Biological Sciences
Oncolytic Viruses
Oncolytic viruses are a type of virus that can selectively infect and kill cancer cells while sparing normal cells. They are being studied as a potential treatment for cancer, either alone or in combination with other therapies. Oncolytic viruses work by replicating within cancer cells, causing them to burst and die, and also by stimulating the immune system to target the cancer.
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11 Key excerpts on "Oncolytic Viruses"
eBook - ePub- Luigi Buonaguro, Sjoerd Van Der Burg(Authors)
- 2022(Publication Date)
- Academic Press(Publisher)
Chapter 1Oncolytic Viruses for antigen delivery
Erkko Ylösmäki1 ,2, Vincenzo Cerullo1 ,2 ,3 ,4, John C. Bell5 and Marie-Claude Bourgeois-Daigneault6 ,7 ,8,1 Laboratory of Immunovirotherapy, Drug Research Program, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland,2 TRIMM, Translational Immunology Research Program, University of Helsinki, Helsinki, Finland,3 iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Helsinki, Finland,4 Department of Molecular Medicine and Medical Biotechnology and CEINGE, Naples University Federico II, Naples, Italy,5 Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada,6 “Centre Hospitalier de l’Université de Montréal” CRCHUM, Montreal, QC, Canada,7 “Institut du cancer de Montréal”, Montreal, QC, Canada,8 Department of Microbiology, Infectious Diseases and Immunology, Faculty of Medicine, University of Montreal, Montreal, QC, CanadaAbstract
New immunotherapies are rapidly changing the way we treat cancer. These immunotherapies aim to harness the power of a patient’s own immune system to control and, in some instances, eliminate cancer. Oncolytic Viruses (OVs) that have been designed to specifically kill cancer cells and leave healthy cells unharmed are being used as immunotherapies to treat various types of cancers. OVs can increase anticancer immunity via the oncolysis-driven release of tumor-associated antigens, leading to in situ anticancer vaccination effects by (1) modulating the immunosuppressive microenvironment of the tumor and (2) attracting immune cells, such as tumor-killing effector T cells into cancerous tissue. OVs can be engineered to deliver immune-activating molecules, such as cytokines or tumor antigens, to further enhance the anticancer effects of these viruses. Furthermore, OVs can be combined with other cancer immunotherapies, such as immune checkpoint inhibitors. Here, we discuss the inherent anticancer immune activating characteristics of OVs, and how OV-induced anticancer immunity can be enhanced and targeted against specific cancer (neo)antigens by rational engineering of OVs.
eBook - ePubGene Therapy of Cancer
Translational Approaches from Preclinical Studies to Clinical Implementation
- Edmund C. Lattime, Stanton L. Gerson(Authors)
- 2013(Publication Date)
- Academic Press(Publisher)
Section II Oncolytic Viruses OutlineSection II. Oncolytic Viruses Chapter 10 Advances in Oncolytic Virotherapy for Brain TumorsChapter 12 Selectively Replicating Oncolytic Adenoviruses Combined with Chemotherapy, Radiotherapy, or Molecular Targeted Therapy for Treatment of Human Cancers Chapter 13 Reoviral Therapy for Cancer Chapter 14 Selectively Replicating Herpes Simplex Viral Vectors Chapter 15 Modified Oncolytic Herpesviruses for Gene Therapy of Cancer Chapter 16 The Lister Strain of Vaccinia Virus as an Anticancer Therapeutic AgentChapter 11 Oncolytic Adenoviruses in the Treatment of Cancer in Humans11Conflict of interest: O.H. and A.H. are shareholders in Oncos Therapeutics Ltd. A.H. is a consultant for Oncos Therapeutics Ltd.
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Section II. Oncolytic Viruses
Overview of Oncolytic Viruses and Clinical Applications
Studies from a number of groups and utilizing a number of viral candidates have focused on the premise that targeting lytic viruses to tumor might be effective in lysing the resultant infected tumor cells and effectively controlling tumor growth. Although the approach has generated significant enthusiasm, a number of inherent limitations of the vectors and delivery approaches have stood in the way of successful clinical therapy.Common limitations have reduced the effectiveness of most oncolytic viral strategies and required that modifications be made in the viruses and their delivery. These include overcoming the inherent immunogenicity of the viruses used; for example, when utilizing adenovirus, one had to deal with preexisting immunity to adenovirus in the majority of individuals. Although novel viruses might circumvent this for a single dose, repeated treatments would be problematic. Delivery to the tumor site or at least preferential infection and replication in tumor cells limited the efficiency of systemic delivery, whereas local delivery to the primary tumor site spared metastatic foci. In addition, limiting viral infection and replication to tumor cells, thus precluding toxicity of normal populations, was also a hurdle.
eBook - PDFGene and Cell Therapy
Therapeutic Mechanisms and Strategies, Fourth Edition
- Nancy Smyth Templeton(Author)
- 2015(Publication Date)
- CRC Press(Publisher)
An overview of historical trials with Oncolytic Viruses has been listed in Table 8.1. 8.3 Oncolytic Viruses An oncolytic virus considered for treatment of cancer should have several important properties. Optimally, a virus must be able to infect, replicate in, and kill human tumor cells includ-ing nondividing cancer cells [2–4]. From a safety standpoint, the parental virus should cause only mild, well-characterized human disease. Further, a nonintegrating virus would decrease the risk of acquiring unwanted changes to the host genome. Viral replication in normal tissues might be prevent-able by genetic engineering or by utilizing agents that are capable of inactivating virus if necessary [18] and or increase the virus immunogenicity [19]. Also, a genetically stable virus that can be easily purified to high titers according to current good manufacturing practices (cGMP) is desirable. There are various approaches for achieving selective viral replication in tumor cells.
eBook - ePub- Boriana Marintcheva(Author)
- 2017(Publication Date)
- Academic Press(Publisher)
Fig. 9.3 ). Similar to phage therapy, the application of OVs in medicine (also known as oncolytic virotherapy) has a long history of fluctuating interest, growing potential and recent advancements. The first data suggesting that viruses could be a potential tool to fight cancer came from observations that cancer patients went into a temporary remission when experiencing illness of viral origin or were undergoing vaccination with virus-based vaccines. These observations correlate with reports dating back to the 19th century (before viruses were discovered) that infectious bodily fluids from humans and animals with certain diseases (mumps, hepatitis) were given to cancer patients in attempts to inflict therapeutic benefits. Such practices had very limited success and quickly were discontinued. Conclusive evidence according to the modern standards was obtained in the mid-20th century when it was shown that mouse sarcoma tumors can be selectively destroyed by Russian Far East encephalitis virus. As one can imagine, the mice died from encephalitis clearly pinpointing the need to separate oncolysis and pathogenicity. With the advancement of molecular biology, detailed characterization of pathogenic viruses became possible, enabling understanding of the natural oncolytic properties of viruses and rational modifications for the purpose of designing Oncolytic Viruses. The first formally approved OVs were reported in Latvia (2004, natural ECHO-7 strain of human enterovirus) and China (2005, genetically engineered adenovirus H101) for the treatment of melanoma and head and neck cancers, respectively. The first OV approved in the United States and Western Europe was reported in 2015 (T-vec, Amgen; a modified Herpes Simplex Virus Type 1) for the treatment of melanoma patients with inoperable tumors. In 2016, there were approximately 40 clinical trials recruiting patients with various cancers for protocols employing herpesvirus, adenovirus, vaccinia virus, measles virus, and poliovirus, among others.Figure 9.3 Conceptual principle of Oncolytic Viruses.Oncolytic Viruses selectively infect and propagate in cancer cells inflicting no harm to normal cells. Selectivity is driven from the complementary nature of the specific properties of the virus and the cellular environment allowing for productive cell entry (based on viral ligand/cellular receptor interaction) and effective viral replication evading the cellular antiviral defenses.9.2.1. Mechanism of Action
Oncolytic Viruses are a unique and multidimensional class of therapeutic agents with rather diverse mechanisms of action. They combat cancer directly, selectively killing malignant cells and/or inducing anticancer immune response, or indirectly lysing endothelial cells of the tumor vasculature and thus depriving tumors from oxygen and nutrients (Fig. 9.4 ).Some viruses are naturally oncolytic and preferentially infect cancer cells with specific characteristics such as: ras mutations (reovirus); interferon response–related mutation (vesicular stomatitis virus [VSV], Newcastle disease virus); presence of specific cell surface receptors (poliovirus/CD155; measles virus/CD46 or CD150); malignancy-driven cellular changes (extracellular matrix alterations promoting herpes simplex virus type 1 [HSV-1] infection). Most of the OVs are genetically engineered and thus can be considered gene therapy agents targeting cancer. Several rational design approaches to engineering have been employed such as alteration of viral surface molecules to ensure OV attachment to cancer cells, deletion of genes essential for propagation in normal cells, placing essential viral genes under the control of tumor-associated transcription factors, expression of molecules stimulating immune response. Another strategy of identifying OVs is conventional selection. For example, a pool of recombinant adenoviruses was generated by coculturing several types of adenoviruses under conditions promoting recombination. The pool was then tested for the ability to propagate and lyse different types of cancer cells, and the most potent viruses were selected. A second round of selection was performed in normal cells to exclude viruses replicating in healthy cells. An OV in clinical testing known as ColoAd1/Enadenotucirev/EnAd was selected for its ability to kill colorectal cancer cells with high potency and specificity. Molecular analysis demonstrated that the recombinant virus is based on Ad11p and Ad3 adenovirus types and harbors several deletions; however, the precise mechanism of its action remains to be understood.
eBook - ePubThe Molecular Basis of Cancer E-Book
The Molecular Basis of Cancer E-Book
- John Mendelsohn, Peter M. Howley, Mark A. Israel, Joe W. Gray, Craig B. Thompson(Authors)
- 2014(Publication Date)
- Saunders(Publisher)
In addition to naturally occurring viruses, many efforts have been made to engineer viruses to replicate in tumor cells selectively. Such agents kill cells through lytic mechanisms and potentially spread from one infected cell to another, amplifying the dose of the selective killing agent. Selectivity for cancer cells can be achieved by several strategies. The first uses DNA synthetic enzymes produced by proliferating tumor cells to support replication of DNA viruses that are otherwise defective. The second takes advantage of genetic defects in cancer cells that supply functions that have been specifically deleted from the oncolytic agent, and the third uses tumor-selective promoters to drive replication of conditionally replicating viruses.Herpes Simplex Viruses
One of the first viruses designed to replicate in cancer selectively were HSVs that had been engineered so that they were unable to express viral genes necessary for DNA replication, such as thymidine kinase or ribonucleotide reductase. Proliferating cells would provide these essential functions, whereas resting normal cells would not. HSV G207 is an example of such an oncolytic virus. In addition to inactivation of a subunit of the viral ribonucleotide reductase gene, both copies of the neurovirulence gene, the gamma(1)34.5 gene, are deleted to further reduce replication in normal tissues.60 Although direct tumor cell killing represents a major mechanism of action of these viruses, evidence from experiments in immunocompetent mouse models suggests that also a vaccination effect mediated by activated T lymphocytes contributes to the effect.61 Phase I clinical trials of G207 and a related virus, HSV1716, have been completed and demonstrated the safety of these viruses.62 Another related HSV mutant, NV1020, has been tested in a Phase I study in patients with hepatic metastases from colorectal cancer. The virus was administered into the hepatic artery in a Phase I study. Only mild toxicity was observed, and a decline in CEA levels was suggestive of some antitumor activity.63 Many innovative approaches have been employed to improve the clinical value of HSV viruses, including expression of prodrug-converting enzymes to elicit bystander cells and the addition of genes encoding cytokines to boost immune recognition of tumor cells. The latter approach has been taken into the clinic in the form of the HSV mutant OncoVex(GM-CSF), a conditionally replicating HSV-1 mutant that expresses the cytokine GM-CSF. A Phase I/II trial with intratumorally injected Oncovex GM-CSF demonstrated that this agent is well tolerated.64
eBook - ePubTranslating Gene Therapy to the Clinic
Techniques and Approaches
- Jeffrey Laurence, Michael Franklin(Authors)
- 2014(Publication Date)
- Academic Press(Publisher)
141 The downside, of course, remains antiviral immune responses which can thwart the spread and replication of the therapeutic agent. Thus, future work will need to elucidate ways to tip the balance of immunity towards antitumor activity and away from antiviral activity; this approach will be critical for improving therapy. Given the limitations of animal models described above, it will be critical to design early phase trials with strong correlative science so that we can learn detailed information about the biology of these agents in humans. Fortunately, ongoing clinical trials will provide a wealth of information in that regard.Acknowledgments
The authors would like to thank Blake Jacobson for his critical review of the manuscript.References
1. Eager R.M, Nemunaitis J. Clinical development directions in oncolytic viral therapy. Cancer Gene Ther. May 2011;18(5):305–317.2. Hammill A.M, Conner J, Cripe T.P. Oncolytic virotherapy reaches adolescence. Pediatr Blood Cancer. December 15, 2010;55(7):1253–1263.3. Breitbach C.J, Reid T, Burke J, Bell J.C, Kirn D.H. Navigating the clinical development landscape for Oncolytic Viruses and other cancer therapeutics: no shortcuts on the road to approval. Cytokine Growth Factor Rev. April–June 2010;21(2–3):85–89.4. Patel M.R, Kratzke R.A. Oncolytic virus therapy for cancer: the first wave of translational clinical trials. Transl Res. April 2013;161(4):355–364.5. Kawakami Y, Li H, Lam J.T, Krasnykh V, Curiel D.T, Blackwell J.L. Substitution of the adenovirus serotype 5 knob with a serotype 3 knob enhances multiple steps in virus replication. Cancer Res. March 15, 2003;63(6):1262–1269.6. Myhre S, Henning P, Friedman M, Stahl S, Lindholm L, Magnusson M.K. Re-targeted adenovirus vectors with dual specificity; binding specificities conferred by two different Affibody molecules in the fiber. Gene Ther
eBook - PDFComputational Biology Of Cancer: Lecture Notes And Mathematical Modeling
Lecture Notes and Mathematical Modeling
- Dominik Wodarz, Natalia Komarova(Authors)
- 2005(Publication Date)
- World Scientific(Publisher)
Yet challenges remain. In Therapeutic approaches: viruses as anti-tumor weapons 207 particular, it is unclear which virus characteristics are most optimal for therapeutic purposes. Viruses have been altered in a variety of ways by targeted mutations, but it is not clear what types of mutants have to be produced in order to achieve extinction of the cancer. Viruses can be al-tered with respect to their rate of infection, rate of replication, or the rate at which they kill cancer cells. Some studies have introduced explosive genes which the virus can deliver to the cancer cells and which will kill the cells instantly. If tumor eradication does not occur, the outcome can be the persistence of both the tumor and the virus infection, and this would be detrimental for patients. Persistence of both tumor and virus has been seen in experiments with a mouse model system by Harrison et al. [Harrison et al. (2001)]. The reason for the failure to eradicate the tumor despite ongoing viral replication was left open to speculation. Mathematical models have been used to address this question. Taking into account the complex interactions between viruses, tumor cells, and immune responses, such models have identified conditions under which on-colytic virus therapy is most likely to result in successful clearance of cancer. This chapter discusses these insights. The models take into account a va-riety of mechanisms which can contribute to cancer elimination. On the most basic level, virus infection and the consequent virus-induced death of the cancer cell can be responsible for tumor eradication. On top of this, the immune system is expected to have an effect. In particular, cytotoxic T lymphocytes (CTL, reviewed in Chapter 11) are likely to be important. These immune responses can kill cells which display foreign or mutated proteins. They may act in two basic ways. They can recognize the virus presented on infected cells and kill virus-infected cells.
eBook - PDF- Joseph G. Sinkovics, Joseph Horvath, Joseph G. Sinkovics, Joseph Horvath(Authors)
- 2004(Publication Date)
- CRC Press(Publisher)
One of the challenges for the fu-ture therefore lies in the identification of optimal target tu-mors for parvovirus-based therapies. MECHANISMS UNDERLYING THE ANTITUMOR ACTIVITY OF NATURAL PARVOVIRUSES Although parvoviruses may kill tumor cells in a direct way under in vivo conditions (viral oncolysis), the success of ther-apy will undoubtedly depend on at least two additional by-stander effects: the immunological consequences of this tumor cell death, and the virus-induced perturbation of the immune system. These various aspects will be discussed separately in the following paragraphs. Direct Evidence of Parvovirus Oncolytic Effects in Cell Cultures Preferential Killing of (Pre) Neoplastic Cells in Culture Cytocidal processes associated with tumor regression in in-fected animals are likely to be mediated, at least in part, by im-mune effector cells and do not constitute proof that the virus has a direct oncolytic activity. Therefore, in vitro cell cultures were used to determine whether parvoviruses could kill (pre) neo-plastic cells in preference to the parental normal cells. Indeed, it was repeatedly observed that various normal human and ro-dent cells were more resistant to wild-type H-1 or MVMp infec-tion than in vitro transformed derivatives or tumor-derived Parvoviruses As Anti-Cancer Agents 643 cells from the same tissue origin [68–75]. This holds true for cells of both mesenchymal and epithelial origins. Cultures of human tumor cells are more particularly sensitive to H-1 virus infection, albeit to various extents [5,69,75,76]. A striking ex-ample of the oncolytic effect of H-1 virus in vitro is illustrated in Figure 3. Several human leukemic cell lines could be killed Figure 3 Hypersensitivity of a human squamous cell carcinoma cell line (c, d) to the cytopathic effects of wild-type parvovirus H-1, in comparison with normal human keatinocytes (a, c). a, c: mock-treated cultures; b, d: H1-virus infected cultures.
eBook - ePubCancer Chemotherapy
Basic Science to the Clinic
- Gary S. Goldberg, Rachel Airley, Gary S. Goldberg, Rachel Airley(Authors)
- 2020(Publication Date)
- Wiley-Blackwell(Publisher)
Like HSV, adenoviruses contain double‐stranded DNA and infect most people, and a wide range of other vertebrate organisms, around the world. They cause a variety of human illnesses ranging from the common cold to multiple organ failure. Examples of oncolytic adenoviruses include ad2/5dl1520 (Onyx‐015®), H101 (Oncorine®), and Ad4CMV‐p53 (Advexin® and Gendicine®). The adenoviral E1B gene, which neutralizes host p53 activity, has been deleted in Onyx‐015 in order to restrict its replication and lysis to p53‐deficient cancer cells. Oncorine is also E1B deleted, as well as partial deletion of its E3 gene that would otherwise protect infected cells from T‐cell‐mediated killing. This E1B/E3 combined deficiency enhances the specificity and safety this oncolytic construct. Advexin and Gendicine are adenoviral constructs that utilize a CMV promoter to produce wild‐type p53 in infected cells to force intrinsic apoptosis mechanisms as they proceed through the cell cycle. Oncolytic adenoviral constructs are being used to treat cancers including metastatic melanoma and head and neck squamous cell carcinoma.Vaccinia virus (VAV) has linear double‐stranded DNA that replicates in the cytoplasm instead of the nucleus. Strains include pathogens that cause cowpox and smallpox discussed earlier in this chapter. Vaccinia virus may have been used as the first oncolytic virus. Reports since the 1920s describe its ability to inhibit tumor growth in animal models. Current oncolytic constructs include GLV‐1h68 (GL‐ONC1), rilimogene galvacirepvec/rilimogene glafolivec (Prostvac®), and JX‐594 (Pexa‐Vec®). GL‐ONC1 is engineered to express a luciferase‐green fluorescent fusion protein fusion, beta‐galactosidase, and beta‐glucuronidase in place of the viral thymidine kinase and hemagglutinin proteins. These modifications are designed to attenuate the virus while it lyses infected cells and induces an antitumor immune response. Prostvac vaccinia constructs express prostate‐specific antigen (PSA) described in sections 1.4 and 5.9, along with LFA3 (lymphocyte function‐associated antigen), ICAM1 (intercellular adhesion molecule 1), and B7.1 (CD80) which stimulate an immune response to infected cells. The treatment regimen involves causing the patient immune system to focus T‐cell responses on prostate cancer cells that produce PSA. The viral thymidine kinase gene has been deleted from Pexa‐Vec constructs to limit its replication to cells with high endogenous thymidine kinase expression that are typically found in cancer cells with mutated RAS and p53 genes, and are also engineered to express beta‐galactosidase and GM‐CSF in order to augment an anticancer immune response.
eBook - ePub- David T. Curiel(Author)
- 2016(Publication Date)
- Academic Press(Publisher)
12Molecular Design of Oncolytic Adenoviruses
Ramon Alemany IDIBELL-Institut Català d’Oncologia, L’Hospitalet de Llobregat, Barcelona, SpainAbstract
This chapter aims to review different genetic modifications that have been used to design tumor-selective (“oncolytic”) adenoviruses. Other nongenetic modifications have been used to improve the antitumor properties of adenoviruses, such as pegylation of the capsid and nonviral delivery of infectious genomes, but these are not in the scope of this chapter. The methods to construct recombinant adenoviruses are presented elsewhere in this book. The chapter explains genetic modifications to achieve tumor-selective replication, to increase oncolytic potency, the insertion of transgenes, and finally, genetic modification of the capsid for tumor targeting and epitope display. The nucleotide positions or insertions or deletions commonly used in the design of oncolytic adenoviruses are indicated based on the human adenovirus type 5 reference material, GenBank Accession Number AY339865.Keywords
Adenovirus; Genetic engineering; Molecular design; Oncolytic; Regulatory sequences1. Introduction
Among different Oncolytic Viruses, adenovirus has several traits that facilitate the design of oncolytic or tumor-selective recombinants. Most serotypes of adenovirus use the fiber (nt 31037–32782 of human Ad5 reference material) to interact with well-defined protein receptors (CAR, CD46, or desmoglein 2) at the cell membrane, allowing for receptor-targeting strategies. Later, in the late phase of the infectious cycle, the newly synthesized fiber will not only pass to the progeny but also will be secreted to the extracellular medium in large amounts, and this can be used to open intercellular junctions on adjacent cells to facilitate virus spread. The penton base RGD (nt 15174–15183) motif is involved in a second step of cell internalization by binding to integrins that drive the virus to the endocytic pathway, and this internalization step can also be modulated in recombinant adenoviruses. The protein surface of the virus, mainly formed by the hexon (nt 18842–21700), contributes to surface charge and to other interactions with host antibodies and other proteins (such as FX clotting factor or scavenger receptors) that can also be modulated to improve systemic tumor targeting. The existence of multiple serotypes of adenovirus may be used to create chimerical viruses that evade preexisting immunity issues. Adenovirus has a natural tropism to infect and replicate in epithelial cells, the origin of most solid tumors. The viral DNA expression occurs in the nuclei of infected cells and it follows a timely orchestrated series of activation steps, initiated by the expression of early 1a (E1a ) genes. This allows the control viral replication replacing the E1a promoter by a tumor-selective promoter. Viral progeny accumulates in the nuclei of infected cells and its release can be accelerated using different genetic modifications. Finally, the adenoviral genome can be armed with transgenes at different insertion sites of the double-stranded linear 36 kb genome. These transgenes can be controlled by exogenous promoters or by endogenous viral promoters that will express the transgene in the appropriate phase of the viral life cycle. With genetic recombineering techniques in yeast1 or bacteria2
eBook - PDF- Kevin J. Harrington, Kevin J. Harrington, Richard G. Vile, Hardev S. Pandha, Hardev S. Pandha, Richard G. Vile, Hardev S. Pandha(Authors)
- 2008(Publication Date)
- Wiley(Publisher)
This approach has shown some promise in a trial in which a vaccinia–GM-CSF recombinant virus was administered intralesionally in patients with recur-rent and/or refractory melanoma (Mastrangelo et al. , 1999). While these trials have begun to show the utility of vaccinia in inducing an immune response to cancer, the preclinical studies described in this chapter show the potential of vaccinia as an onco-lytic virus. It is tumour-selective and can be made more tumour-selective by gene deletions. Based on the tumour selectivity and safety demonstrated by the double-deleted virus, there is a proposed clinical trial in our institution using this virus to treat patients with cutaneous malignancies. In summary, vaccinia appears to have great potential as a targeted therapy for cancer. It has been shown to be safe through an extensive clinical experience in smallpox vaccination and tumour vaccine trials. It is tumour-selective. It has strong promoters and can induce expression of genes to produce a bystander effect. It can induce an immune response against tumours. Perhaps an inducible expression system would allow applica-tion of all these antitumour effects at once by allowing efficient replication before induction of toxic transgenes or cytokine expression. It appears that regulation of the immune response to vaccinia will be very important to the success of its applica-tion as an oncolytic virus. References Alcami A, Symons JA, Collins PD, Williams TJ, Smith GL (1998). Blockade of chemokine activity by a soluble chemokine binding protein from vaccinia virus. J Immunol 160 (2), 624–633. Alvarez-Vallina L, Agha-Mohammadi S, Hawkins RE, Russell SJ (1997). Pharmacological control of antigen responsiveness in genetically modified T lympho-cytes. J Immunol 159 (12), 5889–95. Antoine G, Scheiflinger F Dorner F, Falkner FG (1998). The complete genomic sequence of the modified vaccinia Ankara strain: comparison with other orthopoxviruses.
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