Recently, it has been elucidated that blocking immunosuppressive networks and immune checkpoints realizes a successful immunotherapeutic modality for the treatment of cancer.42–45 Therefore, a combination of Ad-REIC with inhibition of immune checkpoint and/or suppressor cells will offer a more promising strategy for the next generation of cancer immunotherapy. It has been reported that the two main immune checkpoint pathways involve signaling through cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) or programmed cell death protein 1 (PD-1). The CTLA-4 pathway is more important in the early phase of the immune system activation (priming phase), while the PD-1 pathway is more important in the tumor microenvironment during the effector phase.46 A combination of Ad-REIC with PD-1 pathway blockade seems to be more appropriate, since Ad-REIC generates a strong antitumor immunity, as demonstrated in this patient. One of the most important findings (from early clinical trials of PD-1 pathway blockade for advance solid cancers) reveals that programmed death-ligand 1 (PD-L1) expression on tumor cells reflects an immune-active microenvironment and is the single factor most closely correlated with response to anti-PD-1 blockade.43,47 Therefore, in our future study it is crucial to investigate PD-L1 expression status in tumors, before and after Ad-REIC as well in metastatic tumors, if recurrence occurs. In terms of blocking immunosuppressive networks, targeted therapies and cytotoxic agents also modulate immune responses.44 Among them, sunitinib, vascular endothelial growth factor A (VEGF-A), and low-dose cyclophosphamide are possible candidates to combine with Ad-REIC in order to improve clinical outcomes in the treatment of CRPC.
Apart from this combination strategy, the second generation of Ad-REIC using a super gene expression (SGE) system (Ad-SGE-REIC) has already been developed in order to augment the therapeutic effects of in situ Ad-REIC.48 The SGE system is a new plasmid vector, developed by placing three enhancers in tandem after poly A to realize extremely high expression of the targeted REIC gene.49 A Phase I/IIa clinical trial of Ad-SGE-REIC for localized prostate cancer is being conducted at two institutions in the United States (https://clinicaltrials.gov/). Similarly, a Phase I/IIa clinical trial for malignant pleural mesothelioma will be initiated in the near future at three institutions in Japan. In addition, preclinical studies of Ad-REIC on various intractable solid cancers including pancreatic cancer,36 lung cancer,37 and malignant glioma38 have been conducted successfully.
A 63-year-old man with mCRPC after docetaxel failure was successfully treated for two years with in situ Ad-REIC gene therapy. Repeated injections of Ad-REIC into metastatic LNs showed remarkable safety profiles and induced potent direct and indirect antitumor effects, thus paving the way for a new, future cancer therapeutic vaccine against a variety of intractable solid cancers.
We thank Dr. Sabina Mahmood, Dr. Shigeru Kobayashi (Okayama University Graduate School, Okayama, Japan), and Mr. Hitoshi Shiomi (Momotaro-Gene Inc., Okayama, Japan) for providing valuable suggestions and help with the preparation of this manuscript.
Conceived and designed the study: HK, MW, YN. Performed medical operations: HK, KS, YA, TS, HY, MW. Analyzed the data: HK, KS, YA. Wrote the first draft of the manuscript: HK. Contributed to the writing of the manuscript: HK, KS, YA, TS, MW. Agree with manuscript results and conclusions: HK, KS, YA, SE, TH, SK, HY, MW, YN. Jointly developed the structure and arguments for the paper: HK, KS, YA, MW, YN. Made critical revisions and approved final version: HK, HY, MW, YN. All authors reviewed and approved of the final manuscript.
1. Kirby M, Hirst C, Crawford ED. Characterising the castration-resistant prostate cancer population: a systematic review. Int J Clin Pract. 2011;65:1180–92.
2. de Bono JS, Logothetis CJ, Molina A, et al; COU-AA-301 Investigators. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995–1995.
3. Scher HI, Fizazi K, Saad F, et al; AFFIRM Investigators. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187–97.
4. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-timmunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411–22.
5. Smith MR, Saad F, Coleman R, et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet. 2012;379:39–46.
6. Parker C, Nilsson S, Heinrich D, et al; ALSYMPCA Investigators. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369:213–23.
7. Paller CJ, Antonarakis ES. Cabazitaxel: a novel second line treatment for metastatic castration-resistant prostate cancer. Drug Des Devel Ther. 2011;5:117–24.
8. Nasu Y, Djavan B, Marberger M, Kumon H. Prostate cancer gene therapy: outcome of basic research and clinical trials. Tech Urol. 1999;5:185–90.
9. Kumon H. Gene therapy in the 21st century. Mol Urol. 2001;5:45–6.
10. Saika T, Kusaka N, Mouraviev V, et al. Therapeutic effects of adoptive splenocyte transfer following in situ AdIL-12 gene therapy in a mouse prostate cancer model. Cancer Gene Ther. 2006;13:91–8.
11. Nasu Y, Saika T, Ebara S, et al. Suicide gene therapy with adenoviral delivery of HSV-tK gene for patients with local recurrence of prostate cancer after hormonal therapy. Mol Ther. 2007;15:834–40.
12. Fisher PB. Is mda-7/IL-24 a “magic bullet” for cancer? Cancer Res. 2005;65:10128–38.
13. Ren C, Ren CH, Li L, Goltsov AA, Thompson TC. Identification and characterization of RTVP1/GLIPR1-like genes, a novel p53 target gene cluster. Genomics. 2006;88:163–72.
14. Tsuji T, Miyazaki M, Sakaguchi M, Inoue Y, Namba M. A REIC gene shows down-regulation in human immortalized cells and human tumor-derived cell lines. Biochem Biophys Res Commun. 2000;268:20–4.
15. Hermiston TW, Kuhn I. Armed therapeutic viruses: strategies and challenges to arming oncolyticviruses with therapeutic genes. Cancer Gene Ther. 2002;9:1022–35.
16. Hu JC, Coffin RS, Davis CJ, et al. A phase I study of OncoVEXGM-CSF, a second-generation oncolytic herpes simplex virus expressing granulocyte macrophage colony-stimulating factor. Clin Cancer Res. 2006;12:6737–47.
17. Goins WF, Huang S, Cohen JB, Glorioso JC. Engineering HSV-1 vectors for gene therapy. Methods Mol Biol. 2014;1144:63–79.
18. Abarzua F, Sakaguchi M, Takaishi M, et al. Adenovirus-mediated overexpression of REIC/Dkk-3 selectively induces apoptosis in human prostate cancer cells through activation of c-Jun-NH2-kinase. Cancer Res. 2005;65:9617–22.
19. Veeck J, Dahl E. Targeting the Wnt pathway in cancer: the emerging role of Dickkopf-3. Biochim Biophys Acta. 2012;1825:18–28.
20. Kashiwakura Y, Ochiai K, Watanabe M, et al. Down-regulation of inhibition of differentiation-1 via activation of activating transcription factor 3 and Smad regulates REIC/Dickkopf-3-induced apoptosis. Cancer Res. 2008;68:8333–41.
21. Sakaguchi M, Kataoka K, Abarzua F, et al. Overexpression of REIC/Dkk-3 in normal fibroblasts suppresses tumor growth via induction of interleukin-7. J Biol Chem. 2009;284:14236–44.
22. Watanabe M, Kashiwakura Y, Huang P, et al. Immunological aspects of REIC/Dkk-3 in monocyte differentiation and tumor regression. Int J Oncol. 2009;34:657–63.
23. Watanabe M, Nasu Y, Kumon H. Adenovirus-mediated REIC/Dkk-3 gene therapy: development of an autologous cancer vaccination therapy (review). Oncol Lett. 2014;7:595–601.
24. Herman JR, Adler HL, Aguilar-Cordova E, et al. In situ gene therapy for adenocarcinoma of the prostate: a phase I clinical trial. Hum Gene Ther. 1999;10:1239–49.
25. Nasu Y, Bangma CH, Hull GW, et al. Adenovirus-mediated interleukin-12 gene therapy for prostate cancer: suppression of orthotopic tumor growth and pre-established lung metastases in an orthotopic model. Gene Ther. 1999;6:338–49.
26. Breyer B, Jiang W, Cheng H, et al. Adenoviral vector-mediated gene transfer for human gene therapy. Curr Gene Ther. 2001;1:149–62.
27. Swisher SG, Roth JA, Nemunaitis J, et al. Adenovirus-mediated p53 gene transfer in advanced non-small-cell lung cancer. J Natl Cancer Inst. 1999;91:763–71.
28. Lane DP, Cheok CF, Lain S. p53-based cancer therapy. Cold Spring Harb Perspect Biol. 2010;2:a001222.
29. Shi J, Zheng D. An update on gene therapy in China. Curr Opin Mol Ther. 2009;11:547–53.
30. Nasu Y, Bangma CH, Hull GW, et al. Combination gene therapy with adenoviral vector-mediated HSV-tk+GCV and IL-12 in an orthotopic mouse model for prostate cancer. Prostate Cancer Prostatic Dis. 2001;4:44–55.
31. Edamura K, Nasu Y, Takaishi M, et al. Adenovirus-mediated REIC/Dkk-3 gene transfer inhibits tumor growth and metastasis in an orthotopic prostate cancer model. Cancer Gene Ther. 2007;14:765–72.
32. Strebhardt K, Ullrich A. Paul Ehrlich’s magic bullet concept: 100 years of progress. Nat Rev Cancer. 2008;8:473–80.
33. Kurose K, Sakaguchi M, Nasu Y, et al. Decreased expression of REIC/Dkk-3 in human renal clear cell carcinoma. J Urol. 2004;171:1314–8.
34. Tanimoto R, Abarzua F, Sakaguchi M, et al. REIC/Dkk-3 as a potential gene therapeutic agent against human testicular cancer. Int J Mol Med. 2007;19:363–8.
35. Kawasaki K, Watanabe M, Sakaguchi M, et al. REIC/Dkk-3 overexpression downregulates P-glycoprotein in multidrug-resistant MCF7/ADR cells and induces apoptosis in breast cancer. Cancer Gene Ther. 2009;16:65–72.
36. Uchida D, Shiraha H, Kato H, et al. Potential of adenovirus-mediated REIC/Dkk-3 gene therapy for use in the treatment of pancreatic cancer. J Gastroenterol Hepatol. 2014;29:973–83.
37. Shien K, Tanaka N, Watanabe M, et al. Anti-cancer effects of REIC/Dkk-3-encoding adenoviral vector for the treatment of non-small cell lung cancer. PLoS One. 2014;9:e87900.
38. Shimazu Y, Kurozumi K, Ichikawa T, et al. Integrin antagonist augments the therapeutic effect of adenovirus-mediated REIC/Dkk-3 gene therapy for malignant glioma. Gene Ther. 2014;22(2):146–54.
39. Zhang K, Watanabe M, Kashiwakura Y, et al. Expression pattern of REIC/Dkk-3 in various cell types and the implications of the soluble form in prostatic acinar development. Int J Oncol. 2010;37:1495–501.
40. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331:1565–70.
41. Butt AQ, Mills KH. Immunosuppressive networks and checkpoints controlling antitumor immunity and their blockade in the development of cancer immunotherapeutics and vaccines. Oncogene. 2014;33:4623–31.
42. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23.
43. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–54.
44. Vanneman M, Dranoff G. Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer. 2012;12:237–51.
45. Marabelle A, Kohrt H, Sagiv-Barfi I, et al. Depleting tumor-specific Tregs at a single site eradicates disseminated tumors. J Clin Invest. 2013;123:2447–63.
46. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369:122–33.
47. Taube JM, Klein A, Brahmer JR, et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res. 2014;20:5064–74.
48. Watanabe M, Sakaguchi M, Kinoshita R, et al. A novel gene expression system strongly enhances the anticancer effects of REIC/Dkk-3-encoding adenoviral vector. Oncol Rep. 2014;31:1089–95.
49. Sakaguchi M, Watanabe M, Kinoshita R, et al. Dramatic increase in expression of a transgene by insertion of promoters downstream of the cargo gene. Mol Biotechnol. 2014;56:621–30.
Source: Clinical Medicine Insights: Oncology.
Originally published on March 23, 2015.