Following a century of preclinical and clinical work, oncolytic viruses are now proving themselves in randomized phase 3 trials. Interestingly, human data indicates that these agents have potent immunostimulatory activity, raising the possibility that the key consequence of oncolysis might be induction of antitumor immunity, especially in the context of viruses harboring immunostimulatory transgenes. While safety and efficacy of many types of oncolytic viruses, including adenovirus, herpes, reo, and vaccinia seem promising, few mechanisms of action studies have been performed with human substrates. Thus, the relative contribution of “pure” oncolysis, the immune response resulting from oncolysis, and the added benefit of adding a transgene remain poorly understood. Here, the available clinical data on oncolytic viruses is reviewed, with emphasis on immunological aspects. Since the “War on Cancer” was launched in the 1970s, the treatment of most cancers has improved steadily. Nevertheless, most metastatic solid tumors remain incurable. Therefore, new agents with novel mechanisms of action and lacking cross-resistance to the currently available approaches are needed. Due to hypothetical safety concerns, cancer gene therapy approaches have traditionally been based on viruses that are unable to replicate. Although such “vectors” have provided high preclinical efficacy and good clinical safety data, trials have suggested that their efficacy may be limited when faced with advanced and bulky disease, because of limited penetration from the needle tract into further area of the tumor. Nevertheless, in the context of local disease, even replication deficient viruses could have their uses when combined optimally to routine therapies [1, 2]. In the context of cancer therapy, nonreplicating viruses have largely been abandoned in favor of replication competent platforms, since there are few advantages to the former, as safety of the latter has proven excellent. Moreover, one could argue that there are few caveats to arming a virus, over an unarmed virus, assuming that the arming device adds to efficacy. Thus, armed replication competent viruses are now the most popular cancer gene therapy approach. Viruses featuring selective replication in tumor cells, also known as oncolytic viruses, can improve penetration of and dissemination within solid tumor masses [3–5]. Emerging data also suggests their ability to reach distant metastases through vasculature, following release from dying tumor cells [6]. One of the first events during virus replication is amplification of
References
[1]
M. Westphal, S. Yla-Herttuala, J. Martin, et al., “Adenovirus-mediated gene therapy with sitimagene ceradenovec followed by intravenous ganciclovir for patients with operable high-grade glioma (ASPECT): a randomised, open-label, phase 3 trial,” The Lancet Oncology, vol. 14, no. 9, pp. 823–833, 2013.
[2]
J. J. Pan, S. W. Zhang, C. B. Chen et al., “Effect of recombinant adenovirus-p53 combined with radiotherapy on long-term prognosis of advanced nasopharyngeal carcinoma,” Journal of Clinical Oncology, vol. 27, no. 5, pp. 799–804, 2009.
[3]
V. Cerullo, A. Koski, M. Vaha-Koskela, and A. Hemminki, “Chapter eight—oncolytic adenoviruses for cancer immunotherapy: data from mice, hamsters, and humans,” Advances in Cancer Research, vol. 115, pp. 265–318, 2012.
[4]
L. Kangasniemi and A. Hemminki, “Oncolytic adenovirus research and applications,” Future Virology, vol. 5, no. 6, pp. 745–761, 2010.
[5]
M. Raki, D. T. Rein, A. Kanerva, and A. Hemminki, “Gene transfer approaches for gynecological diseases,” Molecular Therapy, vol. 14, no. 2, pp. 154–163, 2006.
[6]
S. Bramante, A. Koski, A. Kipar, et al., “Serotype chimeric oncolytic adenovirus coding for GM-CSF for treatment of sarcoma in rodents and humans,” International Journal of Cancer, 2013.
[7]
J. D. Dias, I. Liikanen, K. Guse et al., “Targeted chemotherapy for head and neck cancer with a chimeric oncolytic adenovirus coding for bifunctional suicide protein FCU1,” Clinical Cancer Research, vol. 16, no. 9, pp. 2540–2549, 2010.
[8]
M. Raki, T. Hakkarainen, G. J. Bauerschmitz et al., “Utility of TK/GCV in the context of highly effective oncolysis mediated by a serotype 3 receptor targeted oncolytic adenovirus,” Gene Therapy, vol. 14, no. 19, pp. 1380–1388, 2007.
[9]
M. Rajecki, A. Kangasm？ki, L. Laasonen et al., “Sodium iodide symporter SPECT imaging of a patient treated with oncolytic adenovirus Ad5/3-Δ24-hNIS,” Molecular Therapy, vol. 19, no. 4, pp. 629–631, 2011.
[10]
E. Kelly and S. J. Russell, “History of oncolytic viruses: genesis to genetic engineering,” Molecular Therapy, vol. 15, no. 4, pp. 651–659, 2007.
[11]
J. R. Bischoff, D. H. Kirn, A. Williams et al., “An adenovirus mutant that replicates selectively in p53-deficient human tumor cells,” Science, vol. 274, no. 5286, pp. 373–376, 1996.
[12]
T. Mineta, S. D. Rabkin, and R. L. Martuza, “Treatment of malignant gliomas using ganciclovir-hypersensitive, ribonucleotide reductase-deficient herpes simplex viral mutant,” Cancer Research, vol. 54, no. 15, pp. 3963–3966, 1994.
[13]
M. J. Mastrangelo, H. C. Maguire Jr., L. C. Eisenlohr et al., “Intratumoral recombinant GM-CSF-encoding virus as gene therapy in patients with cutaneous melanoma,” Cancer Gene Therapy, vol. 6, no. 5, pp. 409–422, 1999.
[14]
T. R. Reid, S. Freeman, L. Post, F. McCormick, and D. Y. Sze, “Effects of Onyx-015 among metastatic colorectal cancer patients that have failed prior treatment with 5-FU/leucovorin,” Cancer Gene Therapy, vol. 12, no. 8, pp. 673–681, 2005.
[15]
A. K. Koski, H. Ahtinen, H. Liljenback, et al., “FDG-PET and CT in response evaluation of oncolytic adenovirus treatments of patients with advanced cancer,” Human Gene Therapy, vol. 24, no. 12, pp. 1029–1041, 2013.
[16]
J. D. Wolchok, A. Hoos, S. O'Day et al., “Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria,” Clinical Cancer Research, vol. 15, no. 23, pp. 7412–7420, 2009.
[17]
V. Cerullo, S. Pesonen, I. Diaconu et al., “Oncolytic adenovirus coding for granulocyte macrophage colony-stimulating factor induces antitumoral immunity in cancer patients,” Cancer Research, vol. 70, no. 11, pp. 4297–4309, 2010.
[18]
A. Hemminki, “Portrait of a leader in immunotherapeutics: oncolytic viruses for treatment of cancer,” Human Vaccines & Immunotherapeutics, vol. 8, no. 8, pp. 1018–1021, 2012.
[19]
A. Koski, L. Kangasniemi, S. Escutenaire et al., “Treatment of cancer patients with a serotype 5/3 chimeric oncolytic adenovirus expressing GMCSF,” Molecular Therapy, vol. 18, no. 10, pp. 1874–1884, 2010.
[20]
S. Pesonen, I. Diaconu, V. Cerullo et al., “Integrin targeted oncolytic adenoviruses Ad5-D24-RGD and Ad5-RGD-D24-GMCSF for treatment of patients with advanced chemotherapy refractory solid tumors,” International Journal of Cancer, vol. 130, no. 8, pp. 1937–1947, 2012.
[21]
O. Hemminki, I. Diaconu, V. Cerullo, et al., “Ad3-hTERT-E1A, a fully serotype 3 oncolytic adenovirus, in patients with chemotherapy refractory cancer,” Molecular Therapy, vol. 20, no. 9, pp. 1821–1830, 2012.
[22]
S. Pesonen, I. Diaconu, L. Kangasniemi et al., “Oncolytic immunotherapy of advanced solid tumors with a CD40L-expressing replicating adenovirus: assessment of safety and immunologic responses in patients,” Cancer Research, vol. 72, no. 7, pp. 1621–1631, 2012.
[23]
P. Nokisalmi, S. Pesonen, S. Escutenaire et al., “Oncolytic adenovirus ICOVIR-7 in patients with advanced and refractory solid tumors,” Clinical Cancer Research, vol. 16, no. 11, pp. 3035–3043, 2010.
[24]
A. Kanerva, P. Nokisalmi, I. Diaconu, et al., “Antiviral and antitumor T-cell immunity in patients treated with GM-CSF-coding oncolytic adenovirus,” Clinical Cancer Research, vol. 19, no. 10, pp. 2734–2744, 2013.
[25]
I. Liikanen, L. Ahtiainen, M. L. Hirvinen, et al., “Oncolytic adenovirus with temozolomide induces autophagy and antitumor immune responses in cancer patients,” Molecular Therapy, vol. 21, no. 6, pp. 1212–1223, 2013.
[26]
R. J. Prestwich, F. Errington, R. M. Diaz et al., “The case of oncolytic viruses versus the immune system: waiting on the judgment of Solomon,” Human Gene Therapy, vol. 20, no. 10, pp. 1119–1132, 2009.
[27]
K. A. Parato, B. D. Lichty, and J. C. Bell, “Diplomatic immunity: turning a foe into an ally,” Current Opinion in Molecular Therapeutics, vol. 11, no. 1, pp. 13–21, 2009.
[28]
V. Cerullo, I. Diaconu, V. Romano, et al., “An oncolytic adenovirus enhanced for toll-like receptor 9 stimulation increases antitumor immune responses and tumor clearance,” Molecular Therapy, vol. 20, no. 11, pp. 2076–2086, 2012.
[29]
I. Diaconu, V. Cerullo, S. Escutenaire et al., “Human adenovirus replication in immunocompetent Syrian hamsters can be attenuated with chlorpromazine or cidofovir,” Journal of Gene Medicine, vol. 12, no. 5, pp. 435–445, 2010.
[30]
I. Liikanen, V. Monsurrò, L. Ahtiainen et al., “Induction of interferon pathways mediates in vivo resistance to oncolytic adenovirus,” Molecular Therapy, vol. 19, no. 10, pp. 1858–1866, 2011.
[31]
G. J. Bauerschmitz, J. T. Lam, A. Kanerva et al., “Treatment of ovarian cancer with a tropism modified oncolytic adenovirus,” Cancer Research, vol. 62, no. 5, pp. 1266–1270, 2002.
[32]
A. Hemminki, I. Dmitriev, B. Liu, R. A. Desmond, R. Alemany, and D. T. Curiel, “Targeting oncolytic adenoviral agents to the epidermal growth factor pathway with a secretory fusion molecule,” Cancer Research, vol. 61, no. 17, pp. 6377–6381, 2001.
[33]
A. Kanerva, M. Wang, G. J. Bauerschmitz et al., “Gene transfer to ovarian cancer versus normal tissues with fiber-modified adenoviruses,” Molecular Therapy, vol. 5, no. 6, pp. 695–704, 2002.
[34]
A. Hemminki, A. Kanerva, B. Liu et al., “Modulation of coxsackie-adenovirus receptor expression for increased adenoviral transgene expression,” Cancer Research, vol. 63, no. 4, pp. 847–853, 2003.
[35]
A. Kanerva and A. Hemminki, “Modified adenoviruses for cancer gene therapy,” International Journal of Cancer, vol. 110, no. 4, pp. 475–480, 2004.
[36]
A. Kanerva, G. J. Bauerschmitz, M. Yamamoto et al., “A cyclooxygenase-2 promoter-based conditionally replicating adenovirus with enhanced infectivity for treatment of ovarian adenocarcinoma,” Gene Therapy, vol. 11, no. 6, pp. 552–559, 2004.
[37]
K. Saukkonen and A. Hemminki, “Tissue-specific promoters for cancer gene therapy,” Expert Opinion on Biological Therapy, vol. 4, no. 5, pp. 683–696, 2004.
[38]
G. J. Bauerschmitz, K. Guse, A. Kanerva et al., “Triple-targeted oncolytic adenoviruses featuring the Cox2 promoter, E1A transcomplementation, and serotype chimerism for enhanced selectivity for ovarian cancer cells,” Molecular Therapy, vol. 14, no. 2, pp. 164–174, 2006.
[39]
S. Pesonen, P. Nokisalmi, S. Escutenaire et al., “Prolonged systemic circulation of chimeric oncolytic adenovirus Ad5/3-Cox2L-D24 in patients with metastatic and refractory solid tumors,” Gene Therapy, vol. 17, no. 7, pp. 892–904, 2010.
[40]
S. Pesonen, H. Helin, P. Nokisalmi et al., “Oncolytic adenovirus treatment of a patient with refractory neuroblastoma,” Acta Oncologica, vol. 49, no. 1, pp. 117–119, 2010.
[41]
A. Kanerva, K. R. Zinn, T. R. Chaudhuri et al., “Enhanced therapeutic efficacy for ovarian cancer with a serotype 3 receptor-targeted oncolytic adenovirus,” Molecular Therapy, vol. 8, no. 3, pp. 449–458, 2003.
[42]
H. Wang, Z. Li, Y. Liu et al., “Desmoglein 2 is a receptor for adenovirus serotypes 3, 7, 11 and 14,” Nature Medicine, vol. 17, no. 1, pp. 96–104, 2011.
[43]
A. Kanerva, G. V. Mikheeva, V. Krasnykh et al., “Targeting adenovirus to the serotype 3 receptor increases gene transfer efficiency to ovarian cancer cells,” Clinical Cancer Research, vol. 8, no. 1, pp. 275–280, 2002.
[44]
J. N. Glasgow, G. J. Bauerschmitz, D. T. Curiel, and A. Hemminki, “Transductional and transcriptional targeting of adenovirus for clinical applications,” Current Gene Therapy, vol. 4, no. 1, pp. 1–14, 2004.
[45]
H. Wang, Z. Li, R. Yumul et al., “Multimerization of adenovirus serotype 3 fiber knob domains is required for efficient binding of virus to desmoglein 2 and subsequent opening of epithelial junctions,” Journal of Virology, vol. 85, no. 13, pp. 6390–6402, 2011.
[46]
O. Hemminki, G. Bauerschmitz, S. Hemmi et al., “Oncolytic adenovirus based on serotype 3,” Cancer Gene Therapy, vol. 18, no. 4, pp. 288–296, 2011.
[47]
T. Ranki, L. Kangasniemi, P. Ahokas, et al., “Preclinical and clinical evaluation of oncolytic immunotherapy with Ad5/3-E2F1-Delta 24-GMCSF (CGTG-602), a GM-CSF producing adenovirus targeted to tumors on four levels,” Molecular Therapy, vol. 20, pp. S36–S36, 2012.
[48]
I. Diaconu, V. Cerullo, M. L. M. Hirvinen et al., “Immune response is an important aspect of the antitumor effect produced by a CD40L-encoding oncolytic adenovirus,” Cancer Research, vol. 72, no. 9, pp. 2327–2338, 2012.
[49]
S. Westberg, A. Sadeghi, E. Svensson, et al., “Treatment efficacy and immune stimulation by AdCD40L gene therapy of spontaneous canine malignant melanoma,” Journal of Immunotherapy, vol. 36, no. 6, pp. 350–358, 2013.
[50]
J. D. Dias, O. Hemminki, I. Diaconu et al., “Targeted cancer immunotherapy with oncolytic adenovirus coding for a fully human monoclonal antibody specific for CTLA-4,” Gene Therapy, vol. 19, no. 10, pp. 988–998, 2012.
[51]
T. Hakkarainen, M. Rajecki, M. Sarparanta et al., “Targeted radiotherapy for prostate cancer with an oncolytic adenovirus coding for human sodium iodide symporter,” Clinical Cancer Research, vol. 15, no. 17, pp. 5396–5403, 2009.
[52]
M. Rajecki, M. Sarparanta, T. Hakkarainen et al., “SPECT/CT imaging of hNIS -expression after intravenous delivery of an oncolytic adenovirus and131I,” PLoS ONE, vol. 7, no. 3, Article ID e32871, 2012.
[53]
K. N. Barton, H. Stricker, M. A. Elshaikh et al., “Feasibility of adenovirus-mediated hnis gene transfer and 131 i radioiodine therapy as a definitive treatment for localized prostate cancer,” Molecular Therapy, vol. 19, no. 7, pp. 1353–1359, 2011.
[54]
M. Rajecki, T. Af H？llstr？m, T. Hakkarainen et al., “Mre11 inhibition by oncolytic adenovirus associates with autophagy and underlies synergy with ionizing radiation,” International Journal of Cancer, vol. 125, no. 10, pp. 2441–2449, 2009.
[55]
I. Liikanen, J. D. Dias, P. Nokisalmi et al., “Adenoviral E4orf3 and E4orf6 proteins, but not E1B55K, increase killing of cancer cells by radiotherapy in vivo,” International Journal of Radiation Oncology Biology Physics, vol. 78, no. 4, pp. 1201–1209, 2010.
[56]
P. Nokisalmi, M. Rajecki, S. Pesonen et al., “Radiation-induced upregulation of gene expression from adenoviral vectors mediated by DNA damage repair and regulation,” International Journal of Radiation Oncology Biology Physics, vol. 83, no. 1, pp. 376–384, 2012.
[57]
M. Raki, A. Kanerva, A. Ristimaki et al., “Combination of gemcitabine and Ad5/3-Δ24, a tropism modified conditionally replicating adenovirus, for the treatment of ovarian cancer,” Gene Therapy, vol. 12, no. 15, pp. 1198–1205, 2005.
[58]
M. Raki, M. S？rkioja, R. A. Desmond et al., “Oncolytic adenovirus Ad5/3-Δ24 and chemotherapy for treatment of orthotopic ovarian cancer,” Gynecologic Oncology, vol. 108, no. 1, pp. 166–172, 2008.
[59]
V. Cerullo, I. Diaconu, L. Kangasniemi et al., “Immunological effects of low-dose cyclophosphamide in cancer patients treated with oncolytic adenovirus,” Molecular Therapy, vol. 19, no. 9, pp. 1737–1746, 2011.
[60]
H. Jiang, C. Gomez-Manzano, H. Aoki et al., “Examination of the therapeutic potential of Delta-24-RGD in brain tumor stem cells: role of autophagic cell death,” Journal of the National Cancer Institute, vol. 99, no. 18, pp. 1410–1414, 2007.
[61]
F. J. Zemp, B. A. McKenzie, X. Lun, et al., “Resistance to oncolytic myxoma virus therapy in nf1(-/-)/trp53(-/-) syngeneic mouse glioma models is independent of anti-viral type-I interferon,” PLoS ONE, vol. 8, Article ID e65801, 2013.
[62]
M. Moerdyk-Schauwecker, N. R. Shah, A. M. Murphy, et al., “Resistance of pancreatic cancer cells to oncolytic vesicular stomatitis virus: role of type I interferon signaling,” Virology, vol. 436, no. 1, pp. 221–234, 2013.
[63]
T. Muster, J. Rajtarova, M. Sachet et al., “Interferon resistance promotes oncolysis by influenza virus NS1-deletion mutants,” International Journal of Cancer, vol. 110, no. 1, pp. 15–21, 2004.
[64]
N. Casares, M. O. Pequignot, A. Tesniere et al., “Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death,” Journal of Experimental Medicine, vol. 202, no. 12, pp. 1691–1701, 2005.
[65]
M. Obeid, A. Tesniere, F. Ghiringhelli et al., “Calreticulin exposure dictates the immunogenicity of cancer cell death,” Nature Medicine, vol. 13, no. 1, pp. 54–61, 2007.
[66]
L. Galluzzi, L. Senovilla, L. Zitvogel, and G. Kroemer, “The secret ally: immunostimulation by anticancer drugs,” Nature Reviews Drug Discovery, vol. 11, no. 3, pp. 215–233, 2012.
[67]
L. Zitvogel, O. Kepp, and G. Kroemer, “Immune parameters affecting the efficacy of chemotherapeutic regimens,” Nature Reviews Clinical Oncology, vol. 8, no. 3, pp. 151–160, 2011.
[68]
A. Hemminki, “From molecular changes to customised therapy,” European Journal of Cancer, vol. 38, no. 3, pp. 333–338, 2002.
[69]
J. R. Brahmer, S. S. Tykodi, L. Q. Chow, et al., “Safety and activity of anti-PD-L1 antibody in patients with advanced cancer,” The New England Journal of Medicine, vol. 366, pp. 2455–2465, 2012.
[70]
S. L. Topalian, F. S. Hodi, J. R. Brahmer, et al., “Safety, activity, and immune correlates of anti-PD-1 antibody in cancer,” The New England Journal of Medicine, vol. 366, pp. 2443–2454, 2012.
[71]
W. Yu and H. Fang, “Clinical trials with oncolytic adenovirus in China,” Current Cancer Drug Targets, vol. 7, no. 2, pp. 141–148, 2007.
[72]
R. H. I. Andtbacka, F. A. Collichio, T. Amatruda, et al., “OptiM: a randomized phase III trial of talimogene laherparepvec (T-VEC) versus subcutaneous (SC) granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment (tx) of unresected stage IIIB/C and IV melanoma,” in Proceedings of the ASCO Annual Meeting, 2013.
