Stimulating the Antitumor Immune Response Using Immunocytokines: A Preclinical and Clinical Overview
Abstract
:1. Introduction
2. Methods
3. Immunocytokines
4. IL-2
4.1. IL-2 Ig-Fused ICKs
4.2. Engineered IL-2 Ig-Fused ICKs
4.3. Other IL-2 Fusion Proteins
5. IL-15
5.1. IL-15 Ig-Fused ICKs
5.2. Engineered IL-15-Fused ICKs
5.3. Other IL-15 Fusion Proteins
5.4. Attenuated IL-15 with Tumor Cleavable Masking Systems
6. TNF
7. IL-12
7.1. IL-12 Ig-Fused ICKs
7.2. Other IL-12-Fused ICKs
8. IL-21
9. IL-10
10. GM-CSF
11. IFNγ
12. IFNα
13. Summary and Perspectives
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Abbas, A.K.; Lichtman, A.H.; Pillai, S.; Baker, D.L. Basic Immunology: Functions and Disorders of the Immune System, 8th ed.; Elsevier, Saunders: Philadelphia, PA, USA, 2015. [Google Scholar]
- Dinarello, C.A. Overview of the IL-1 Family in Innate Inflammation and Acquired Immunity. Immunol. Rev. 2018, 281, 8–27. [Google Scholar] [CrossRef]
- Dinarello, C.A. Historical Review of Cytokines. Eur. J. Immunol. 2007, 37 (Suppl. S1), S34–S45. [Google Scholar] [CrossRef] [PubMed]
- Rosenwasser, L.J.; Dinarello, C.A.; Rosenthal, A.S. Adherent Cell Function in Murine T-Lymphocyte Antigen Recognition. IV. Enhancement of Murine T-Cell Antigen Recognition by Human Leukocytic Pyrogen. J. Exp. Med. 1979, 150, 709–714. [Google Scholar] [CrossRef]
- Kiessling, R.; Klein, E.; Wigzell, H. “Natural” Killer Cells in the Mouse. I. Cytotoxic Cells with Specificity for Mouse Moloney Leukemia Cells. Specificity and Distribution According to Genotype. Eur. J. Immunol. 1975, 5, 112–117. [Google Scholar] [CrossRef]
- Slingluff, C.L.; Cox, A.L.; Stover, J.M.; Moore, M.M.; Hunt, D.F.; Engelhard, V.H. Cytotoxic T-Lymphocyte Response to Autologous Human Squamous Cell Cancer of the Lung: Epitope Reconstitution with Peptides Extracted from HLA-Aw68. Cancer Res. 1994, 54, 2731–2737. [Google Scholar]
- Chan, C.W.; Housseau, F. The ‘Kiss of Death’ by Dendritic Cells to Cancer Cells. Cell Death Differ. 2008, 15, 58–69. [Google Scholar] [CrossRef]
- Xiong, S.; Dong, L.; Cheng, L. Neutrophils in Cancer Carcinogenesis and Metastasis. J. Hematol. Oncol. 2021, 14, 173. [Google Scholar] [CrossRef]
- Matlung, H.L.; Babes, L.; Zhao, X.W.; van Houdt, M.; Treffers, L.W.; van Rees, D.J.; Franke, K.; Schornagel, K.; Verkuijlen, P.; Janssen, H.; et al. Neutrophils Kill Antibody-Opsonized Cancer Cells by Trogoptosis. Cell Rep. 2018, 23, 3946–3959.e6. [Google Scholar] [CrossRef]
- Wu, L.; Saxena, S.; Singh, R.K. Neutrophils in the Tumor Microenvironment. Adv. Exp. Med. Biol. 2020, 1224, 1–20. [Google Scholar] [CrossRef]
- Sarvaria, A.; Madrigal, J.A.; Saudemont, A. B Cell Regulation in Cancer and Anti-Tumor Immunity. Cell Mol. Immunol. 2017, 14, 662–674. [Google Scholar] [CrossRef]
- Jorgovanovic, D.; Song, M.; Wang, L.; Zhang, Y. Roles of IFN-γ in Tumor Progression and Regression: A Review. Biomark. Res. 2020, 8, 49. [Google Scholar] [CrossRef] [PubMed]
- Li, Z.; Chen, L.; Qin, Z. Paradoxical Roles of IL-4 in Tumor Immunity. Cell Mol. Immunol. 2009, 6, 415–422. [Google Scholar] [CrossRef] [PubMed]
- Oft, M. IL-10: Master Switch from Tumor-Promoting Inflammation to Antitumor Immunity. Cancer Immunol. Res. 2014, 2, 194–199. [Google Scholar] [CrossRef]
- Landskron, G.; De la Fuente, M.; Thuwajit, P.; Thuwajit, C.; Hermoso, M.A. Chronic Inflammation and Cytokines in the Tumor Microenvironment. J. Immunol. Res. 2014, 2014, 149185. [Google Scholar] [CrossRef] [PubMed]
- Mumm, J.B.; Oft, M. Cytokine-Based Transformation of Immune Surveillance into Tumor-Promoting Inflammation. Oncogene 2008, 27, 5913–5919. [Google Scholar] [CrossRef] [PubMed]
- Philip, M.; Rowley, D.A.; Schreiber, H. Inflammation as a Tumor Promoter in Cancer Induction. Semin. Cancer Biol. 2004, 14, 433–439. [Google Scholar] [CrossRef] [PubMed]
- Massagué, J.; Blain, S.W.; Lo, R.S. TGFβ Signaling in Growth Control, Cancer, and Heritable Disorders. Cell 2000, 103, 295–309. [Google Scholar] [CrossRef] [PubMed]
- Chawla-Sarkar, M.; Leaman, D.W.; Borden, E.C. Preferential Induction of Apoptosis by Interferon (IFN)-Beta Compared with IFN-Alpha2: Correlation with TRAIL/Apo2L Induction in Melanoma Cell Lines. Clin. Cancer Res. 2001, 7, 1821–1831. [Google Scholar] [PubMed]
- Steen, H.C.; Gamero, A.M. Interferon-Lambda as a Potential Therapeutic Agent in Cancer Treatment. J. Interferon Cytokine Res. 2010, 30, 597–602. [Google Scholar] [CrossRef]
- Heichler, C.; Scheibe, K.; Schmied, A.; Geppert, C.I.; Schmid, B.; Wirtz, S.; Thoma, O.-M.; Kramer, V.; Waldner, M.J.; Büttner, C.; et al. STAT3 Activation through IL-6/IL-11 in Cancer-Associated Fibroblasts Promotes Colorectal Tumour Development and Correlates with Poor Prognosis. Gut 2020, 69, 1269–1282. [Google Scholar] [CrossRef]
- Montfort, A.; Colacios, C.; Levade, T.; Andrieu-Abadie, N.; Meyer, N.; Ségui, B. The TNF Paradox in Cancer Progression and Immunotherapy. Front. Immunol. 2019, 10, 1818. [Google Scholar] [CrossRef] [PubMed]
- Baba, A.B.; Rah, B.; Bhat, G.R.; Mushtaq, I.; Parveen, S.; Hassan, R.; Hameed Zargar, M.; Afroze, D. Transforming Growth Factor-Beta (TGF-β) Signaling in Cancer-A Betrayal Within. Front. Pharmacol. 2022, 13, 791272. [Google Scholar] [CrossRef] [PubMed]
- Grivennikov, S.I.; Greten, F.R.; Karin, M. Immunity, Inflammation, and Cancer. Cell 2010, 140, 883–899. [Google Scholar] [CrossRef] [PubMed]
- Gresser, I.; Bourali, C. Antitumor Effects of Interferon Preparations in Mice. JNCI J. Natl. Cancer Inst. 1970, 45, 365–376. [Google Scholar] [CrossRef] [PubMed]
- Borden, E.C.; Sen, G.C.; Uze, G.; Silverman, R.H.; Ransohoff, R.M.; Foster, G.R.; Stark, G.R. Interferons at Age 50: Past, Current and Future Impact on Biomedicine. Nat. Rev. Drug Discov. 2007, 6, 975–990. [Google Scholar] [CrossRef] [PubMed]
- Jiang, T.; Zhou, C.; Ren, S. Role of IL-2 in Cancer Immunotherapy. Oncoimmunology 2016, 5, e1163462. [Google Scholar] [CrossRef] [PubMed]
- Zídek, Z.; Anzenbacher, P.; Kmoníčková, E. Current Status and Challenges of Cytokine Pharmacology. Br. J. Pharmacol. 2009, 157, 342–361. [Google Scholar] [CrossRef] [PubMed]
- Boersma, B.; Jiskoot, W.; Lowe, P.; Bourquin, C. The Interleukin-1 Cytokine Family Members: Role in Cancer Pathogenesis and Potential Therapeutic Applications in Cancer Immunotherapy. Cytokine Growth Factor. Rev. 2021, 62, 1–14. [Google Scholar] [CrossRef] [PubMed]
- Gowin, K.; Jain, T.; Kosiorek, H.; Tibes, R.; Camoriano, J.; Palmer, J.; Mesa, R. Pegylated Interferon Alpha-2a Is Clinically Effective and Tolerable in Myeloproliferative Neoplasm Patients Treated off Clinical Trial. Leuk. Res. 2017, 54, 73–77. [Google Scholar] [CrossRef]
- Sunela, K.L.; Koskinen, S.; Kellokumpu-Lehtinen, P.-L. A Phase-II Study of Combination of Pegylated Interferon Alfa-2a and Capecitabine in Locally Advanced or Metastatic Renal Cell Cancer. Cancer Chemother. Pharmacol. 2010, 66, 59–67. [Google Scholar] [CrossRef]
- Bentebibel, S.-E.; Hurwitz, M.E.; Bernatchez, C.; Haymaker, C.; Hudgens, C.W.; Kluger, H.M.; Tetzlaff, M.T.; Tagliaferri, M.A.; Zalevsky, J.; Hoch, U.; et al. A First-in-Human Study and Biomarker Analysis of NKTR-214, a Novel IL2Rβγ-Biased Cytokine, in Patients with Advanced or Metastatic Solid Tumors. Cancer Discov. 2019, 9, 711–721. [Google Scholar] [CrossRef] [PubMed]
- Mattos, A.; de Jager-Krikken, A.; de Haan, M.; Beljaars, L.; Poelstra, K. PEGylation of Interleukin-10 Improves the Pharmacokinetic Profile and Enhances the Antifibrotic Effectivity in CCl4-Induced Fibrogenesis in Mice. J. Control. Release 2012, 162, 84–91. [Google Scholar] [CrossRef]
- Pettit, D.K.; Bonnert, T.P.; Eisenman, J.; Srinivasan, S.; Paxton, R.; Beers, C.; Lynch, D.; Miller, B.; Yost, J.; Grabstein, K.H.; et al. Structure-Function Studies of Interleukin 15 Using Site-Specific Mutagenesis, Polyethylene Glycol Conjugation, and Homology Modeling. J. Biol. Chem. 1997, 272, 2312–2318. [Google Scholar] [CrossRef] [PubMed]
- Robinson, T.O.; Hegde, S.M.; Chang, A.; Gangadharan, A.; Rivas, S.; Madakamutil, L.; Zalevsky, J.; Miyazaki, T.; Schluns, K.S. NKTR-255 Is a Polymer-Conjugated IL-15 with Unique Mechanisms of Action on T and Natural Killer Cells. J. Clin. Investig. 2021, 131, e144365. [Google Scholar] [CrossRef]
- Podobnik, B.; Helk, B.; Smilović, V.; Škrajnar, Š.; Fidler, K.; Jevševar, S.; Godwin, A.; Williams, P. Conjugation of PolyPEG to Interferon Alpha Extends Serum Half-Life While Maintaining Low Viscosity of the Conjugate. Bioconjugate Chem. 2015, 26, 452–459. [Google Scholar] [CrossRef]
- Joung, C.-H.; Shin, J.-Y.; Koo, J.-K.; Lim, J.J.; Wang, J.-S.; Lee, S.-J.; Tan, H.-K.; Kim, S.-L.; Lim, S.-M. Production and Characterization of Long-Acting Recombinant Human Albumin-EPO Fusion Protein Expressed in CHO Cell. Protein Expr. Purif. 2009, 68, 137–145. [Google Scholar] [CrossRef]
- Xu, W.; Jones, M.; Liu, B.; Zhu, X.; Johnson, C.B.; Edwards, A.C.; Kong, L.; Jeng, E.K.; Han, K.; Marcus, W.D.; 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. 2013, 73, 3075–3086. [Google Scholar] [CrossRef] [PubMed]
- Chen, S.; Huang, Q.; Liu, J.; Xing, J.; Zhang, N.; Liu, Y.; Wang, Z.; Li, Q. A Targeted IL-15 Fusion Protein with Potent Anti-Tumor Activity. Cancer Biol. Ther. 2015, 16, 1415–1421. [Google Scholar] [CrossRef]
- Zhao, J.; Si, Y.; Cheng, M.; Yang, Y.; Niu, Y.; Li, X.; Liu, X.; Yang, W. Albumin Fusion of Interleukin-28B: Production and Characterization of Its Biological Activities and Protein Stability. PLoS ONE 2013, 8, e64301. [Google Scholar] [CrossRef]
- Momin, N.; Mehta, N.K.; Bennett, N.R.; Ma, L.; Palmeri, J.R.; Chinn, M.M.; Lutz, E.A.; Kang, B.; Irvine, D.J.; Spranger, S.; et al. Anchoring of Intratumorally Administered Cytokines to Collagen Safely Potentiates Systemic Cancer Immunotherapy. Sci. Transl. Med. 2019, 11, eaaw2614. [Google Scholar] [CrossRef]
- Chen, B.; Mu, C.; Zhang, Z.; He, X.; Liu, X. The Love-Hate Relationship Between TGF-β Signaling and the Immune System During Development and Tumorigenesis. Front. Immunol. 2022, 13. [Google Scholar] [CrossRef]
- Kwaśniak, K.; Czarnik-Kwaśniak, J.; Maziarz, A.; Aebisher, D.; Zielińska, K.; Karczmarek-Borowska, B.; Tabarkiewicz, J. Scientific Reports Concerning the Impact of Interleukin 4, Interleukin 10 and Transforming Growth Factor β on Cancer Cells. Cent. Eur. J. Immunol. 2019, 44, 190–200. [Google Scholar] [CrossRef]
- Gout, D.Y.; Groen, L.S.; van Egmond, M. The Present and Future of Immunocytokines for Cancer Treatment. Cell. Mol. Life Sci. 2022, 79, 509. [Google Scholar] [CrossRef]
- Lyu, M.-A.; Kurzrock, R.; Rosenblum, M.G. The Immunocytokine scFv23/TNF Targeting HER-2/Neu Induces Synergistic Cytotoxic Effects with 5-Fluorouracil in TNF-Resistant Pancreatic Cancer Cell Lines. Biochem. Pharmacol. 2008, 75, 836–846. [Google Scholar] [CrossRef]
- Menssen, H.D.; Harnack, U.; Erben, U.; Neri, D.; Hirsch, B.; Dürkop, H. Antibody-Based Delivery of Tumor Necrosis Factor (L19-TNFα) and Interleukin-2 (L19-IL2) to Tumor-Associated Blood Vessels Has Potent Immunological and Anticancer Activity in the Syngeneic J558L BALB/c Myeloma Model. J. Cancer Res. Clin. Oncol. 2018, 144, 499–507. [Google Scholar] [CrossRef]
- Schwager, K.; Hemmerle, T.; Aebischer, D.; Neri, D. The Immunocytokine L19–IL2 Eradicates Cancer When Used in Combination with CTLA-4 Blockade or with L19-TNF. J. Investig. Dermatol. 2013, 133, 751–758. [Google Scholar] [CrossRef]
- Villa, A.; Ongaro, T. Il2 Immunoconjugates. EP3660039A1, 3 June 2020. Available online: https://patents.google.com/patent/EP3660039A1/en (accessed on 20 September 2023).
- Kontermann, R.E. Antibody–Cytokine Fusion Proteins. Arch. Biochem. Biophys. 2012, 526, 194–205. [Google Scholar] [CrossRef]
- Murer, P.; Neri, D. Antibody-Cytokine Fusion Proteins: A Novel Class of Biopharmaceuticals for the Therapy of Cancer and of Chronic Inflammation. New Biotechnol. 2019, 52, 42–53. [Google Scholar] [CrossRef]
- Ghetie, V.; Popov, S.; Borvak, J.; Radu, C.; Matesoi, D.; Medesan, C.; Ober, R.J.; Ward, E.S. Increasing the Serum Persistence of an IgG Fragment by Random Mutagenesis. Nat. Biotechnol. 1997, 15, 637–640. [Google Scholar] [CrossRef]
- Siegemund, M.; Seifert, O.; Zarani, M.; Džinić, T.; De Leo, V.; Göttsch, D.; Münkel, S.; Hutt, M.; Pfizenmaier, K.; Kontermann, R.E. An Optimized Antibody-Single-Chain TRAIL Fusion Protein for Cancer Therapy. MAbs 2016, 8, 879–891. [Google Scholar] [CrossRef]
- Bachmann, M.F.; Oxenius, A. Interleukin 2: From Immunostimulation to Immunoregulation and Back Again. EMBO Rep. 2007, 8, 1142–1148. [Google Scholar] [CrossRef] [PubMed]
- Gillis, S.; Baker, P.E.; Ruscetti, F.W.; Smith, K.A. Long-Term Culture of Human Antigen-Specific Cytotoxic T-Cell Lines. J. Exp. Med. 1978, 148, 1093–1098. [Google Scholar] [CrossRef] [PubMed]
- Gillis, S.; Smith, K.A. Long Term Culture of Tumour-Specific Cytotoxic T Cells. Nature 1977, 268, 154–156. [Google Scholar] [CrossRef] [PubMed]
- Morgan, D.A.; Ruscetti, F.W.; Gallo, R. Selective In Vitro Growth of T Lymphocytes from Normal Human Bone Marrows. Science 1976, 193, 1007–1008. [Google Scholar] [CrossRef] [PubMed]
- Orozco Valencia, A.; Camargo Knirsch, M.; Suavinho Ferro, E.; Antonio Stephano, M. Interleukin-2 as Immunotherapeutic in the Autoimmune Diseases. Int. Immunopharmacol. 2020, 81, 106296. [Google Scholar] [CrossRef] [PubMed]
- Siegel, J.P.; Sharon, M.; Smith, P.L.; Leonard, W.J. The IL-2 Receptor Beta Chain (P70): Role in Mediating Signals for LAK, NK, and Proliferative Activities. Science 1987, 238, 75–78. [Google Scholar] [CrossRef] [PubMed]
- Atkins, M.B.; Lotze, M.T.; Dutcher, J.P.; Fisher, R.I.; Weiss, G.; Margolin, K.; Abrams, J.; Sznol, M.; Parkinson, D.; Hawkins, M.; et al. High-Dose Recombinant Interleukin 2 Therapy for Patients with Metastatic Melanoma: Analysis of 270 Patients Treated between 1985 and 1993. J. Clin. Oncol. 1999, 17, 2105–2116. [Google Scholar] [CrossRef] [PubMed]
- Klapper, J.A.; Downey, S.G.; Smith, F.O.; Yang, J.C.; Hughes, M.S.; Kammula, U.S.; Sherry, R.M.; Royal, R.E.; Steinberg, S.M.; Rosenberg, S. High-Dose Interleukin-2 for the Treatment of Metastatic Renal Cell Carcinoma: A Retrospective Analysis of Response and Survival in Patients Treated in the Surgery Branch at the National Cancer Institute between 1986 and 2006. Cancer 2008, 113, 293–301. [Google Scholar] [CrossRef] [PubMed]
- Rosenberg, S.A. IL-2: The First Effective Immunotherapy for Human Cancer. J. Immunol. 2014, 192, 5451–5458. [Google Scholar] [CrossRef]
- Lotze, M.T.; Matory, Y.L.; Ettinghausen, S.E.; Rayner, A.A.; Sharrow, S.O.; Seipp, C.A.; Custer, M.C.; Rosenberg, S.A. In Vivo Administration of Purified Human Interleukin 2. II. Half Life, Immunologic Effects, and Expansion of Peripheral Lymphoid Cells In Vivo with Recombinant IL 2. J. Immunol. 1985, 135, 2865–2875. [Google Scholar] [CrossRef]
- Baldo, B.A. Side Effects of Cytokines Approved for Therapy. Drug Saf. 2014, 37, 921–943. [Google Scholar] [CrossRef] [PubMed]
- Xiang, R.; Lode, H.N.; Dolman, C.S.; Dreier, T.; Varki, N.M.; Qian, X.; Lo, K.M.; Lan, Y.; Super, M.; Gillies, S.D.; et al. Elimination of Established Murine Colon Carcinoma Metastases by Antibody-Interleukin 2 Fusion Protein Therapy. Cancer Res. 1997, 57, 4948–4955. [Google Scholar] [PubMed]
- Harvill, E.T.; Morrison, S.L. An IgG3-IL2 Fusion Protein Activates Complement, Binds Fc Gamma RI, Generates LAK Activity and Shows Enhanced Binding to the High Affinity IL-2R. Immunotechnology 1995, 1, 95–105. [Google Scholar] [CrossRef] [PubMed]
- Sabzevari, H.; Gillies, S.D.; Mueller, B.M.; Pancook, J.D.; Reisfeld, R.A. A Recombinant Antibody-Interleukin 2 Fusion Protein Suppresses Growth of Hepatic Human Neuroblastoma Metastases in Severe Combined Immunodeficiency Mice. Proc. Natl. Acad. Sci. USA 1994, 91, 9626–9630. [Google Scholar] [CrossRef] [PubMed]
- Pancook, J.D.; Becker, J.C.; Gillies, S.D.; Reisfeld, R.A. Eradication of Established Hepatic Human Neuroblastoma Metastases in Mice with Severe Combined Immunodeficiency by Antibody-Targeted Interleukin-2. Cancer Immunol. Immunother. 1996, 42, 88–92. [Google Scholar] [CrossRef] [PubMed]
- Becker, J.C.; Pancook, J.D.; Gillies, S.D.; Furukawa, K.; Reisfeld, R.A. T Cell-Mediated Eradication of Murine Metastatic Melanoma Induced by Targeted Interleukin 2 Therapy. J. Exp. Med. 1996, 183, 2361–2366. [Google Scholar] [CrossRef] [PubMed]
- Munn, D.H.; Cheung, N.K. Interleukin-2 Enhancement of Monoclonal Antibody-Mediated Cellular Cytotoxicity against Human Melanoma. Cancer Res. 1987, 47 Pt 1, 6600–6605. [Google Scholar] [PubMed]
- Children’s Oncology Group. A Phase II Study of Hu14.18-IL2 in Children with Recurrent or Refractory Neuroblastoma; Clinical Trial Registration NCT00082758; clinicaltrials.gov; Children’s Oncology Group: Monrovia, CA, USA, 2015. Available online: https://clinicaltrials.gov/ct2/show/NCT00082758 (accessed on 23 March 2023).
- University of Wisconsin, Madison. A Pilot Trial of HU14.18-IL2 (EMD273063) in Subjects with Completely Resectable Recurrent Stage III or Stage IV Melanoma; Clinical Trial Registration NCT00590824; clinicaltrials.gov; University of Wisconsin, Madison: Madison, WI, USA, 2019. Available online: https://clinicaltrials.gov/ct2/show/NCT00590824 (accessed on 23 March 2023).
- Children’s Oncology Group. Feasibility/Phase II Study of Hu14.18-IL2 Immunocytokine + GM-CSF and Isotretinoin in Patients with Relapsed or Refractory Neuroblastoma; Clinical Trial Registration NCT01334515; clinicaltrials.gov; Children’s Oncology Group: Monrovia, CA, USA, 2019. Available online: https://clinicaltrials.gov/ct2/show/NCT01334515 (accessed on 23 March 2023).
- University of Wisconsin, Madison. Phase II Trial of Hu14.18-IL2 (EMD 273063) in Subjects with Advanced Melanoma; Clinical Trial Registration NCT00109863; clinicaltrials.gov; University of Wisconsin, Madison: Madison, WI, USA, 2019. Available online: https://clinicaltrials.gov/ct2/show/NCT00109863 (accessed on 23 March 2023).
- King, D.M.; Albertini, M.R.; Schalch, H.; Hank, J.A.; Gan, J.; Surfus, J.; Mahvi, D.; Schiller, J.H.; Warner, T.; Kim, K.; et al. Phase I Clinical Trial of the Immunocytokine EMD 273063 in Melanoma Patients. JCO 2004, 22, 4463–4473. [Google Scholar] [CrossRef] [PubMed]
- Yang, R.K.; Kuznetsov, I.B.; Ranheim, E.A.; Wei, J.S.; Sindiri, S.; Gryder, B.E.; Gangalapudi, V.; Song, Y.K.; Patel, V.; Hank, J.A.; et al. Outcome-Related Signatures Identified by Whole Transcriptome Sequencing of Resectable Stage III/IV Melanoma Evaluated after Starting Hu14.18-IL2. Clin. Cancer Res. 2020, 26, 3296–3306. [Google Scholar] [CrossRef]
- Gillies, S.D. A New Platform for Constructing Antibody-Cytokine Fusion Proteins (Immunocytokines) with Improved Biological Properties and Adaptable Cytokine Activity. Protein Eng. Des. Sel. 2013, 26, 561–569. [Google Scholar] [CrossRef]
- Friedberg, J.W.; Neuberg, D.; Gribben, J.G.; Fisher, D.C.; and Koval, M.; Poor, C.M.; Green, L.M.; Daley, J.; Soiffer, R.; Ritz, J.; et al. Combination Immunotherapy with Rituximab and Interleukin 2 in Patients with Relapsed or Refractory Follicular Non-Hodgkin’s Lymphoma. Br. J. Haematol. 2002, 117, 828–834. [Google Scholar] [CrossRef]
- Gluck, W.L.; Hurst, D.; Yuen, A.; Levine, A.M.; Dayton, M.A.; Gockerman, J.P.; Lucas, J.; Denis-Mize, K.; Tong, B.; Navis, D.; et al. Phase I Studies of Interleukin (IL)-2 and Rituximab in B-Cell Non-Hodgkin’s Lymphoma: IL-2 Mediated Natural Killer Cell Expansion Correlations with Clinical Response. Clin. Cancer Res. 2004, 10, 2253–2264. [Google Scholar] [CrossRef]
- Gillies, S.D.; Lan, Y.; Williams, S.; Carr, F.; Forman, S.; Raubitschek, A.; Lo, K.-M. An Anti-CD20-IL-2 Immunocytokine Is Highly Efficacious in a SCID Mouse Model of Established Human B Lymphoma. Blood 2005, 105, 3972–3978. [Google Scholar] [CrossRef]
- Bachanova, V.; Lansigan, F.; Quick, D.P.; Vlock, D.; Gillies, S.; Nakamura, R. Remission Induction in a Phase I/II Study of an Anti-CD20-Interleukin-2 Immunocytokine DI-Leu16-IL2 in Patients with Relapsed B-Cell Lymphoma. Blood 2015, 126, 1533. [Google Scholar] [CrossRef]
- Lansigan, F.; Nakamura, R.; Quick, D.; Vlock, D.; Raubitschek, A.; Gillies, S.; Bachanova, V. DI-Leu16-IL2, an Anti-CD20-Interleukin-2 Immunocytokine, Is Safe and Active in Patients with Relapsed and Refractory B-Cell Lymphoma: A Report of Maximum Tolerated Dose, Optimal Biologic Dose, and Recommended Phase 2 Dose. Blood 2016, 128, 620. [Google Scholar] [CrossRef]
- Holden, S.A.; Lan, Y.; Pardo, A.M.; Wesolowski, J.S.; Gillies, S.D. Augmentation of Antitumor Activity of an Antibody-Interleukin 2 Immunocytokine with Chemotherapeutic Agents. Clin. Cancer Res. 2001, 7, 2862–2869. [Google Scholar]
- EMD Serono. Phase I Dose-Escalation Study of the Pharmacokinetic, Safety, Tolerability, and Biologic Activity of huKS-IL-2 Administered Daily as a 1-Hour Intravenous Infusion for Five Consecutive Days for Treatment of Refractory Epithelial Cancer; Clinical Trial Registration NCT00016237; clinicaltrials.gov; EMD Serono: Rockland, MA, USA, 2013. Available online: https://clinicaltrials.gov/ct2/show/NCT00016237 (accessed on 23 March 2023).
- EMD Serono. A Study to Find the Highest Dose of Biological Study Drug (EMD 273066) That Can Be Given Safely to Patients with Recurrent EpCAM Positive Ovarian, Prostate, Colorectal or Non-Small Cell Lung Cancers When First Given a Low Dose of Cyclophosphamide; Clinical Trial Registration NCT00132522; clinicaltrials.gov; EMD Serono: Rockland, MA, USA, 2013. Available online: https://clinicaltrials.gov/ct2/show/NCT00132522 (accessed on 23 March 2023).
- Connor, J.P.; Cristea, M.C.; Lewis, N.L.; Lewis, L.D.; Komarnitsky, P.B.; Mattiacci, M.R.; Felder, M.; Stewart, S.; Harter, J.; Henslee-Downey, J.; et al. A Phase 1b Study of Humanized KS-Interleukin-2 (huKS-IL2) Immunocytokine with Cyclophosphamide in Patients with EpCAM-Positive Advanced Solid Tumors. BMC Cancer 2013, 13, 20. [Google Scholar] [CrossRef]
- Ko, Y.-J.; Bubley, G.J.; Weber, R.; Redfern, C.; Gold, D.P.; Finke, L.; Kovar, A.; Dahl, T.; Gillies, S.D. Safety, Pharmacokinetics, and Biological Pharmacodynamics of the Immunocytokine EMD 273066 (huKS-IL2): Results of a Phase I Trial in Patients with Prostate Cancer. J. Immunother. 2004, 27, 232. [Google Scholar] [CrossRef]
- Gladkov, O.; Ramlau, R.; Serwatowski, P.; Milanowski, J.; Tomeczko, J.; Komarnitsky, P.B.; Kramer, D.; Krzakowski, M.J. Cyclophosphamide and Tucotuzumab (huKS-IL2) Following First-Line Chemotherapy in Responding Patients with Extensive-Disease Small-Cell Lung Cancer. Anticancer Drugs 2015, 26, 1061–1068. [Google Scholar] [CrossRef]
- Ran, S.; He, J.; Huang, X.; Soares, M.; Scothorn, D.; Thorpe, P.E. Antitumor Effects of a Monoclonal Antibody That Binds Anionic Phospholipids on the Surface of Tumor Blood Vessels in Mice. Clin. Cancer Res. 2005, 11, 1551–1562. [Google Scholar] [CrossRef]
- Huang, X.; Ye, D.; Thorpe, P.E. Enhancing the Potency of a Whole-Cell Breast Cancer Vaccine in Mice with an Antibody-IL-2 Immunocytokine That Targets Exposed Phosphatidylserine. Vaccine 2011, 29, 4785–4793. [Google Scholar] [CrossRef]
- Duffy, M.J. Carcinoembryonic Antigen as a Marker for Colorectal Cancer: Is It Clinically Useful? Clin. Chem. 2001, 47, 624–630. [Google Scholar] [CrossRef]
- Goldstein, M.J.; Mitchell, E.P. Carcinoembryonic Antigen in the Staging and Follow-up of Patients with Colorectal Cancer. Cancer Investig. 2005, 23, 338–351. [Google Scholar] [CrossRef]
- Lee, J.S.; Park, S.; Park, J.M.; Cho, J.H.; Kim, S.I.; Park, B.-W. Elevated Levels of Preoperative CA 15-3 and CEA Serum Levels Have Independently Poor Prognostic Significance in Breast Cancer. Ann. Oncol. 2013, 24, 1225–1231. [Google Scholar] [CrossRef]
- Shao, Y.; Sun, X.; He, Y.; Liu, C.; Liu, H. Elevated Levels of Serum Tumor Markers CEA and CA15-3 Are Prognostic Parameters for Different Molecular Subtypes of Breast Cancer. PLoS ONE 2015, 10, e0133830. [Google Scholar] [CrossRef]
- Williams, L.; Li, L.; Yazaki, P.J.; Wong, P.; Hong, T.; Poku, E.K.; Hui, S.; Ghimire, H.; Shively, J.E.; Kujawski, M. Comparison of IL-2-Antibody to IL-2-Fc with or without Stereotactic Radiation Therapy in CEA Immunocompetent Mice with CEA Positive Tumors. Cancer Med. 2024, 13, e6909. [Google Scholar] [CrossRef]
- Vazquez-Lombardi, R.; Loetsch, C.; Zinkl, D.; Jackson, J.; Schofield, P.; Deenick, E.K.; King, C.; Phan, T.G.; Webster, K.E.; Sprent, J.; et al. Potent Antitumour Activity of Interleukin-2-Fc Fusion Proteins Requires Fc-Mediated Depletion of Regulatory T-Cells. Nat. Commun. 2017, 8, 15373. [Google Scholar] [CrossRef]
- Williams, L.; Li, L.; Yazaki, P.J.; Wong, P.; Miller, A.; Hong, T.; Poku, E.K.; Bhattacharya, S.; Shively, J.E.; Kujawski, M. Generation of IL-2-Fc-Antibody Conjugates by Click Chemistry. Biotechnol. J. 2023, 18, 2300115. [Google Scholar] [CrossRef]
- Chang, S.S. Overview of Prostate-Specific Membrane Antigen. Rev. Urol. 2004, 6 (Suppl. S10), S13–S18. [Google Scholar]
- Sugimoto, Y.; Hirota, M.; Yoshikawa, K.; Sumitomo, M.; Nakamura, K.; Ueda, R.; Niwa, R.; Suzawa, T.; Yamasaki, M.; Shitara, K.; et al. The Therapeutic Potential of a Novel PSMA Antibody and Its IL-2 Conjugate in Prostate Cancer. Anticancer Res. 2014, 34, 89–97. [Google Scholar]
- Penichet, M.L.; Dela Cruz, J.S.; Shin, S.-U.; Morrison, S.L. A Recombinant IgG3-(IL-2) Fusion Protein for the Treatment of Human HER2/Neu Expressing Tumors. HAB 2001, 10, 43–49. [Google Scholar] [CrossRef]
- Shusterman, S.; London, W.B.; Gillies, S.D.; Hank, J.A.; Voss, S.D.; Seeger, R.C.; Reynolds, C.P.; Kimball, J.; Albertini, M.R.; Wagner, B.; et al. Antitumor Activity of Hu14.18-IL2 in Patients with Relapsed/Refractory Neuroblastoma: A Children’s Oncology Group (COG) Phase II Study. JCO 2010, 28, 4969–4975. [Google Scholar] [CrossRef]
- Albertini, M.R.; Yang, R.K.; Ranheim, E.A.; Hank, J.A.; Zuleger, C.L.; Weber, S.; Neuman, H.; Hartig, G.; Weigel, T.; Mahvi, D.; et al. Pilot Trial of the Hu14.18-IL2 Immunocytokine in Patients with Completely Resectable Recurrent Stage III or Stage IV Melanoma. Cancer Immunol. Immunother. 2018, 67, 1647–1658. [Google Scholar] [CrossRef]
- Albertini, M.R.; Hank, J.A.; Gadbaw, B.; Kostlevy, J.; Haldeman, J.; Schalch, H.; Gan, J.; Kim, K.; Eickhoff, J.; Gillies, S.D.; et al. Phase II Trial of Hu14.18-IL2 for Patients with Metastatic Melanoma. Cancer Immunol. Immunother. 2012, 61, 2261–2271. [Google Scholar] [CrossRef]
- Epstein, A.L.; Mizokami, M.M.; Li, J.; Hu, P.; Khawli, L.A. Identification of a Protein Fragment of Interleukin 2 Responsible for Vasopermeability. JNCI J. Natl. Cancer Inst. 2003, 95, 741–749. [Google Scholar] [CrossRef] [PubMed]
- Shanafelt, A.B.; Lin, Y.; Shanafelt, M.-C.; Forte, C.P.; Dubois-Stringfellow, N.; Carter, C.; Gibbons, J.A.; Cheng, S.; Delaria, K.A.; Fleischer, R.; et al. A T-Cell-Selective Interleukin 2 Mutein Exhibits Potent Antitumor Activity and Is Well Tolerated In Vivo. Nat. Biotechnol. 2000, 18, 1197–1202. [Google Scholar] [CrossRef]
- Gillies, S.D.; Lan, Y.; Hettmann, T.; Brunkhorst, B.; Sun, Y.; Mueller, S.O.; Lo, K.-M. A Low-Toxicity IL-2-Based Immunocytokine Retains Antitumor Activity despite Its High Degree of IL-2 Receptor Selectivity. Clin. Cancer Res. 2011, 17, 3673–3685. [Google Scholar] [CrossRef]
- Laurent, J.; Touvrey, C.; Gillessen, S.; Joffraud, M.; Vicari, M.; Bertrand, C.; Ongarello, S.; Liedert, B.; Gallerani, E.; Beck, J.; et al. T-Cell Activation by Treatment of Cancer Patients with EMD 521873 (Selectikine), an IL-2/Anti-DNA Fusion Protein. J. Transl. Med. 2013, 11, 5. [Google Scholar] [CrossRef]
- EMD Serono. A Safety Study for MSB0010445 in Combination with Stereotactic Body Radiation in Advanced Melanoma Subjects Following Prior Treatment with Ipilimumab; Clinical Trial Registration NCT01973608; clinicaltrials.gov; EMD Serono: Rockland, MA, USA, 2016. Available online: https://clinicaltrials.gov/ct2/show/NCT01973608 (accessed on 23 March 2023).
- Merck KGaA. A Phase 1, Open-Label, Two-Group, Dose- Escalation Study to Investigate the Safety, Tolerability, Pharmacokinetics, Biological and Clinical Activity of EMD 521873 Alone and in Combination with Fixed Low Doses of Cyclophosphamide in Patients with Metastatic or Locally Advanced Solid Tumors or B-Cell Non-Hodgkin Lymphoma; Clinical Trial Registration NCT01032681; clinicaltrials.gov; Merck KGaA: Darmstadt, Germany, 2014. Available online: https://clinicaltrials.gov/ct2/show/NCT01032681 (accessed on 23 March 2023).
- Merck KGaA. An Open-Label, Phase Ib, Dose-Escalation Trial on the Safety, Tolerability, Pharmacokinetics, Immunogenicity, Biological Effects and Antitumor Activity of EMD 521873 in Combination With Local Irradiation (20 Gy) of Primary Tumors or Metastases in Subjects with Non-Small Cell Lung Cancer Stage IIIb with Malignant Pleural Effusion or Stage IV with Disease Control (Partial Response or Stable Disease) after Application of 4 Cycles of Platinum-Based, First-Line Chemotherapy; Clinical Trial Registration NCT00879866; clinicaltrials.gov; Merck KGaA: Darmstadt, Germany, 2014. Available online: https://clinicaltrials.gov/ct2/show/NCT00879866 (accessed on 23 March 2023).
- Sun, Z.; Ren, Z.; Yang, K.; Liu, Z.; Cao, S.; Deng, S.; Xu, L.; Liang, Y.; Guo, J.; Bian, Y.; et al. A Next-Generation Tumor-Targeting IL-2 Preferentially Promotes Tumor-Infiltrating CD8+ T-Cell Response and Effective Tumor Control. Nat. Commun. 2019, 10, 3874. [Google Scholar] [CrossRef]
- Spolski, R.; Li, P.; Leonard, W.J. Biology and Regulation of IL-2: From Molecular Mechanisms to Human Therapy. Nat. Rev. Immunol. 2018, 18, 648–659. [Google Scholar] [CrossRef]
- Levin, A.M.; Bates, D.L.; Ring, A.M.; Krieg, C.; Lin, J.T.; Su, L.; Moraga, I.; Raeber, M.E.; Bowman, G.R.; Novick, P.; et al. Exploiting a Natural Conformational Switch to Engineer an Interleukin-2 ‘Superkine’. Nature 2012, 484, 529–533. [Google Scholar] [CrossRef]
- Klein, C.; Waldhauer, I.; Nicolini, V.; Dunn, C.; Freimoser-Grundschober, A.; Danny, G.; Boerman, O.; Nayak, T.; Herter, S.; Van Puijenbroek, E.; et al. Novel Tumor-Targeted, Engineered IL-2 Variant (IL2v)-Based Immunocytokines for Immunotherapy of Cancer. Blood 2013, 122, 2278. [Google Scholar] [CrossRef]
- Chen, X.; Ai, X.; Wu, C.; Wang, H.; Zeng, G.; Yang, P.; Liu, G. A Novel Human IL-2 Mutein with Minimal Systemic Toxicity Exerts Greater Antitumor Efficacy than Wild-Type IL-2. Cell Death Dis. 2018, 9, 989. [Google Scholar] [CrossRef]
- Tichet, M.; Wullschleger, S.; Chryplewicz, A.; Fournier, N.; Marcone, R.; Kauzlaric, A.; Homicsko, K.; Deak, L.C.; Umaña, P.; Klein, C.; et al. Bispecific PD1-IL2v and Anti-PD-L1 Break Tumor Immunity Resistance by Enhancing Stem-like Tumor-Reactive CD8+ T Cells and Reprogramming Macrophages. Immunity 2023, 56, 162–179.e6. [Google Scholar] [CrossRef]
- Klein, C.; Waldhauer, I.; Nicolini, V.G.; Freimoser-Grundschober, A.; Nayak, T.; Vugts, D.J.; Dunn, C.; Bolijn, M.; Benz, J.; Stihle, M.; et al. Cergutuzumab Amunaleukin (CEA-IL2v), a CEA-Targeted IL-2 Variant-Based Immunocytokine for Combination Cancer Immunotherapy: Overcoming Limitations of Aldesleukin and Conventional IL-2-Based Immunocytokines. OncoImmunology 2017, 6, e1277306. [Google Scholar] [CrossRef]
- Kuo, T.T.; Aveson, V.G. Neonatal Fc Receptor and IgG-Based Therapeutics. mAbs 2011, 3, 422–430. [Google Scholar] [CrossRef]
- Waldhauer, I.; Gonzalez-Nicolini, V.; Freimoser-Grundschober, A.; Nayak, T.K.; Fahrni, L.; Hosse, R.J.; Gerrits, D.; Geven, E.J.W.; Sam, J.; Lang, S.; et al. Simlukafusp Alfa (FAP-IL2v) Immunocytokine Is a Versatile Combination Partner for Cancer Immunotherapy. mAbs 2021, 13, 1913791. [Google Scholar] [CrossRef]
- Doroshow, D.B.; Bhalla, S.; Beasley, M.B.; Sholl, L.M.; Kerr, K.M.; Gnjatic, S.; Wistuba, I.I.; Rimm, D.L.; Tsao, M.S.; Hirsch, F.R. PD-L1 as a Biomarker of Response to Immune-Checkpoint Inhibitors. Nat. Rev. Clin. Oncol. 2021, 18, 345–362. [Google Scholar] [CrossRef]
- Wu, W.; Chia, T.; Lu, J.; Li, X.; Guan, J.; Li, Y.; Fu, F.; Zhou, S.; Feng, Y.; Deng, J.; et al. IL-2Rα-Biased Agonist Enhances Antitumor Immunity by Invigorating Tumor-Infiltrating CD25+CD8+ T Cells. Nat. Cancer 2023, 4, 1309–1325. [Google Scholar] [CrossRef]
- Weide, B.; Eigentler, T.; Catania, C.; Ascierto, P.A.; Cascinu, S.; Becker, J.C.; Hauschild, A.; Romanini, A.; Danielli, R.; Dummer, R.; et al. A Phase II Study of the L19IL2 Immunocytokine in Combination with Dacarbazine in Advanced Metastatic Melanoma Patients. Cancer Immunol. Immunother. 2019, 68, 1547–1559. [Google Scholar] [CrossRef]
- Catania, C.; Maur, M.; Berardi, R.; Rocca, A.; Giacomo, A.M.D.; Spitaleri, G.; Masini, C.; Pierantoni, C.; González-Iglesias, R.; Zigon, G.; et al. The Tumor-Targeting Immunocytokine F16-IL2 in Combination with Doxorubicin: Dose Escalation in Patients with Advanced Solid Tumors and Expansion into Patients with Metastatic Breast Cancer. Cell Adh. Migr. 2015, 9, 14–21. [Google Scholar] [CrossRef]
- Schliemann, C.; Gutbrodt, K.L.; Kerkhoff, A.; Pohlen, M.; Wiebe, S.; Silling, G.; Angenendt, L.; Kessler, T.; Mesters, R.M.; Giovannoni, L.; et al. Targeting Interleukin-2 to the Bone Marrow Stroma for Therapy of Acute Myeloid Leukemia Relapsing after Allogeneic Hematopoietic Stem Cell Transplantation. Cancer Immunol. Res. 2015, 3, 547–556. [Google Scholar] [CrossRef]
- Wen, J.; Zhu, X.; Liu, B.; You, L.; Kong, L.; Lee, H.; Han, K.; Wong, J.L.; Rhode, P.R.; Wong, H.C. Targeting Activity of a TCR/IL-2 Fusion Protein against Established Tumors. Cancer Immunol. Immunother. 2008, 57, 1781–1794. [Google Scholar] [CrossRef]
- Card, K.F.; Price-Schiavi, S.A.; Liu, B.; Thomson, E.; Nieves, E.; Belmont, H.; Builes, J.; Jiao, J.; Hernandez, J.; Weidanz, J.; et al. A Soluble Single-Chain T-Cell Receptor IL-2 Fusion Protein Retains MHC-Restricted Peptide Specificity and IL-2 Bioactivity. Cancer Immunol. Immunother. 2004, 53, 345–357. [Google Scholar] [CrossRef]
- Syn, N.L.; Teng, M.W.L.; Mok, T.S.K.; Soo, R.A. De-Novo and Acquired Resistance to Immune Checkpoint Targeting. Lancet Oncol. 2017, 18, e731–e741. [Google Scholar] [CrossRef]
- Pyo, K.-H.; Koh, Y.J.; Synn, C.-B.; Kim, J.H.; Byeon, Y.; Jo, H.N.; Kim, Y.S.; Lee, W.; Kim, D.H.; Lee, S.; et al. Abstract 1826: Comprehensive Preclinical Study on GI-101, a Novel CD80-IgG4-IL2 Variant Protein, as a Therapeutic Antibody Candidate with Bispecific Immuno-Oncology Target. Cancer Res. 2021, 81 (Suppl. S13), 1826. [Google Scholar] [CrossRef]
- Yamaguchi, T.; Chang, C.J.; Karger, A.; Keller, M.; Pfaff, F.; Wangkahart, E.; Wang, T.; Secombes, C.J.; Kimoto, A.; Furihata, M.; et al. Ancient Cytokine Interleukin 15-Like (IL-15L) Induces a Type 2 Immune Response. Front. Immunol. 2020, 11, 549319. [Google Scholar] [CrossRef]
- Waldmann, T.A. The Shared and Contrasting Roles of IL2 and IL15 in the Life and Death of Normal and Neoplastic Lymphocytes: Implications for Cancer Therapy. Cancer Immunol. Res. 2015, 3, 219–227. [Google Scholar] [CrossRef]
- Conlon, K.C.; Lugli, E.; Welles, H.C.; Rosenberg, S.A.; Fojo, A.T.; Morris, J.C.; Fleisher, T.A.; Dubois, S.P.; Perera, L.P.; Stewart, D.M.; 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, 74–82. [Google Scholar] [CrossRef]
- Berger, C.; Berger, M.; Hackman, R.C.; Gough, M.; Elliott, C.; Jensen, M.C.; Riddell, S.R. Safety and Immunologic Effects of IL-15 Administration in Nonhuman Primates. Blood 2009, 114, 2417–2426. [Google Scholar] [CrossRef]
- Conlon, K.C.; Potter, E.L.; Pittaluga, S.; Lee, C.-C.R.; Miljkovic, M.D.; Fleisher, T.A.; Dubois, S.; Bryant, B.R.; Petrus, M.; Perera, L.P.; et al. IL15 by Continuous Intravenous Infusion to Adult Patients with Solid Tumors in a Phase I Trial Induced Dramatic NK-Cell Subset Expansion. Clin. Cancer Res. 2019, 25, 4945–4954. [Google Scholar] [CrossRef] [PubMed]
- Waldmann, T.A.; Lugli, E.; Roederer, M.; Perera, L.P.; Smedley, J.V.; Macallister, R.P.; Goldman, C.K.; Bryant, B.R.; Decker, J.M.; Fleisher, T.A.; et al. Safety (Toxicity), Pharmacokinetics, Immunogenicity, and Impact on Elements of the Normal Immune System of Recombinant Human IL-15 in Rhesus Macaques. Blood 2011, 117, 4787–4795. [Google Scholar] [CrossRef] [PubMed]
- Kermer, V.; Baum, V.; Hornig, N.; Kontermann, R.E.; Müller, D. An Antibody Fusion Protein for Cancer Immunotherapy Mimicking IL-15 Trans-Presentation at the Tumor Site. Mol. Cancer Ther. 2012, 11, 1279–1288. [Google Scholar] [CrossRef] [PubMed]
- Vincent, M.; Bessard, A.; Cochonneau, D.; Teppaz, G.; Solé, V.; Maillasson, M.; Birklé, S.; Garrigue-Antar, L.; Quéméner, A.; Jacques, Y. Tumor Targeting of the IL-15 Superagonist RLI by an Anti-GD2 Antibody Strongly Enhances Its Antitumor Potency. Int. J. Cancer 2013, 133, 757–765. [Google Scholar] [CrossRef] [PubMed]
- Nguyen, R.; Zhang, X.; Sun, M.; Abbas, S.; Seibert, C.; Kelly, M.C.; Shern, J.F.; Thiele, C.J. Anti-GD2 Antibodies Conjugated to IL15 and IL21 Mediate Potent Antitumor Cytotoxicity against Neuroblastoma. Clin. Cancer Res. 2022, 28, 3785–3796. [Google Scholar] [CrossRef] [PubMed]
- Kim, P.S.; Kwilas, A.R.; Xu, W.; Alter, S.; Jeng, E.K.; Wong, H.C.; Schlom, J.; Hodge, J.W. 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 2016, 7, 16130–16145. [Google Scholar] [CrossRef] [PubMed]
- Kotecki, N.; Rottey, S.; Delafontaine, B.; Garralda, E.; Galvao, V.; Miguel, M.d.; Saavedra, O.; Boni, V.; McEwen, A.; Singhal, S.; et al. 728 A Phase 1/2 Study of JK08, an IL-15 Antibody Fusion Protein Targeting CTLA-4, in Patients with Advanced Solid Tumors. J. Immunother. Cancer 2023, 11 (Suppl. S1), A823. [Google Scholar] [CrossRef]
- Martomo, S.A.; Lu, D.; Polonskaya, Z.; Luna, X.; Zhang, Z.; Feldstein, S.; Lumban-Tobing, R.; Almstead, D.K.; Miyara, F.; Patel, J. Single-Dose Anti–PD-L1/IL-15 Fusion Protein KD033 Generates Synergistic Antitumor Immunity with Robust Tumor-Immune Gene Signatures and Memory Responses. Mol. Cancer Ther. 2021, 20, 347–356. [Google Scholar] [CrossRef] [PubMed]
- Ledermann, J.A.; Zurawski, B.; Raspagliesi, F.; De Giorgi, U.; Arranz Arija, J.; Romeo Marin, M.; Lisyanskaya, A.; Póka, R.L.; Markowska, J.; Cebotaru, C.; et al. Maintenance Therapy of Patients with Recurrent Epithelial Ovarian Carcinoma with the Anti-Tumor-Associated-Mucin-1 Antibody Gatipotuzumab: Results from a Double-Blind, Placebo-Controlled, Randomized, Phase II Study. ESMO Open 2022, 7, 100311. [Google Scholar] [CrossRef] [PubMed]
- Gellert, J.; Jäkel, A.; Danielczyk, A.; Goletz, C.; Lischke, T.; Flechner, A.; Dix, L.; Günzl, A.; Kehler, P. GT-00AxIL15, a Novel Tumor-Targeted IL-15-Based Immunocytokine for the Treatment of TA-MUC1-Positive Solid Tumors: Preclinical In Vitro and In Vivo Pharmacodynamics and Biodistribution Studies. Int. J. Mol. Sci. 2024, 25, 1406. [Google Scholar] [CrossRef]
- Zhu, X.; Marcus, W.D.; Xu, W.; Lee, H.; Han, K.; Egan, J.O.; Yovandich, J.L.; Rhode, P.R.; Wong, H.C. Novel Human Interleukin-15 Agonists. J. Immunol. 2009, 183, 3598–3607. [Google Scholar] [CrossRef] [PubMed]
- Alter, S.; Rhode, P.R.; Jeng, E.K.; Wong, H.C. Targeted IL-15-Based Protein Fusion Complexes as Cancer Immunotherapy Approaches. J. Immunol. Sci. 2018, 2, 15–18. [Google Scholar] [CrossRef]
- Liu, B.; Kong, L.; Marcus, W.D.; Chen, X.; Han, K.; Rhode, P.R.; Wong, H.C. Evaluation of a Novel CD20-Targeted IL-15 Immunotherapeutic with Potent Activity against B Cell Lymphoma. J. Immunother. Cancer 2014, 2, P122. [Google Scholar] [CrossRef]
- Hicks, K.C.; Knudson, K.M.; Ozawa, Y.; Schlom, J.; Gameiro, S.R. 1222P—Evaluation of the Anti-Tumour Efficacy and Immune Effects of N-809, a Novel IL-15 Superagonist/Anti-PD-L1 Bispecific Agent. Ann. Oncol. 2019, 30, v500. [Google Scholar] [CrossRef]
- Xu, Y.; Carrascosa, L.C.; Yeung, Y.A.; Chu, M.L.-H.; Yang, W.; Djuretic, I.; Pappas, D.C.; Zeytounian, J.; Ge, Z.; de Ruiter, V.; et al. An Engineered IL15 Cytokine Mutein Fused to an Anti-PD1 Improves Intratumoral T-Cell Function and Antitumor Immunity. Cancer Immunol. Res. 2021, 9, 1141–1157. [Google Scholar] [CrossRef]
- Maruhashi, T.; Sugiura, D.; Okazaki, I.; Okazaki, T. LAG-3: From Molecular Functions to Clinical Applications. J. Immunother. Cancer 2020, 8, e001014. [Google Scholar] [CrossRef]
- Bernett, M.J.; Schubbert, S.; Hackett, M.; Ochyl, L.J.; Scott, L.E.; Bonzon, C.; Rashid, R.; Avery, K.N.; Leung, I.W.; Rodriguez, N.; et al. Abstract 2080: LAG3-Targeted IL15/IL15Rα-Fc (LAG3 x IL15) Fusion Proteins for Preferential TIL Expansion. Cancer Res. 2022, 82 (Suppl. S12), 2080. [Google Scholar] [CrossRef]
- Chung, K.Y.; Park, H.; Abdul-Karim, R.M.; Doroshow, D.B.; Chaves, J.; Coleman, T.A.; Nakai, K.; Patel, P.; Wang, J.; Zhang, H.; et al. Phase I Study of BJ-001, a Tumor-Targeting Interleukin-15 Fusion Protein, in Patients with Solid Tumor. JCO 2021, 39 (Suppl. S15), e14545. [Google Scholar] [CrossRef]
- Kermer, V.; Hornig, N.; Harder, M.; Bondarieva, A.; Kontermann, R.E.; Müller, D. Combining Antibody-Directed Presentation of IL-15 and 4-1BBL in a Trifunctional Fusion Protein for Cancer Immunotherapy. Mol. Cancer Ther. 2014, 13, 112–121. [Google Scholar] [CrossRef]
- Beha, N.; Harder, M.; Ring, S.; Kontermann, R.E.; Müller, D. IL15-Based Trifunctional Antibody-Fusion Proteins with Costimulatory TNF-Superfamily Ligands in the Single-Chain Format for Cancer Immunotherapy. Mol. Cancer Ther. 2019, 18, 1278–1288. [Google Scholar] [CrossRef]
- Kaspar, M.; Trachsel, E.; Neri, D. The Antibody-Mediated Targeted Delivery of Interleukin-15 and GM-CSF to the Tumor Neovasculature Inhibits Tumor Growth and Metastasis. Cancer Res. 2007, 67, 4940–4948. [Google Scholar] [CrossRef] [PubMed]
- Corbellari, R.; Stringhini, M.; Mock, J.; Ongaro, T.; Villa, A.; Neri, D.; De Luca, R. A Novel Antibody–IL15 Fusion Protein Selectively Localizes to Tumors, Synergizes with TNF-Based Immunocytokine, and Inhibits Metastasis. Mol. Cancer Ther. 2021, 20, 859–871. [Google Scholar] [CrossRef] [PubMed]
- Liu, H.; Wang, S.; Xin, J.; Wang, J.; Yao, C.; Zhang, Z. Role of NKG2D and Its Ligands in Cancer Immunotherapy. Am. J. Cancer Res. 2019, 9, 2064–2078. [Google Scholar] [PubMed]
- González, S.; López-Soto, A.; Xin, J.; Wang, J.; Yao, C.; Zhang, Z. NKG2D Ligands: Key Targets of the Immune Response. Trends Immunol. 2008, 29, 397–403. [Google Scholar] [CrossRef] [PubMed]
- Schmiedel, D.; Mandelboim, O. NKG2D Ligands–Critical Targets for Cancer Immune Escape and Therapy. Front. Immunol. 2018, 9, 2040. [Google Scholar] [CrossRef]
- Xia, Y.; Chen, B.; Shao, X.; Xiao, W.; Qian, L.; Ding, Y.; Ji, M.; Gong, W. Treatment with a Fusion Protein of the Extracellular Domains of NKG2D to IL-15 Retards Colon Cancer Growth in Mice. J. Immunother. 2014, 37, 257–266. [Google Scholar] [CrossRef] [PubMed]
- Liu, B.; Zhu, X.; Kong, L.; Wang, M.; Spanoudis, C.; Chaturvedi, P.; George, V.; Jiao, J.; You, L.; Egan, J.O.; et al. Bifunctional TGF-β Trap/IL-15 Protein Complex Elicits Potent NK Cell and CD8+ T Cell Immunity against Solid Tumors. Mol. Ther. 2021, 29, 2949–2962. [Google Scholar] [CrossRef]
- Chaturvedi, P.; George, V.; Shrestha, N.; Wang, M.; Dee, M.J.; Zhu, X.; Liu, B.; Egan, J.; D’Eramo, F.; Spanoudis, C.; et al. Immunotherapeutic HCW9218 Augments Anti-Tumor Activity of Chemotherapy via NK Cell-Mediated Reduction of Therapy-Induced Senescent Cells. Mol. Ther. 2022, 30, 1171–1187. [Google Scholar] [CrossRef] [PubMed]
- Shi, W.; Liu, N.; Liu, Z.; Yang, Y.; Zeng, Q.; Wang, Y.; Song, L.; Hu, F.; Fu, J.; Chen, J.; et al. Next-Generation Anti-PD-L1/IL-15 Immunocytokine Elicits Superior Antitumor Immunity in Cold Tumors with Minimal Toxicity. Cell Reports Medicine 2024, 5, 101531. [Google Scholar] [CrossRef]
- Matthews, N.; Watkins, J.F. Tumour-Necrosis Factor from the Rabbit. I. Mode of Action, Specificity and Physicochemical Properties. Br. J. Cancer 1978, 38, 302–309. [Google Scholar] [CrossRef]
- Green, S.; Dobrjansky, A.; Chiasson, M.A. Murine Tumor Necrosis-Inducing Factor: Purification and Effects on Myelomonocytic Leukemia Cells. J. Natl. Cancer Inst. 1982, 68, 997–1003. [Google Scholar] [PubMed]
- Kriegler, M.; Perez, C.; DeFay, K.; Albert, I.; Lu, S.D. A Novel Form of TNF/Cachectin Is a Cell Surface Cytotoxic Transmembrane Protein: Ramifications for the Complex Physiology of TNF. Cell 1988, 53, 45–53. [Google Scholar] [CrossRef] [PubMed]
- Black, R.A.; Rauch, C.T.; Kozlosky, C.J.; Peschon, J.J.; Slack, J.L.; Wolfson, M.F.; Castner, B.J.; Stocking, K.L.; Reddy, P.; Srinivasan, S.; et al. A Metalloproteinase Disintegrin That Releases Tumour-Necrosis Factor-Alpha from Cells. Nature 1997, 385, 729–733. [Google Scholar] [CrossRef] [PubMed]
- Wang, X.; Lin, Y. Tumor Necrosis Factor and Cancer, Buddies or Foes? Acta Pharmacol. Sin. 2008, 29, 1275–1288. [Google Scholar] [CrossRef] [PubMed]
- Gamm, H.; Lindemann, A.; Mertelsmann, R.; Herrmann, F. Phase I Trial of Recombinant Human Tumour Necrosis Factor Alpha in Patients with Advanced Malignancy. Eur. J. Cancer 1991, 27, 856–863. [Google Scholar] [CrossRef] [PubMed]
- Watanabe, N.; Niitsu, Y.; Umeno, H.; Kuriyama, H.; Neda, H.; Yamauchi, N.; Maeda, M.; Urushizaki, I. Toxic Effect of Tumor Necrosis Factor on Tumor Vasculature in Mice. Cancer Res. 1988, 48, 2179–2183. [Google Scholar] [PubMed]
- Rosenblum, M.G.; Cheung, L.; Mujoo, K.; Murray, J.L. An Antimelanoma Immunotoxin Containing Recombinant Human Tumor Necrosis Factor: Tissue Disposition, Pharmacokinetic, and Therapeutic Studies in Xenograft Models. Cancer Immunol. Immunother. 1995, 40, 322–328. [Google Scholar] [CrossRef] [PubMed]
- Rosenblum, M.G.; Cheung, L.; Murray, J.L.; Bartholomew, R. Antibody-Mediated Delivery of Tumor Necrosis Factor (TNF-Alpha): Improvement of Cytotoxicity and Reduction of Cellular Resistance. Cancer Commun. 1991, 3, 21–27. [Google Scholar] [PubMed]
- Fercher, C.; Keshvari, S.; McGuckin, M.A.; Barnard, R.T. Evolution of the Magic Bullet: Single Chain Antibody Fragments for the Targeted Delivery of Immunomodulatory Proteins. Exp. Biol. Med. 2018, 243, 166–183. [Google Scholar] [CrossRef]
- Dakhel, S.; Lizak, C.; Matasci, M.; Mock, J.; Villa, A.; Neri, D.; Cazzamalli, S. An Attenuated Targeted-TNF Localizes to Tumors In Vivo and Regains Activity at the Site of Disease. Int. J. Mol. Sci. 2021, 22, 10020. [Google Scholar] [CrossRef]
- Spitaleri, G.; Berardi, R.; Pierantoni, C.; De Pas, T.; Noberasco, C.; Libbra, C.; González-Iglesias, R.; Giovannoni, L.; Tasciotti, A.; Neri, D.; et al. Phase I/II Study of the Tumour-Targeting Human Monoclonal Antibody-Cytokine Fusion Protein L19-TNF in Patients with Advanced Solid Tumours. J. Cancer Res. Clin. Oncol. 2013, 139, 447–455. [Google Scholar] [CrossRef] [PubMed]
- Papadia, F.; Basso, V.; Patuzzo, R.; Maurichi, A.; Di Florio, A.; Zardi, L.; Ventura, E.; González-Iglesias, R.; Lovato, V.; Giovannoni, L.; et al. Isolated Limb Perfusion with the Tumor-Targeting Human Monoclonal Antibody–Cytokine Fusion Protein L19-TNF plus Melphalan and Mild Hyperthermia in Patients with Locally Advanced Extremity Melanoma. J. Surg. Oncol. 2013, 107, 173–179. [Google Scholar] [CrossRef] [PubMed]
- Danielli, R.; Patuzzo, R.; Di Giacomo, A.M.; Gallino, G.; Maurichi, A.; Di Florio, A.; Cutaia, O.; Lazzeri, A.; Fazio, C.; Miracco, C.; et al. Intralesional Administration of L19-IL2/L19-TNF in Stage III or Stage IVM1a Melanoma Patients: Results of a Phase II Study. Cancer Immunol. Immunother. 2015, 64, 999–1009. [Google Scholar] [CrossRef] [PubMed]
- Hemmerle, T.; Probst, P.; Giovannoni, L.; Green, A.J.; Meyer, T.; Neri, D. The Antibody-Based Targeted Delivery of TNF in Combination with Doxorubicin Eradicates Sarcomas in Mice and Confers Protective Immunity. Br. J. Cancer 2013, 109, 1206–1213. [Google Scholar] [CrossRef] [PubMed]
- Probst, P.; Kopp, J.; Oxenius, A.; Colombo, M.P.; Ritz, D.; Fugmann, T.; Neri, D. Sarcoma Eradication by Doxorubicin and Targeted TNF Relies upon CD8+ T Cell Recognition of a Retroviral Antigen. Cancer Res. 2017, 77, 3644–3654. [Google Scholar] [CrossRef] [PubMed]
- Pastorekova, S.; Gillies, R.J. The Role of Carbonic Anhydrase IX in Cancer Development: Links to Hypoxia, Acidosis, and Beyond. Cancer Metastasis Rev. 2019, 38, 65–77. [Google Scholar] [CrossRef]
- Bauer, S.; Oosterwijk-Wakka, J.C.; Adrian, N.; Oosterwijk, E.; Fischer, E.; Wüest, T.; Stenner, F.; Perani, A.; Cohen, L.; Knuth, A.; et al. Targeted Therapy of Renal Cell Carcinoma: Synergistic Activity of cG250-TNF and IFNg. Int. J. Cancer 2009, 125, 115–123. [Google Scholar] [CrossRef] [PubMed]
- Zhi, M.; Wu, K.-C.; Dong, L.; Hao, Z.-M.; Deng, T.-Z.; Hong, L.; Liang, S.-H.; Zhao, P.-T.; Qiao, T.-D.; Wang, Y.; et al. Characterization of a Specific Phage-Displayed Peptide Binding to Vasculature of Human Gastric Cancer. Cancer Biol. Ther. 2004, 3, 1232–1235. [Google Scholar] [CrossRef] [PubMed]
- Chen, B.; Cao, S.; Zhang, Y.; Wang, X.; Liu, J.; Hui, X.; Wan, Y.; Du, W.; Wang, L.; Wu, K.; et al. A Novel Peptide (GX1) Homing to Gastric Cancer Vasculature Inhibits Angiogenesis and Cooperates with TNF Alpha in Anti-Tumor Therapy. BMC Cell Biol. 2009, 10, 63. [Google Scholar] [CrossRef]
- Gubler, U.; Chua, A.O.; Schoenhaut, D.S.; Dwyer, C.M.; McComas, W.; Motyka, R.; Nabavi, N.; Wolitzky, A.G.; Quinn, P.M.; Familletti, P.C. Coexpression of Two Distinct Genes Is Required to Generate Secreted Bioactive Cytotoxic Lymphocyte Maturation Factor. Proc. Natl. Acad. Sci. USA 1991, 88, 4143–4147. [Google Scholar] [CrossRef]
- Zaharoff, D.A.; Hance, K.W.; Rogers, C.J.; Schlom, J.; Greiner, J.W. Intratumoral Immunotherapy of Established Solid Tumors with Chitosan/IL-12. J. Immunother. 2010, 33, 697. [Google Scholar] [CrossRef]
- Smyth, M.J.; Taniguchi, M.; Street, S.E.A. The Anti-Tumor Activity of IL-12: Mechanisms of Innate Immunity That Are Model and Dose Dependent1. J. Immunol. 2000, 165, 2665–2670. [Google Scholar] [CrossRef] [PubMed]
- Brunda, M.J.; Luistro, L.; Warrier, R.R.; Wright, R.B.; Hubbard, B.R.; Murphy, M.; Wolf, S.F.; Gately, M.K. Antitumor and Antimetastatic Activity of Interleukin 12 against Murine Tumors. J. Exp. Med. 1993, 178, 1223–1230. [Google Scholar] [CrossRef]
- Car, B.D.; Eng, V.M.; Schnyder, B.; LeHir, M.; Shakhov, A.N.; Woerly, G.; Huang, S.; Aguet, M.; Anderson, T.D.; Ryffel, B. Role of Interferon-Gamma in Interleukin 12-Induced Pathology in Mice. Am. J. Pathol. 1995, 147, 1693–1707. [Google Scholar] [PubMed]
- Lasek, W.; Zagożdżon, R.; Jakobisiak, M. Interleukin 12: Still a Promising Candidate for Tumor Immunotherapy? Cancer Immunol. Immunother. 2014, 63, 419–435. [Google Scholar] [CrossRef]
- Leonard, J.P.; Sherman, M.L.; Fisher, G.L.; Buchanan, L.J.; Larsen, G.; Atkins, M.B.; Sosman, J.A.; Dutcher, J.P.; Vogelzang, N.J.; Ryan, J.L. Effects of Single-Dose Interleukin-12 Exposure on Interleukin-12–Associated Toxicity and Interferon-γ Production. Blood 1997, 90, 2541–2548. [Google Scholar] [CrossRef]
- Hurteau, J.A.; Blessing, J.A.; DeCesare, S.L.; Creasman, W.T. Evaluation of Recombinant Human Interleukin-12 in Patients with Recurrent or Refractory Ovarian Cancer: A Gynecologic Oncology Group Study. Gynecol. Oncol. 2001, 82, 7–10. [Google Scholar] [CrossRef] [PubMed]
- Motzer, R.J.; Rakhit, A.; Thompson, J.A.; Nemunaitis, J.; Murphy, B.A.; Ellerhorst, J.; Schwartz, L.H.; Berg, W.J.; Bukowski, R.M. Randomized Multicenter Phase II Trial of Subcutaneous Recombinant Human Interleukin-12 Versus Interferon-A2a for Patients with Advanced Renal Cell Carcinoma. J. Interferon Cytokine Res. 2001, 21, 257–263. [Google Scholar] [CrossRef]
- Mansurov, A.; Ishihara, J.; Hosseinchi, P.; Potin, L.; Marchell, T.M.; Ishihara, A.; Williford, J.-M.; Alpar, A.T.; Raczy, M.M.; Gray, L.T.; et al. Collagen-Binding IL-12 Enhances Tumour Inflammation and Drives the Complete Remission of Established Immunologically Cold Mouse Tumours. Nat. Biomed. Eng. 2020, 4, 531–543. [Google Scholar] [CrossRef]
- Portielje, J.E.A.; Lamers, C.H.J.; Kruit, W.H.J.; Sparreboom, A.; Bolhuis, R.L.H.; Stoter, G.; Huber, C.; Gratama, J.W. Repeated Administrations of Interleukin (IL)-12 Are Associated with Persistently Elevated Plasma Levels of IL-10 and Declining IFN-γ, Tumor Necrosis Factor-α, IL-6, and IL-8 Responses. Clin. Cancer Res. 2003, 9, 76–83. [Google Scholar]
- Greiner, J.W.; Morillon, Y.M.; Schlom, J. NHS-IL12, a Tumor-Targeting Immunocytokine. Immunotargets Ther. 2021, 10, 155–169. [Google Scholar] [CrossRef] [PubMed]
- Morillon, Y.M.; Su, Z.; Schlom, J.; Greiner, J.W. Temporal Changes within the (Bladder) Tumor Microenvironment That Accompany the Therapeutic Effects of the Immunocytokine NHS-IL12. J. Immunother. Cancer 2019, 7, 150. [Google Scholar] [CrossRef] [PubMed]
- Vandeveer, A.J.; Schlom, J.; Greiner, J.W. Abstract 1480: Systemic Immunotherapeutic Efficacy of an Immunocytokine, NHS-muIL12, in a Superficial Murine Orthotopic Bladder Cancer Model. Cancer Res. 2016, 76 (Suppl. S14), 1480. [Google Scholar] [CrossRef]
- Strauss, J.; Heery, C.R.; Kim, J.W.; Jochems, C.; Donahue, R.N.; Montgomery, A.S.; McMahon, S.; Lamping, E.; Marté, J.L.; Madan, R.A.; et al. First-in-Human Phase I Trial of a Tumor-Targeted Cytokine (NHS-IL12) in Subjects with Metastatic Solid Tumors. Clin. Cancer Res. 2019, 25, 99–109. [Google Scholar] [CrossRef] [PubMed]
- Gatti-Mays, M.E.; Tschernia, N.P.; Strauss, J.; Madan, R.A.; Karzai, F.H.; Bilusic, M.; Redman, J.; Sater, H.A.; Floudas, C.S.; Toney, N.J.; et al. A Phase I Single-Arm Study of Biweekly NHS-IL12 in Patients with Metastatic Solid Tumors. Oncologist 2023, 28, 364-e217. [Google Scholar] [CrossRef] [PubMed]
- Rudman, S.; Jameson, M.; McKeage, M.; Savage, P.; Jodrell, D.; Harries, M.; Acton, G.; Erlandsson, F.; Spicer, J. A Phase 1 Study of AS1409, a Novel Antibody-Cytokine Fusion Protein, in Patients with Malignant Melanoma or Renal Cell Carcinoma. Clin. Cancer Res. 2011, 17, 1998–2005. [Google Scholar] [CrossRef] [PubMed]
- Midulla, M.; Verma, R.; Pignatelli, M.; Ritter, M.A.; Courtenay-Luck, N.S.; George, A.J.T. Source of Oncofetal ED-B-Containing Fibronectin: Implications of Production by Both Tumor and Endothelial Cells1. Cancer Res. 2000, 60, 164–169. [Google Scholar] [PubMed]
- Zardi, L.; Carnemolla, B.; Siri, A.; Petersen, T.E.; Paolella, G.; Sebastio, G.; Baralle, F.E. Transformed Human Cells Produce a New Fibronectin Isoform by Preferential Alternative Splicing of a Previously Unobserved Exon. EMBO J. 1987, 6, 2337–2342. [Google Scholar] [CrossRef] [PubMed]
- Lo, K.-M.; Lan, Y.; Siri, A.; Petersen, T.E.; Paolella, G.; Sebastio, G.; Baralle, F.E. huBC1-IL12, an Immunocytokine Which Targets EDB-Containing Oncofetal Fibronectin in Tumors and Tumor Vasculature, Shows Potent Anti-Tumor Activity in Human Tumor Models. Cancer Immunol. Immunother. 2007, 56, 447–457. [Google Scholar] [CrossRef]
- Li, J.; Hu, P.; Khawli, L.A.; Yun, A.; Epstein, A.L. chTNT-3/Hu IL-12 Fusion Protein for the Immunotherapy of Experimental Solid Tumors. Hybrid. Hybridomics 2004, 23, 1–10. [Google Scholar] [CrossRef]
- Nadal, L.; Peissert, F.; Elsayed, A.; Weiss, T.; Look, T.; Weller, M.; Piro, G.; Carbone, C.; Tortora, G.; Matasci, M.; et al. Generation and In Vivo Validation of an IL-12 Fusion Protein Based on a Novel Anti-Human FAP Monoclonal Antibody. J. Immunother. Cancer 2022, 10, e005282. [Google Scholar] [CrossRef] [PubMed]
- Ongaro, T.; Guarino, S.R.; Scietti, L.; Palamini, M.; Wulhfard, S.; Neri, D.; Villa, A.; Forneris, F. Inference of Molecular Structure for Characterization and Improvement of Clinical Grade Immunocytokines. J. Struct. Biol. 2021, 213, 107696. [Google Scholar] [CrossRef]
- Pasche, N.; Wulhfard, S.; Pretto, F.; Carugati, E.; Neri, D. The Antibody-Based Delivery of Interleukin-12 to the Tumor Neovasculature Eradicates Murine Models of Cancer in Combination with Paclitaxel. Clin. Cancer Res. 2012, 18, 4092–4103. [Google Scholar] [CrossRef]
- Halin, C.; Rondini, S.; Nilsson, F.; Berndt, A.; Kosmehl, H.; Zardi, L.; Neri, D. Enhancement of the Antitumor Activity of Interleukin-12 by Targeted Delivery to Neovasculature. Nat. Biotechnol. 2002, 20, 264–269. [Google Scholar] [CrossRef]
- Sommavilla, R.; Pasche, N.; Trachsel, E.; Giovannoni, L.; Roesli, C.; Villa, A.; Neri, D.; Kaspar, M. Expression, Engineering and Characterization of the Tumor-Targeting Heterodimeric Immunocytokine F8-IL12. Protein Eng. Des. Sel. 2010, 23, 653–661. [Google Scholar] [CrossRef] [PubMed]
- Ongaro, T.; Matasci, M.; Cazzamalli, S.; Gouyou, B.; De Luca, R.; Neri, D.; Villa, A. A Novel Anti-Cancer L19-Interleukin-12 Fusion Protein with an Optimized Peptide Linker Efficiently Localizes In Vivo at the Site of Tumors. J. Biotechnol. 2019, 291, 17–25. [Google Scholar] [CrossRef] [PubMed]
- Kim, J.H.; Song, D.H.; Youn, S.-J.; Kim, J.W.; Cho, G.; Kim, S.C.; Lee, H.; Jin, M.S.; Lee, J.-O. Crystal Structures of Mono- and Bi-Specific Diabodies and Reduction of Their Structural Flexibility by Introduction of Disulfide Bridges at the Fv Interface. Sci. Rep. 2016, 6, 34515. [Google Scholar] [CrossRef] [PubMed]
- Ishihara, J.; Ishihara, A.; Sasaki, K.; Lee, S.S.-Y.; Williford, J.-M.; Yasui, M.; Abe, H.; Potin, L.; Hosseinchi, P.; Fukunaga, K.; et al. Targeted Antibody and Cytokine Cancer Immunotherapies through Collagen Affinity. Sci. Transl. Med. 2019, 11, eaau3259. [Google Scholar] [CrossRef]
- Bhatia, V.; Kamat, N.V.; Pariva, T.E.; Wu, L.-T.; Tsao, A.; Sasaki, K.; Sun, H.; Javier, G.; Nutt, S.; Coleman, I.; et al. Targeting Advanced Prostate Cancer with STEAP1 Chimeric Antigen Receptor T Cell and Tumor-Localized IL-12 Immunotherapy. Nat. Commun. 2023, 14, 2041. [Google Scholar] [CrossRef]
- Spolski, R.; Leonard, W.J. Interleukin-21: A Double-Edged Sword with Therapeutic Potential. Nat. Rev. Drug Discov. 2014, 13, 379–395. [Google Scholar] [CrossRef]
- Zeng, R.; Spolski, R.; Finkelstein, S.E.; Oh, S.; Kovanen, P.E.; Hinrichs, C.S.; Pise-Masison, C.A.; Radonovich, M.F.; Brady, J.N.; Restifo, N.P.; et al. Synergy of IL-21 and IL-15 in Regulating CD8+ T Cell Expansion and Function. J. Exp. Med. 2005, 201, 139–148. [Google Scholar] [CrossRef] [PubMed]
- Petrella, T.M.; Mihalcioiu, C.L.D.; McWhirter, E.; Belanger, K.; Savage, K.J.; Song, X.; Hamid, O.; Cheng, T.; Davis, M.L.; Lee, C.W.; et al. Final Efficacy Results of NCIC CTG IND.202: A Randomized Phase II Study of Recombinant Interleukin-21 (rIL21) in Patients with Recurrent or Metastatic Melanoma (MM). JCO 2013, 31 (Suppl. S15), 9032. [Google Scholar] [CrossRef]
- Zorzi, A.; Linciano, S.; Angelini, A. Non-Covalent Albumin-Binding Ligands for Extending the Circulating Half-Life of Small Biotherapeutics. Medchemcomm 2019, 10, 1068–1081. [Google Scholar] [CrossRef] [PubMed]
- Liu, H.; Wang, R.; An, D.; Liu, H.; Ye, F.; Li, B.; Zhang, J.; Liu, P.; Zhang, X.; Yao, S.; et al. An Engineered IL-21 with Half-Life Extension Enhances Anti-Tumor Immunity as a Monotherapy or in Combination with PD-1 or TIGIT Blockade. Int. Immunopharmacol. 2021, 101, 108307. [Google Scholar] [CrossRef]
- Wu, S.; Sun, R.; Tan, B.; Chen, B.; Zhou, W.; Gao, D.S.; Zhong, J.; Huang, H.; Jiang, J.; Lu, B. The Half-Life-Extended IL21 Can Be Combined with Multiple Checkpoint Inhibitors for Tumor Immunotherapy. Front. Cell Dev. Biol. 2021, 9, 779865. [Google Scholar] [CrossRef] [PubMed]
- Deng, S.; Sun, Z.; Qiao, J.; Liang, Y.; Liu, L.; Dong, C.; Shen, A.; Wang, Y.; Tang, H.; Fu, Y.-X.; et al. Targeting Tumors with IL-21 Reshapes the Tumor Microenvironment by Proliferating PD-1intTim-3–CD8+ T Cells. JCI Insight 2020, 5, e132000. [Google Scholar] [CrossRef]
- Di Nitto, C.; Neri, D.; Weiss, T.; Weller, M.; De Luca, R. Design and Characterization of Novel Antibody-Cytokine Fusion Proteins Based on Interleukin-21. Antibodies 2022, 11, 19. [Google Scholar] [CrossRef]
- Durm, G.; Frentzas, S.; Rasmussen, E.; Najmi, S.; Sadraei, N.H. Abstract CT205: Design and Rationale of a Phase 1 Study Evaluating AMG 256, a Novel, Targeted, PD-1 Antibody x IL-21 Mutein Bifunctional Fusion Protein, in Patients with Advanced Solid Tumors. Cancer Res. 2021, 81 (Suppl. S13), CT205. [Google Scholar] [CrossRef]
- Shen, S.; Sckisel, G.; Sahoo, A.; Lalani, A.; Otter, D.D.; Pearson, J.; DeVoss, J.; Cheng, J.; Casey, S.C.; Case, R.; et al. Engineered IL-21 Cytokine Muteins Fused to Anti-PD-1 Antibodies Can Improve CD8+ T Cell Function and Anti-Tumor Immunity. Front. Immunol. 2020, 11, 832. [Google Scholar] [CrossRef]
- Chaudhry, A.; Rudensky, A.Y. Control of Inflammation by Integration of Environmental Cues by Regulatory T Cells. J. Clin. Investig. 2013, 123, 939–944. [Google Scholar] [CrossRef]
- Glocker, E.-O.; Kotlarz, D.; Boztug, K.; Gertz, E.M.; Schäffer, A.A.; Noyan, F.; Perro, M.; Diestelhorst, J.; Allroth, A.; Murugan, D.; et al. Inflammatory Bowel Disease and Mutations Affecting the Interleukin-10 Receptor. N. Engl. J. Med. 2009, 361, 2033–2045. [Google Scholar] [CrossRef] [PubMed]
- Neven, B.; Mamessier, E.; Bruneau, J.; Kaltenbach, S.; Kotlarz, D.; Suarez, F.; Masliah-Planchon, J.; Billot, K.; Canioni, D.; Frange, P.; et al. A Mendelian Predisposition to B-Cell Lymphoma Caused by IL-10R Deficiency. Blood 2013, 122, 3713–3722. [Google Scholar] [CrossRef] [PubMed]
- Berg, D.J.; Davidson, N.; Kühn, R.; Müller, W.; Menon, S.; Holland, G.; Thompson-Snipes, L.; Leach, M.W.; Rennick, D. Enterocolitis and Colon Cancer in Interleukin-10-Deficient Mice Are Associated with Aberrant Cytokine Production and CD4(+) TH1-like Responses. J. Clin. Investig. 1996, 98, 1010–1020. [Google Scholar] [CrossRef] [PubMed]
- Emmerich, J.; Mumm, J.B.; Chan, I.H.; LaFace, D.; Truong, H.; McClanahan, T.; Gorman, D.M.; Oft, M. IL-10 Directly Activates and Expands Tumor-Resident CD8+ T Cells without De Novo Infiltration from Secondary Lymphoid Organs. Cancer Res. 2012, 72, 3570–3581. [Google Scholar] [CrossRef] [PubMed]
- Naing, A.; Infante, J.R.; Papadopoulos, K.P.; Chan, I.H.; Shen, C.; Ratti, N.P.; Rojo, B.; Autio, K.A.; Wong, D.J.; Patel, M.R.; et al. PEGylated IL-10 (Pegilodecakin) Induces Systemic Immune Activation, CD8+ T Cell Invigoration and Polyclonal T Cell Expansion in Cancer Patients. Cancer Cell 2018, 34, 775–791.e3. [Google Scholar] [CrossRef] [PubMed]
- Hecht, J.R.; Lonardi, S.; Bendell, J.; Sim, H.-W.; Macarulla, T.; Lopez, C.D.; Van Cutsem, E.; Muñoz Martin, A.J.; Park, J.O.; Greil, R.; et al. Randomized Phase III Study of FOLFOX Alone or with Pegilodecakin as Second-Line Therapy in Patients with Metastatic Pancreatic Cancer That Progressed after Gemcitabine (SEQUOIA). J. Clin. Oncol. 2021, 39, 1108–1118. [Google Scholar] [CrossRef] [PubMed]
- Spigel, D.; Jotte, R.; Nemunaitis, J.; Shum, M.; Schneider, J.; Goldschmidt, J.; Eisenstein, J.; Berz, D.; Seneviratne, L.; Socoteanu, M.; et al. Randomized Phase 2 Studies of Checkpoint Inhibitors Alone or in Combination with Pegilodecakin in Patients with Metastatic NSCLC (CYPRESS 1 and CYPRESS 2). J. Thorac. Oncol. 2021, 16, 327–333. [Google Scholar] [CrossRef]
- Galeazzi, M.; Sebastiani, G.; Voll, R.; Viapiana, O.; Dudler, J.; Zufferey, P.; Selvi, E.; Finzel, S.; Bootz, F.S.; Neri, D.; et al. FRI0118 Dekavil (F8IL10)—Update on the Results of Clinical Trials Investigating the Immunocytokine in Patients with Rheumatoid Arthritis. Ann. Rheum. Dis. 2018, 77 (Suppl. S2), 603–604. [Google Scholar] [CrossRef]
- Qiao, J.; Liu, Z.; Dong, C.; Luan, Y.; Zhang, A.; Moore, C.; Fu, K.; Peng, J.; Wang, Y.; Ren, Z.; et al. Targeting Tumors with IL-10 Prevents Dendritic Cell-Mediated CD8+ T Cell Apoptosis. Cancer Cell 2019, 35, 901–915.e4. [Google Scholar] [CrossRef]
- Chang, Y.-W.; Hsiao, H.-W.; Chen, J.-P.; Tzeng, S.-F.; Tsai, C.-H.; Wu, C.-Y.; Hsieh, H.-H.; Carmona, S.J.; Andreatta, M.; Di Conza, G.; et al. A CSF-1R-Blocking Antibody/IL-10 Fusion Protein Increases Anti-Tumor Immunity by Effectuating Tumor-Resident CD8+ T Cells. Cell Rep. Med. 2023, 4, 101154. [Google Scholar] [CrossRef]
- Kumar, A.; Taghi Khani, A.; Sanchez Ortiz, A.; Swaminathan, S. GM-CSF: A Double-Edged Sword in Cancer Immunotherapy. Front. Immunol. 2022, 13, 901277. [Google Scholar] [CrossRef]
- Liu, B.L.; Robinson, M.; Han, Z.-Q.; Branston, R.H.; English, C.; Reay, P.; McGrath, Y.; Thomas, S.K.; Thornton, M.; Bullock, P.; et al. ICP34.5 Deleted Herpes Simplex Virus with Enhanced Oncolytic, Immune Stimulating, and Anti-Tumour Properties. Gene Ther. 2003, 10, 292–303. [Google Scholar] [CrossRef] [PubMed]
- Spitler, L.E.; Weber, R.W.; Allen, R.E.; Meyer, J.; Cruickshank, S.; Garbe, E.; Lin, H.-Y.; Soong, S. Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF, Sargramostim) Administered for 3 Years as Adjuvant Therapy of Stages II(T4), III, and IV Melanoma. J. Immunother. 2009, 32, 632–637. [Google Scholar] [CrossRef]
- Spitler, L.E.; Cao, H.; Piironen, T.; Whiteside, T.L.; Weber, R.W.; Cruickshank, S. Biological Effects of Anti-Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) Antibody Formation in Patients Treated With GM-CSF (Sargramostim) as Adjuvant Therapy of Melanoma. Am. J. Clin. Oncol. 2017, 40, 207–213. [Google Scholar] [CrossRef] [PubMed]
- Pampena, M.B.; Cartar, H.C.; Cueto, G.R.; Levy, E.M.; Blanco, P.A.; Barrio, M.M.; Mordoh, J. Dissecting the Immune Stimulation Promoted by CSF-470 Vaccine Plus Adjuvants in Cutaneous Melanoma Patients: Long Term Antitumor Immunity and Short Term Release of Acute Inflammatory Reactants. Front. Immunol. 2018, 9, 2531. [Google Scholar] [CrossRef]
- Mordoh, A.; Aris, M.; Carri, I.; Bravo, A.I.; Podaza, E.; Pardo, J.C.T.; Cueto, G.R.; Barrio, M.M.; Mordoh, J. An Update of Cutaneous Melanoma Patients Treated in Adjuvancy with the Allogeneic Melanoma Vaccine VACCIMEL and Presentation of a Selected Case Report with In-Transit Metastases. Front. Immunol. 2022, 13, 842555. [Google Scholar] [CrossRef]
- Brunsvig, P.F.; Guren, T.K.; Nyakas, M.; Steinfeldt-Reisse, C.H.; Rasch, W.; Kyte, J.A.; Juul, H.V.; Aamdal, S.; Gaudernack, G.; Inderberg, E.M. Long-Term Outcomes of a Phase I Study with UV1, a Second Generation Telomerase Based Vaccine, in Patients with Advanced Non-Small Cell Lung Cancer. Front. Immunol. 2020, 11, 572172. [Google Scholar] [CrossRef]
- Chen, Z.; Zhang, S.; Han, N.; Jiang, J.; Xu, Y.; Ma, D.; Lu, L.; Guo, X.; Qiu, M.; Huang, Q.; et al. A Neoantigen-Based Peptide Vaccine for Patients with Advanced Pancreatic Cancer Refractory to Standard Treatment. Front. Immunol. 2021, 12, 691605. [Google Scholar] [CrossRef] [PubMed]
- Hong, I.-S. Stimulatory versus Suppressive Effects of GM-CSF on Tumor Progression in Multiple Cancer Types. Exp. Mol. Med. 2016, 48, e242. [Google Scholar] [CrossRef]
- Serafini, P.; Carbley, R.; Noonan, K.A.; Tan, G.; Bronte, V.; Borrello, I. High-Dose Granulocyte-Macrophage Colony-Stimulating Factor-Producing Vaccines Impair the Immune Response through the Recruitment of Myeloid Suppressor Cells. Cancer Res. 2004, 64, 6337–6343. [Google Scholar] [CrossRef]
- Dela Cruz, J.S.; Trinh, K.R.; Morrison, S.L.; Penichet, M.L. Recombinant Anti-Human HER2/Neu IgG3-(GM-CSF) Fusion Protein Retains Antigen Specificity and Cytokine Function and Demonstrates Antitumor Activity1. J. Immunol. 2000, 165, 5112–5121. [Google Scholar] [CrossRef] [PubMed]
- Huang, L.; Ge, X.; Liu, Y.; Li, H.; Zhang, Z. The Role of Toll-like Receptor Agonists and Their Nanomedicines for Tumor Immunotherapy. Pharmaceutics 2022, 14, 1228. [Google Scholar] [CrossRef]
- Huang, C.-Y.; Chen, J.J.W.; Shen, K.-Y.; Chang, L.-S.; Yeh, Y.-C.; Chen, I.-H.; Chong, P.; Liu, S.-J.; Leng, C.-H. Recombinant Lipidated HPV E7 Induces a Th-1-Biased Immune Response and Protective Immunity against Cervical Cancer in a Mouse Model. PLoS ONE 2012, 7, e40970. [Google Scholar] [CrossRef] [PubMed]
- Yan, W.-L.; Wu, C.-C.; Shen, K.-Y.; Liu, S.-J. Activation of GM-CSF and TLR2 Signaling Synergistically Enhances Antigen-Specific Antitumor Immunity and Modulates the Tumor Microenvironment. J. Immunother. Cancer 2021, 9, e002758. [Google Scholar] [CrossRef]
- Ni, L.; Lu, J. Interferon Gamma in Cancer Immunotherapy. Cancer Med. 2018, 7, 4509–4516. [Google Scholar] [CrossRef]
- Pujade-Lauraine, E.; Guastalla, J.P.; Colombo, N.; Devillier, P.; François, E.; Fumoleau, P.; Monnier, A.; Nooy, M.; Mignot, L.; Bugat, R.; et al. Intraperitoneal Recombinant Interferon Gamma in Ovarian Cancer Patients with Residual Disease at Second-Look Laparotomy. JCO 1996, 14, 343–350. [Google Scholar] [CrossRef] [PubMed]
- Windbichler, G.H.; Hausmaninger, H.; Stummvoll, W.; Graf, A.H.; Kainz, C.; Lahodny, J.; Denison, U.; Müller-Holzner, E.; Marth, C. Interferon-Gamma in the First-Line Therapy of Ovarian Cancer: A Randomized Phase III Trial. Br. J. Cancer 2000, 82, 1138–1144. [Google Scholar] [CrossRef] [PubMed]
- Alberts, D.S.; Marth, C.; Alvarez, R.D.; Johnson, G.; Bidzinski, M.; Kardatzke, D.R.; Bradford, W.Z.; Loutit, J.; Kirn, D.H.; Clouser, M.C.; et al. Randomized Phase 3 Trial of Interferon Gamma-1b plus Standard Carboplatin/Paclitaxel versus Carboplatin/Paclitaxel Alone for First-Line Treatment of Advanced Ovarian and Primary Peritoneal Carcinomas: Results from a Prospectively Designed Analysis of Progression-Free Survival. Gynecol. Oncol. 2008, 109, 174–181. [Google Scholar] [CrossRef] [PubMed]
- Ebbinghaus, C. An Antibody-Interferon Gamma Fusion Protein for Cancer Therapy. Ph.D. Thesis, ETH Zurich, Zurich, Switzerland, 2004; p. 134S. [Google Scholar] [CrossRef]
- Hemmerle, T.; Neri, D. The Dose-Dependent Tumor Targeting of Antibody–IFNγ Fusion Proteins Reveals an Unexpected Receptor-Trapping Mechanism In Vivo. Cancer Immunol. Res. 2014, 2, 559–567. [Google Scholar] [CrossRef]
- Di Nitto, C.; Gilardoni, E.; Mock, J.; Nadal, L.; Weiss, T.; Weller, M.; Seehusen, F.; Libbra, C.; Puca, E.; Neri, D.; et al. An Engineered IFNγ-Antibody Fusion Protein with Improved Tumor-Homing Properties. Pharmaceutics 2023, 15, 377. [Google Scholar] [CrossRef]
- Mizokami, M.M.; Hu, P.; Khawli, L.A.; Li, J.; Epstein, A.L. Chimeric TNT-3 Antibody/Murine Interferon-γ Fusion Protein for the Immunotherapy of Solid Malignancies. Hybrid. Hybridomics 2003, 22, 197–207. [Google Scholar] [CrossRef] [PubMed]
- Belardelli, F.; Ferrantini, M.; Proietti, E.; Kirkwood, J.M. Interferon-Alpha in Tumor Immunity and Immunotherapy. Cytokine Growth Factor Rev. 2002, 13, 119–134. [Google Scholar] [CrossRef]
- Baron, S.; Tyring, S.K.; Fleischmann, W.R., Jr.; Coppenhaver, D.H.; Niesel, D.W.; Klimpel, G.R.; Stanton, G.J.; Hughes, T.K. The Interferons: Mechanisms of Action and Clinical Applications. JAMA 1991, 266, 1375–1383. [Google Scholar] [CrossRef] [PubMed]
- Farkas, Á.; Kemény, L. Interferon-α in the Generation of Monocyte-derived Dendritic Cells: Recent Advances and Implications for Dermatology. Br. J. Dermatol. 2011, 165, 247–254. [Google Scholar] [CrossRef]
- Borden, E.C.; Parkinson, D. A Perspective on the Clinical Effectiveness and Tolerance of Interferon-Alpha. Semin. Oncol. 1998, 25 (Suppl. S1), 3–8. [Google Scholar]
- Xuan, C.; Steward, K.K.; Timmerman, J.M.; Morrison, S.L. Targeted Delivery of Interferon-Alpha via Fusion to Anti-CD20 Results in Potent Antitumor Activity against B-Cell Lymphoma. Blood 2010, 115, 2864–2871. [Google Scholar] [CrossRef] [PubMed]
- Li, Z.; Zhu, Y.; Li, C.; Trinh, R.; Ren, X.; Sun, F.; Wang, Y.; Shang, P.; Wang, T.; Wang, M.; et al. Anti-VEGFR2-Interferon-A2 Regulates the Tumor Microenvironment and Exhibits Potent Antitumor Efficacy against Colorectal Cancer. OncoImmunology 2017, 6, e1290038. [Google Scholar] [CrossRef]
- Shang, P.; Gao, R.; Zhu, Y.; Zhang, X.; Wang, Y.; Guo, M.; Peng, H.; Wang, M.; Zhang, J. VEGFR2-Targeted Antibody Fused with IFNαmut Regulates the Tumor Microenvironment of Colorectal Cancer and Exhibits Potent Anti-Tumor and Anti-Metastasis Activity. Acta Pharm. Sin. B 2021, 11, 420–433. [Google Scholar] [CrossRef]
- Hutmacher, C.; Neri, D. Antibody-Cytokine Fusion Proteins: Biopharmaceuticals with Immunomodulatory Properties for Cancer Therapy. Adv. Drug Deliv. Rev. 2019, 141, 67–91. [Google Scholar] [CrossRef]
- Puskas, J.; Skrombolas, D.; Sedlacek, A.; Lord, E.; Sullivan, M.; Frelinger, J. Development of an Attenuated Interleukin-2 Fusion Protein That Can Be Activated by Tumour-Expressed Proteases. Immunology 2011, 133, 206–220. [Google Scholar] [CrossRef]
- Garcin, G.; Paul, F.; Staufenbiel, M.; Bordat, Y.; Van der Heyden, J.; Wilmes, S.; Cartron, G.; Apparailly, F.; De Koker, S.; Piehler, J.; et al. High Efficiency Cell-Specific Targeting of Cytokine Activity. Nat Commun 2014, 5, 3016. [Google Scholar] [CrossRef] [PubMed]
- Hank, J.A.; Gan, J.; Ryu, H.; Ostendorf, A.; Stauder, M.C.; Sternberg, A.; Albertini, M.; Lo, K.-M.; Gillies, S.D.; Eickhoff, J.; et al. Immunogenicity of the Hu14.18-IL2 Immunocytokine Molecule in Adults With Melanoma and Children With Neuroblastoma. Clinical Cancer Research 2009, 15, 5923–5930. [Google Scholar] [CrossRef] [PubMed]
- Prodi, E.; Corbellari, R.; Matasci, M.; Neri, D.; De Luca, R. Abstract 1877: Tripokin: Potential Best-in-Class for Tumor Targeted Interleukin-2 (IL2) Potentiated by Tumor Necrosis Factor (TNF). Cancer Res. 2023, 83 (Suppl. S7), 1877. [Google Scholar] [CrossRef]
- Schanzer, J.M.; Fichtner, I.; Baeuerle, P.A.; Kufer, P. Antitumor Activity of a Dual Cytokine/Single-Chain Antibody Fusion Protein for Simultaneous Delivery of GM-CSF and IL-2 to Ep-CAM Expressing Tumor Cells. J. Immunother. 2006, 29, 477–488. [Google Scholar] [CrossRef]
- Tian, Z.; Liu, M.; Zhang, Y.; Wang, X. Bispecific T Cell Engagers: An Emerging Therapy for Management of Hematologic Malignancies. J. Hematol. Oncol. 2021, 14, 75. [Google Scholar] [CrossRef]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2024 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 (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Boersma, B.; Poinot, H.; Pommier, A. Stimulating the Antitumor Immune Response Using Immunocytokines: A Preclinical and Clinical Overview. Pharmaceutics 2024, 16, 974. https://doi.org/10.3390/pharmaceutics16080974
Boersma B, Poinot H, Pommier A. Stimulating the Antitumor Immune Response Using Immunocytokines: A Preclinical and Clinical Overview. Pharmaceutics. 2024; 16(8):974. https://doi.org/10.3390/pharmaceutics16080974
Chicago/Turabian StyleBoersma, Bart, Hélène Poinot, and Aurélien Pommier. 2024. "Stimulating the Antitumor Immune Response Using Immunocytokines: A Preclinical and Clinical Overview" Pharmaceutics 16, no. 8: 974. https://doi.org/10.3390/pharmaceutics16080974
APA StyleBoersma, B., Poinot, H., & Pommier, A. (2024). Stimulating the Antitumor Immune Response Using Immunocytokines: A Preclinical and Clinical Overview. Pharmaceutics, 16(8), 974. https://doi.org/10.3390/pharmaceutics16080974