 TriKE Exhibits Potent Killing of Ovarian Cancer
3.4. cam1615B7H3 TriKE Targets Prostate Cancer
3.5. cam1615B7H3 TriKE Targets Lung Cancer
3.6. High Dimensional Analysis of cam1615B7H3 TriKE Activated Cells
3.7. cam1615B7H3 TriKE Mediates Anti-Tumor Activity In Vivo
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Greaves, P.; Gribben, J.G. The role of B7 family molecules in hematologic malignancy. Blood 2013, 121, 734–744. [Google Scholar] [CrossRef] [PubMed]
- Chapoval, A.I.; Ni, J.; Lau, J.S.; Wilcox, R.A.; Flies, D.B.; Liu, D.; Dong, H.; Sica, G.L.; Zhu, G.; Tamada, K.; et al. B7-H3: A costimulatory molecule for T cell activation and IFN-gamma production. Nat. Immunol. 2001, 2, 269–274. [Google Scholar] [CrossRef] [PubMed]
- Li, G.; Quan, Y.; Che, F.; Wang, L. B7-H3 in tumors: Friend or foe for tumor immunity? Cancer Chemother. Pharmacol. 2018, 81, 245–253. [Google Scholar] [CrossRef]
- Hofmeyer, K.A.; Ray, A.; Zang, X. The contrasting role of B7-H3. Proc. Natl. Acad. Sci. USA 2008, 105, 10277–10278. [Google Scholar] [CrossRef] [Green Version]
- Castellanos, J.R.; Purvis, I.J.; Labak, C.M.; Guda, M.R.; Tsung, A.J.; Velpula, K.K.; Asuthkar, S. B7-H3 role in the immune landscape of cancer. Am. J. Clin. Exp. Immunol. 2017, 6, 66–75. [Google Scholar] [PubMed]
- Chen, C.; Shen, Y.; Qu, Q.X.; Chen, X.Q.; Zhang, X.G.; Huang, J.A. Induced expression of B7-H3 on the lung cancer cells and macrophages suppresses T-cell mediating anti-tumor immune response. Exp. Cell. Res. 2013, 319, 96–102. [Google Scholar] [CrossRef]
- Vigdorovich, V.; Ramagopal, U.A.; Lazar-Molnar, E.; Sylvestre, E.; Lee, J.S.; Hofmeyer, K.A.; Zang, X.; Nathenson, S.G.; Almo, S.C. Structure and T cell inhibition properties of B7 family member, B7-H3. Structure 2013, 21, 707–717. [Google Scholar] [CrossRef] [Green Version]
- Picarda, E.; Ohaegbulam, K.C.; Zang, X. Molecular Pathways: Targeting B7-H3 (CD276) for Human Cancer Immunotherapy. Clin. Cancer Res. 2016, 22, 3425–3431. [Google Scholar] [CrossRef] [Green Version]
- Du, H.; Hirabayashi, K.; Ahn, S.; Kren, N.P.; Montgomery, S.A.; Wang, X.; Tiruthani, K.; Mirlekar, B.; Michaud, D.; Greene, K.; et al. Antitumor Responses in the Absence of Toxicity in Solid Tumors by Targeting B7-H3 via Chimeric Antigen Receptor T Cells. Cancer Cell 2019, 35, 221–237 e228. [Google Scholar] [CrossRef] [Green Version]
- Fauci, J.M.; Straughn, J.M., Jr.; Ferrone, S.; Buchsbaum, D.J. A review of B7-H3 and B7-H4 immune molecules and their role in ovarian cancer. Gynecol. Oncol. 2012, 127, 420–425. [Google Scholar] [CrossRef]
- Zang, X.; Sullivan, P.S.; Soslow, R.A.; Waitz, R.; Reuter, V.E.; Wilton, A.; Thaler, H.T.; Arul, M.; Slovin, S.F.; Wei, J.; et al. Tumor associated endothelial expression of B7-H3 predicts survival in ovarian carcinomas. Mod. Pathol. 2010, 23, 1104–1112. [Google Scholar] [CrossRef] [PubMed]
- Dong, P.; Xiong, Y.; Yue, J.; Hanley, S.J.B.; Watari, H. B7H3 As a Promoter of Metastasis and Promising Therapeutic Target. Front. Oncol. 2018, 8, 264. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- May, M.B.; Glode, A. Blinatumomab: A novel, bispecific, T-cell engaging antibody. Am. J. Health Syst. Pharm. 2016, 73, e6–e13. [Google Scholar] [CrossRef] [PubMed]
- Barrett, D.M.; Teachey, D.T.; Grupp, S.A. Toxicity management for patients receiving novel T-cell engaging therapies. Curr. Opin. Pediatr. 2014, 26, 43–49. [Google Scholar] [CrossRef]
- Gleason, M.K.; Ross, J.A.; Warlick, E.D.; Lund, T.C.; Verneris, M.R.; Wiernik, A.; Spellman, S.; Haagenson, M.D.; Lenvik, A.J.; Litzow, M.R.; et al. CD16xCD33 bispecific killer cell engager (BiKE) activates NK cells against primary MDS and MDSC CD33+ targets. Blood 2014, 123, 3016–3026. [Google Scholar] [CrossRef]
- Alderson, K.L.; Sondel, P.M. Clinical cancer therapy by NK cells via antibody-dependent cell-mediated cytotoxicity. J. Biomed. Biotechnol. 2011, 2011, 379123. [Google Scholar] [CrossRef]
- Schmohl, J.U.; Gleason, M.K.; Dougherty, P.R.; Miller, J.S.; Vallera, D.A. Heterodimeric Bispecific Single Chain Variable Fragments (scFv) Killer Engagers (BiKEs) Enhance NK-cell Activity Against CD133+ Colorectal Cancer Cells. Target. Oncol. 2015. [Google Scholar] [CrossRef] [Green Version]
- Felices, M.; Kodal, B.; Hinderlie, P.; Kaminski, M.F.; Cooley, S.; Weisdorf, D.J.; Vallera, D.A.; Miller, J.S.; Bachanova, V. Novel CD19-targeted TriKE restores NK cell function and proliferative capacity in CLL. Blood Adv. 2019, 3, 897–907. [Google Scholar] [CrossRef]
- Schmohl, J.U.; Felices, M.; Oh, F.; Lenvik, A.J.; Lebeau, A.M.; Panyam, J.; Miller, J.S.; Vallera, D.A. Engineering of Anti-CD133 Tri-Specific Molecule Capable of Inducing NK Expansion and Driving Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC). Cancer Res. Treat. 2017. [Google Scholar] [CrossRef] [Green Version]
- Schmohl, J.U.; Felices, M.; Taras, E.; Miller, J.S.; Vallera, D.A. Enhanced ADCC and NK Cell Activation of an Anticarcinoma Bispecific Antibody by Genetic Insertion of a Modified IL-15 Cross-linker. Mol. Ther. 2016, 24, 1312–1322. [Google Scholar] [CrossRef] [Green Version]
- Schmohl, J.U.; Felices, M.; Todhunter, D.; Taras, E.; Miller, J.S.; Vallera, D.A. Tetraspecific scFv construct provides NK cell mediated ADCC and self-sustaining stimuli via insertion of IL-15 as a cross-linker. Oncotarget 2016, 7, 73830–73844. [Google Scholar] [CrossRef] [PubMed]
- Vallera, D.A.; Felices, M.; McElmurry, R.; McCullar, V.; Zhou, X.; Schmohl, J.U.; Zhang, B.; Lenvik, A.J.; Panoskaltsis-Mortari, A.; Verneris, M.R.; et al. IL15 Trispecific Killer Engagers (TriKE) Make Natural Killer Cells Specific to CD33+ Targets While Also Inducing Persistence, In Vivo Expansion, and Enhanced Function. Clin. Cancer Res. 2016, 22, 3440–3450. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Felices, M.; Lenvik, T.R.; Kodal, B.; Lenvik, A.J.; Hinderlie, P.; Bendzick, L.E.; Schirm, D.K.; Kaminski, M.F.; McElmurry, R.T.; Geller, M.A.; et al. Potent Cytolytic Activity and Specific IL15 Delivery in a Second-Generation Trispecific Killer Engager. Cancer Immunol. Res. 2020. [Google Scholar] [CrossRef] [PubMed]
- Carson, W.E.; Giri, J.G.; Lindemann, M.J.; Linett, M.L.; Ahdieh, M.; Paxton, R.; Anderson, D.; Eisenmann, J.; Grabstein, K.; Caligiuri, M.A. Interleukin (IL) 15 is a novel cytokine that activates human natural killer cells via components of the IL-2 receptor. J. Exp. Med. 1994, 180, 1395–1403. [Google Scholar] [CrossRef]
- Behar, G.; Siberil, S.; Groulet, A.; Chames, P.; Pugniere, M.; Boix, C.; Sautes-Fridman, C.; Teillaud, J.L.; Baty, D. Isolation and characterization of anti-FcgammaRIII (CD16) llama single-domain antibodies that activate natural killer cells. Protein Eng. Des. Sel. 2008, 21, 1–10. [Google Scholar] [CrossRef]
- Vincke, C.; Loris, R.; Saerens, D.; Martinez-Rodriguez, S.; Muyldermans, S.; Conrath, K. General strategy to humanize a camelid single-domain antibody and identification of a universal humanized nanobody scaffold. J. Biol. Chem. 2009, 284, 3273–3284. [Google Scholar] [CrossRef] [Green Version]
- Fauci, J.M.; Sabbatino, F.; Wang, Y.; Londono-Joshi, A.I.; Straughn, J.M., Jr.; Landen, C.N.; Ferrone, S.; Buchsbaum, D.J. Monoclonal antibody-based immunotherapy of ovarian cancer: Targeting ovarian cancer cells with the B7-H3-specific mAb 376.96. Gynecol. Oncol. 2014, 132, 203–210. [Google Scholar] [CrossRef]
- Felices, M.; Chu, S.; Kodal, B.; Bendzick, L.; Ryan, C.; Lenvik, A.J.; Boylan, K.L.; Wong, H.C.; Skubitz, A.P.; Miller, J.S.; et al. IL-15 super-agonist (ALT-803) enhances natural killer (NK) cell function against ovarian cancer. Gynecol. Oncol. 2017. [Google Scholar] [CrossRef]
- Rhode, P.R.; Egan, J.O.; Xu, W.; Hong, H.; Webb, G.M.; 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, 49–60. [Google Scholar] [CrossRef] [Green Version]
- Uppendahl, L.D.; Felices, M.; Bendzick, L.; Ryan, C.; Kodal, B.; Hinderlie, P.; Boylan, K.L.M.; Skubitz, A.P.N.; Miller, J.S.; Geller, M.A. Cytokine-induced memory-like natural killer cells have enhanced function, proliferation, and in vivo expansion against ovarian cancer cells. Gynecol. Oncol. 2019. [Google Scholar] [CrossRef]
- Loo, D.; Alderson, R.F.; Chen, F.Z.; Huang, L.; Zhang, W.; Gorlatov, S.; Burke, S.; Ciccarone, V.; Li, H.; Yang, Y.; et al. Development of an Fc-enhanced anti-B7-H3 monoclonal antibody with potent antitumor activity. Clin. Cancer Res. 2012, 18, 3834–3845. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kramer, K.; Kushner, B.H.; Modak, S.; Pandit-Taskar, N.; Smith-Jones, P.; Zanzonico, P.; Humm, J.L.; Xu, H.; Wolden, S.L.; Souweidane, M.M.; et al. Compartmental intrathecal radioimmunotherapy: Results for treatment for metastatic CNS neuroblastoma. J. Neurooncol. 2010, 97, 409–418. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kramer, K.; Smith, M.; Souweidane, M.M. Safety profile of long-term intraventricular access devices in pediatric patients receiving radioimmunotherapy for central nervous system malignancies. Pediatr. Blood Cancer 2014, 61, 1590–1592. [Google Scholar] [CrossRef] [PubMed]
- Souweidane, M.M.; Kramer, K.; Pandit-Taskar, N.; Zhou, Z.; Haque, S.; Zanzonico, P.; Carrasquillo, J.A.; Lyashchenko, S.K.; Thakur, S.B.; Donzelli, M.; et al. Convection-enhanced delivery for diffuse intrinsic pontine glioma: A single-centre, dose-escalation, phase 1 trial. Lancet Oncol. 2018, 19, 1040–1050. [Google Scholar] [CrossRef]
- Seaman, S.; Zhu, Z.; Saha, S.; Zhang, X.M.; Yang, M.Y.; Hilton, M.B.; Morris, K.; Szot, C.; Morris, H.; Swing, D.A.; et al. Eradication of Tumors through Simultaneous Ablation of CD276/B7-H3-Positive Tumor Cells and Tumor Vasculature. Cancer Cell 2017, 31, 501–515.e508. [Google Scholar] [CrossRef] [Green Version]
- Benzon, B.; Zhao, S.G.; Haffner, M.C.; Takhar, M.; Erho, N.; Yousefi, K.; Hurley, P.; Bishop, J.L.; Tosoian, J.; Ghabili, K.; et al. Correlation of B7-H3 with androgen receptor, immune pathways and poor outcome in prostate cancer: An expression-based analysis. Prostate Cancer Prostatic Dis. 2017, 20, 28–35. [Google Scholar] [CrossRef]
- Inamura, K.; Yokouchi, Y.; Kobayashi, M.; Sakakibara, R.; Ninomiya, H.; Subat, S.; Nagano, H.; Nomura, K.; Okumura, S.; Shibutani, T.; et al. Tumor B7-H3 (CD276) expression and smoking history in relation to lung adenocarcinoma prognosis. Lung Cancer 2017, 103, 44–51. [Google Scholar] [CrossRef]
- Loos, M.; Hedderich, D.M.; Friess, H.; Kleeff, J. B7-h3 and its role in antitumor immunity. Clin. Dev. Immunol. 2010, 2010, 683875. [Google Scholar] [CrossRef]
- Yamato, I.; Sho, M.; Nomi, T.; Akahori, T.; Shimada, K.; Hotta, K.; Kanehiro, H.; Konishi, N.; Yagita, H.; Nakajima, Y. Clinical importance of B7-H3 expression in human pancreatic cancer. Br. J. Cancer 2009, 101, 1709–1716. [Google Scholar] [CrossRef]
- Cooley, S.; He, F.; Bachanova, V.; Vercellotti, G.M.; DeFor, T.E.; Curtsinger, J.M.; Robertson, P.; Grzywacz, B.; Conlon, K.C.; Waldmann, T.A.; et al. First-in-human trial of rhIL-15 and haploidentical natural killer cell therapy for advanced acute myeloid leukemia. Blood Adv. 2019, 3, 1970–1980. [Google Scholar] [CrossRef]
- Dubois, S.; Conlon, K.C.; Muller, J.R.; Hsu-Albert, J.; Beltran, N.; Bryant, B.R.; Waldmann, T.A. IL15 Infusion of Cancer Patients Expands the Subpopulation of Cytotoxic CD56(bright) NK Cells and Increases NK-Cell Cytokine Release Capabilities. Cancer Immunol. Res. 2017, 5, 929–938. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Miller, J.S.; Morishima, C.; McNeel, D.G.; Patel, M.R.; Kohrt, H.E.K.; Thompson, J.A.; Sondel, P.M.; Wakelee, H.A.; Disis, M.L.; Kaiser, J.C.; et al. A First-in-Human Phase I Study of Subcutaneous Outpatient Recombinant Human IL15 (rhIL15) in Adults with Advanced Solid Tumors. Clin. Cancer Res. 2018, 24, 1525–1535. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Romee, R.; Cooley, S.; Berrien-Elliott, M.M.; Westervelt, P.; Verneris, M.R.; Wagner, J.E.; Weisdorf, D.J.; Blazar, B.R.; Ustun, C.; DeFor, T.E.; 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, 2515–2527. [Google Scholar] [CrossRef] [PubMed]
- Sarhan, D.; Brandt, L.; Felices, M.; Guldevall, K.; Lenvik, T.; Hinderlie, P.; Curtsinger, J.; Warlick, E.; Spellman, S.R.; Blazar, B.R.; et al. 161533 TriKE stimulates NK-cell function to overcome myeloid-derived suppressor cells in MDS. Blood Adv. 2018, 2, 1459–1469. [Google Scholar] [CrossRef] [Green Version]
- Felices, M.; Lenvik, A.J.; McElmurry, R.; Chu, S.; Hinderlie, P.; Bendzick, L.; Geller, M.A.; Tolar, J.; Blazar, B.R.; Miller, J.S. Continuous treatment with IL-15 exhausts human NK cells via a metabolic defect. JCI Insight 2018, 3. [Google Scholar] [CrossRef]
- Bi, J.; Tian, Z. NK Cell Exhaustion. Front Immunol. 2017, 8, 760. [Google Scholar] [CrossRef]
- Romee, R.; Foley, B.; Lenvik, T.; Wang, Y.; Zhang, B.; Ankarlo, D.; Luo, X.; Cooley, S.; Verneris, M.; Walcheck, B.; et al. NK cell CD16 surface expression and function is regulated by a disintegrin and metalloprotease-17 (ADAM17). Blood 2013, 121, 3599–3608. [Google Scholar] [CrossRef]
- Belisle, J.A.; Gubbels, J.A.; Raphael, C.A.; Migneault, M.; Rancourt, C.; Connor, J.P.; Patankar, M.S. Peritoneal natural killer cells from epithelial ovarian cancer patients show an altered phenotype and bind to the tumour marker MUC16 (CA125). Immunology 2007, 122, 418–429. [Google Scholar] [CrossRef]
- Watanabe, M.; Kono, K.; Kawaguchi, Y.; Mizukami, Y.; Mimura, K.; Maruyama, T.; Izawa, S.; Fujii, H. NK cell dysfunction with down-regulated CD16 and up-regulated CD56 molecules in patients with esophageal squamous cell carcinoma. Dis. Esophagus 2010, 23, 675–681. [Google Scholar] [CrossRef]
- Petricevic, B.; Laengle, J.; Singer, J.; Sachet, M.; Fazekas, J.; Steger, G.; Bartsch, R.; Jensen-Jarolim, E.; Bergmann, M. Trastuzumab mediates antibody-dependent cell-mediated cytotoxicity and phagocytosis to the same extent in both adjuvant and metastatic HER2/neu breast cancer patients. J. Transl. Med. 2013, 11, 307. [Google Scholar] [CrossRef] [Green Version]
- Rossello, A.; Nuti, E.; Ferrini, S.; Fabbi, M. Targeting ADAM17 Sheddase Activity in Cancer. Curr. Drug Targets 2016, 17, 1908–1927. [Google Scholar] [CrossRef] [PubMed]
- Jing, Y.; Ni, Z.; Wu, J.; Higgins, L.; Markowski, T.W.; Kaufman, D.S.; Walcheck, B. Identification of an ADAM17 cleavage region in human CD16 (FcgammaRIII) and the engineering of a non-cleavable version of the receptor in NK cells. PLoS ONE 2015, 10, e0121788. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhu, H.; Blum, R.H.; Bjordahl, R.; Gaidarova, S.; Rogers, P.; Lee, T.T.; Abujarour, R.; Bonello, G.B.; Wu, J.; Tsai, P.F.; et al. Pluripotent stem cell-derived NK cells with high-affinity noncleavable CD16a mediate improved antitumor activity. Blood 2020, 135, 399–410. [Google Scholar] [CrossRef] [PubMed]
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Vallera, D.A.; Ferrone, S.; Kodal, B.; Hinderlie, P.; Bendzick, L.; Ettestad, B.; Hallstrom, C.; Zorko, N.A.; Rao, A.; Fujioka, N.; et al. NK-Cell-Mediated Targeting of Various Solid Tumors Using a B7-H3 Tri-Specific Killer Engager In Vitro and In Vivo. Cancers 2020, 12, 2659. https://doi.org/10.3390/cancers12092659
Vallera DA, Ferrone S, Kodal B, Hinderlie P, Bendzick L, Ettestad B, Hallstrom C, Zorko NA, Rao A, Fujioka N, et al. NK-Cell-Mediated Targeting of Various Solid Tumors Using a B7-H3 Tri-Specific Killer Engager In Vitro and In Vivo. Cancers. 2020; 12(9):2659. https://doi.org/10.3390/cancers12092659
Chicago/Turabian StyleVallera, Daniel A., Soldano Ferrone, Behiye Kodal, Peter Hinderlie, Laura Bendzick, Brianna Ettestad, Caroline Hallstrom, Nicholas A. Zorko, Arpit Rao, Naomi Fujioka, and et al. 2020. "NK-Cell-Mediated Targeting of Various Solid Tumors Using a B7-H3 Tri-Specific Killer Engager In Vitro and In Vivo" Cancers 12, no. 9: 2659. https://doi.org/10.3390/cancers12092659