The safest and most effective cytokine therapies require the favorable accumulation of the cytokine in the tumor environment. While direct treatment into the neoplasm is ideal, systemic tumor-targeted therapies will be more feasible. Electroporation-mediated transfection of cytokine plasmid DNA including a tumor-targeting peptide-encoding sequence is one method for obtaining a tumor-targeted cytokine produced by the tumor-bearing patient’s tissues. Here, the impact on efficacy of the location of targeting peptide, choice of targeting peptide, tumor histotype, and cytokine utilization are studied in multiple syngeneic murine tumor models. Within the same tumor model, the location of the targeting peptide could either improve or reduce the antitumor effect of interleukin (IL)12 gene treatments, yet in other tumor models the tumor-targeted IL12 plasmid DNAs were equally effective regardless of the peptide location. Similarly, the same targeting peptide that enhances IL12 therapies in one model fails to improve the effect of either IL15 or PF4 for inhibiting tumor growth in the same model. These interesting and sometimes contrasting results highlight both the efficacy and personalization of tumor-targeted cytokine gene therapies while exposing important aspects of these same therapies which must be considered before progressing into approved treatment options. 1. Introduction Immunotherapy is one of the most promising treatment strategies for cancer and other diseases; however, several obstacles need to be overcome before immunotherapies are widely accepted in the clinics. Several cytokines and chemokines, such as interleukin (IL) 2 [1, 2], interferon (IFN) α [3], IL12 [4–8], IL15 [9–12], and chemokine platelet factor 4 (PF4) [13–15], are very effective for inhibiting tumor growth via immunomodulatory mechanisms in mouse models, and dozens of either active or completed clinical trials utilize cytokines alone or as an adjuvant for treating cancer [16]. However, only IL-2 and IFNα have been approved by the FDA for the treatment of a small subset of cancers, and these therapies are only administered systemically in recombinant protein form [17]. One strategy that may soon help improve these therapies is gene therapy, the administration of DNA which encodes for a therapeutic protein. Although not ideal for producing all types of therapeutic proteins, the increase in safety and efficacy while reducing costs makes immune gene therapies feasible [18–20]. For most immune gene therapies the gene product must be located in the tumor microenvironment to be most
References
[1]
Y.-J. Ko, G. J. Bubley, R. Weber et al., “Safety, pharmacokinetics, and biological pharmacodynamics of the immunocytokine EMD 273066 (huKS-IL2): results of a phase I trial in patients with prostate cancer,” Journal of Immunotherapy, vol. 27, no. 3, pp. 232–239, 2004.
[2]
S. K. Seung, B. Curti, M. Crittenden, and W. Urba, “Radiation and immunotherapy: renewed allies in the war on cancer,” Oncoimmunology, vol. 1, no. 9, pp. 1645–1647, 2012.
[3]
R. Craig, J. Cutrera, S. Zhu, X. Xia, Y.-H. Lee, and S. Li, “Administering plasmid DNA encoding tumor vessel-anchored IFN-α for localizing gene product within or into tumors,” Molecular Therapy, vol. 16, no. 5, pp. 901–906, 2008.
[4]
M. B. Atkins, M. J. Robertson, M. Gordon et al., “Phase I evaluation of intravenous recombinant human interleukin 12 in patients with advanced malignancies,” Clinical Cancer Research, vol. 3, no. 3, pp. 409–417, 1997.
[5]
J. Cutrera, D. Dibra, X. Xia, A. Hasan, S. Reed, and S. Li, “Discovery of a linear peptide for improving tumor targeting of gene products and treatment of distal tumors by IL-12 gene therapy,” Molecular Therapy, vol. 19, no. 8, pp. 1468–1477, 2011.
[6]
S. D. Reed, A. Fulmer, J. Buckholz et al., “Bleomycin/interleukin-12 electrochemogene therapy for treating naturally occurring spontaneous neoplasms in dogs,” Cancer Gene Therapy, vol. 17, no. 7, pp. 457–464, 2010.
[7]
M. J. Robertson, C. Cameron, M. B. Atkins et al., “Immunological effects of interleukin 12 administered by bolus intravenous injection to patients with cancer,” Clinical Cancer Research, vol. 5, no. 1, pp. 9–16, 1999.
[8]
M. N. Torrero, X. Xia, W. Henk, S. Yu, and S. Li, “Stat1 deficiency in the host enhances interleukin-12-mediated tumor regression,” Cancer Research, vol. 66, no. 8, pp. 4461–4467, 2006.
[9]
E. Chertova, C. Bergamaschi, O. Chertov, et al., “Characterization and favorable in vivo properties of heterodimeric soluble IL-15.IL-15 Ralpha cytokine compared to IL-15 monomer,” Journal of Biological Chemistry, vol. 288, no. 25, pp. 18093–18103, 2013.
[10]
M. Kaspar, E. Trachsel, and D. Neri, “The antibody-mediated targeted delivery of interleukin-15 and GM-CSF to the tumor neovasculature inhibits tumor growth and metastasis,” Cancer Research, vol. 67, no. 10, pp. 4940–4948, 2007.
[11]
R. M. Teague, B. D. Sather, J. A. Sacks et al., “Interleukin-15 rescues tolerant CD8+ T cells for use in adoptive immunotherapy of established tumors,” Nature Medicine, vol. 12, no. 3, pp. 335–341, 2006.
[12]
W. Xu, M. Jones, B. Liu, et al., “Efficacy and mechanism-of-action of a novel superagonist interleukin-15: interleukin-15 receptor alphaSu/Fc fusion complex in syngeneic murine models of multiple myeloma,” Cancer Research, vol. 73, no. 10, pp. 3075–3086, 2013.
[13]
G. Lippi and E. J. Favaloro, “Recombinant platelet factor 4: a therapeutic, anti-neoplastic chimera?” Seminars in Thrombosis and Hemostasis, vol. 36, no. 5, pp. 558–569, 2010.
[14]
Z. Wang and H. Huang, “Platelet factor-4 (CXCL4/PF-4): an angiostatic chemokine for cancer therapy,” Cancer Letters, vol. 331, no. 2, pp. 147–153, 2013.
[15]
L. Yang, J. Du, J. Hou, H. Jiang, and J. Zou, “Platelet factor-4 and its p17-70 peptide inhibit myeloma proliferation and angiogenesis in vivo,” BMC Cancer, vol. 11, article 261, 2011.
National Cancer Institute, “Biological Therapies for Cancer,” Cancer Fact Sheets, 2013, http://www.cancer.gov/cancertopics/factsheet/Therapy/biological.
[18]
A. J. Mellott, M. L. Forrest, and M. S. Detamore, “Physical non-viral gene delivery methods for tissue engineering,” Annals of Biomedical Engineering, vol. 41, no. 3, pp. 446–468, 2013.
[19]
J. L. Santos, D. Pandita, J. Rodrigues, A. P. Pêgo, P. L. Granja, and H. Tomás, “Non-viral gene delivery to mesenchymal stem cells: methods, strategies and application in bone tissue engineering and regeneration,” Current Gene Therapy, vol. 11, no. 1, pp. 46–57, 2011.
[20]
W. Wang, W. Li, N. Ma, and G. Steinhoff, “Non-viral gene delivery methods,” Current Pharmaceutical Biotechnology, vol. 14, no. 1, pp. 46–60, 2013.
[21]
A. I. Daud, R. C. DeConti, S. Andrews et al., “Phase I trial of interleukin-12 plasmid electroporation in patients with metastatic melanoma,” Journal of Clinical Oncology, vol. 26, no. 36, pp. 5896–5903, 2008.
[22]
M. Jakobisiak, J. Golab, and W. Lasek, “Interleukin 15 as a promising candidate for tumor immunotherapy,” Cytokine and Growth Factor Reviews, vol. 22, no. 2, pp. 99–108, 2011.
[23]
R. Craig and S. Li, “Function and molecular mechanism of tumor-targeted peptides for delivering therapeutic genes and chemical drugs,” Mini-Reviews in Medicinal Chemistry, vol. 6, no. 7, pp. 757–764, 2006.
[24]
M. Croft, C. A. Benedict, and C. F. Ware, “Clinical targeting of the TNF and TNFR superfamilies,” Nature Reviews Drug Discovery, vol. 12, no. 2, pp. 147–168, 2013.
[25]
J. Cutrera and S. Li, “Passive and active tumor homing cytokine therapy,” in Targeted Cancer Immune Therapy, J. Lustgarten, Y. Cui, and S. Li, Eds., pp. 97–113, Springer, New York, NY, USA, 2009.
[26]
P. Fournier and V. Schirrmacher, “Bispecific antibodies and trispecific immunocytokines for targeting the immune system against cancer: preparing for the future,” BioDrugs, vol. 27, no. 1, pp. 35–53, 2013.
[27]
A. Satelli and S. Li, “Vimentin in cancer and its potential as a molecular target for cancer therapy,” Cellular and Molecular Life Sciences, vol. 68, no. 18, pp. 3033–3046, 2011.
[28]
J. Cutrera, B. Johnson, L. Ellis, and S. Li, “Intraosseous inoculation of tumor cells into bone marrow promotes distant metastatic tumor development: a novel tool for mechanistic and therapeutic studies,” Cancer Letters, vol. 329, no. 1, pp. 68–73, 2013.
[29]
F. Curnis, A. Gasparri, A. Sacchi, R. Longhi, and A. Corti, “Coupling tumor necrosis factor-α with αV integrin ligands improves its antineoplastic activity,” Cancer Research, vol. 64, no. 2, pp. 565–571, 2004.
[30]
G. Colombo, F. Curnis, G. M. S. De Mori et al., “Structure-activity relationships of linear and cyclic peptides containing the NGR tumor-homing motif,” Journal of Biological Chemistry, vol. 277, no. 49, pp. 47891–47897, 2002.
[31]
A. Corti, F. Curnis, W. Arap, and R. Pasqualini, “The neovasculature homing motif NGR: more than meets the eye,” Blood, vol. 112, no. 7, pp. 2628–2635, 2008.
[32]
S. Bhatia, M. E. Menezes, S. K. Das, et al., “Innovative approaches for enhancing cancer gene therapy,” Discovery Medicine, vol. 15, no. 84, pp. 309–317, 2013.
[33]
E. Cha and A. Daud, “Plasmid IL-12 electroporation in melanoma,” Human Vaccines and Immunotherapeutics, vol. 8, no. 11, pp. 1734–1738, 2012.
[34]
L. Heller, K. Merkler, J. Westover et al., “Evaluation of toxicity following electrically mediated interleukin-12 gene delivery in a B16 mouse melanoma model,” Clinical Cancer Research, vol. 12, no. 10, pp. 3177–3183, 2006.
[35]
J. Park, K. Singha, S. Son, et al., “A review of RGD-functionalized nonviral gene delivery vectors for cancer therapy,” Cancer Gene Therapy, vol. 19, no. 11, pp. 741–748, 2012.
[36]
W. Chen, P. A. Jarzyna, G. A. F. van Tilborg et al., “RGD peptide functionalized and reconstituted high-density lipoprotein nanoparticles as a versatile and multimodal tumor targeting molecular imaging probe,” FASEB Journal, vol. 24, no. 6, pp. 1689–1699, 2010.
[37]
H. Dehari, Y. Ito, T. Nakamura et al., “Enhanced antitumor effect of RGD fiber-modified adenovirus for gene therapy of oral cancer,” Cancer Gene Therapy, vol. 10, no. 1, pp. 75–85, 2003.
[38]
D. Ma, Y. Chen, L. Fang et al., “Purification and characterization of RGD tumor-homing peptide conjugated human tumor necrosis factor α over-expressed in Escherichia coli,” Journal of Chromatography B, vol. 857, no. 2, pp. 231–239, 2007.
[39]
Y. Okada, N. Okada, H. Mizuguchi et al., “Optimization of antitumor efficacy and safety of in vivo cytokine gene therapy using RGD fiber-mutant adenovirus vector for preexisting murine melanoma,” Biochimica et Biophysica Acta, vol. 1670, no. 3, pp. 172–180, 2004.
[40]
Y. Okada, N. Okada, S. Nakagawa et al., “Tumor necrosis factor α-gene therapy for an established murine melanoma using RGD (Arg-Gly-Asp) fiber-mutant adenovirus vectors,” Japanese Journal of Cancer Research, vol. 93, no. 4, pp. 436–444, 2002.
[41]
K. Temming, R. M. Schiffelers, G. Molema, and R. J. Kok, “RGD-based strategies for selective delivery of therapeutics and imaging agents to the tumour vasculature,” Drug Resistance Updates, vol. 8, no. 6, pp. 381–402, 2005.
[42]
H. Wang, K. Chen, W. Cai et al., “Integrin-targeted imaging and therapy with RGD4C-TNF fusion protein,” Molecular Cancer Therapeutics, vol. 7, no. 5, pp. 1044–1053, 2008.
[43]
A. Briat, C. H. F. Wenk, M. Ahmadi et al., “Reduction of renal uptake of 111In-DOTA-labeled and A700-labeled RAFT-RGD during integrin αvβ3 targeting using single positron emission computed tomography and optical imaging,” Cancer Science, vol. 103, no. 6, pp. 1105–1110, 2012.
[44]
L. Sancey, E. Garanger, S. Foillard, et al., “Clustering and internalization of integrin αvβ3 with a tetrameric RGD-synthetic peptide,” Molecular Therapy, vol. 17, no. 5, pp. 837–843, 2009.
[45]
L. Diao and B. Meibohm, “Pharmacokinetics and pharmacokinetic-pharmacodynamic correlations of therapeutic peptides,” Clinical Pharmacokinetics, vol. 52, no. 10, pp. 855–868, 2013.
