The use of live viruses for the treatment of cancer has been extensively studied in several preclinical and clinical models, as discussed in Nemunaitis’ thorough historical review of the subject.
The initial evaluation of any new agent meant to treat a disease process must prove first and foremost that it is safe to humans. Accordingly, the use of live, replication-competent viruses has, in general, proven to be safe with low toxicity profiles when administered to humans. This has been documented with the widespread use of rabies, polio, influenza, and smallpox vaccine viruses. The enhanced infective and binding properties coupled with the lower innate pathogenicity of several of these viral strains also make them attractive to researchers in the field of cancer immunology.
Mechanisms of Action
The exact mechanisms of virus-mediated antitumor responses have not been fully elucidated, but they undoubtedly involve the killing of tumor cells and complex interactions between virus-infected tumor cells and reactive immune pathways. Some examples include the up-regulation of major histocompatiblity complex (MHC) expression, stimulation of T-cell-mediated immunity, and virally induced changes in tumor antigen expression.
In fact, virus-augmented antitumor immunity has historically been attributed to the "helper antigen" effect, as first described by Lindenmann and Klein. This is similar to the concept of "haptenization" in that the immune response against autologous tumor may be enhanced if strong viral antigens are recognized in association with weak tumor immunogens. During cellular infection, viral antigens incorporate into the entire plasma membrane juxtaposing these strong and weak immunogens. Indeed, these observations led to clinical trials utilizing virally induced tumor lysates as adjuvants in the treatment of human cancers.[4-6]
The ability of oncolytic viruses to selectively target and lyse tumor cells without damaging normal tissues results in tumor cell destruction and the spread of progeny virions to adjacent tumor cells. Recent advances in molecular and recombinant DNA technology have enabled investigators to modify these viruses, allowing for increased target specificity and oncolytic activity.
Dr. Neumunaitis provides an excellent example of this with the genetically modified adenovirus ONYX-015. This virus has been altered such that it selectively targets cells that have a mutated or nonfunctioning p53 tumor suppressor gene product. Another example of this is provided by work performed by Lee and colleagues . These researchers showed that the human reovirus is selectively restricted to cells with an activated Ras pathway, a mutation found in several cancer types. This virus was effective as an oncolytic agent in a human glioblastoma xenograft and murine breast carcinoma model.
1. Archer TP, Bretscher P: Immunotherapy of the rat 13762SC mammary adenocarcinoma by vaccinia virus augmentation of tumor immunity. Clin Expl Metastasis 8:519-532, 1990.
2. Lindenmann J, Klein PA: Viral oncolysis: Increased immunogenicity of host cell antigen associated with influenza virus. J Exp Med 126:93-108, 1967.
3. Austin FC, Boone CW: Virus augmentation of the antigenicity of tumor cell extracts. Cancer Res 30:301-345, 1979.
4. Wallack MK, Balch CM, Sivanandham M, et al: A phase III randomized double-blind multiinstitutional trial of vaccinia melanoma oncolysate-active specific immunotherapy of patients with stage II melanoma. Cancer 75:34-42, 1995.
5. Eder JP, Kantoff PW, Roper K, et al: A phase I trial of a recombinant vaccinia virus expressing prostate-specific antigen in advanced prostate cancer. Clin Cancer Res 6:1632-1638, 2000.
6. Hersey P, Edwards A, D’Alessandro G, et al: Phase II study of vaccinia melanoma cell lysates (VMCL) as adjuvant to surgical treatment of stage II melanoma. Cancer Immunol Immunother 22:221-231, 1986.
7. Norman KL, Coffey MC, Hirasawa K, et al: Reovirus oncolysis of human breast cancer. Hum Gene Ther 13:641-652, 2002.
8. Hodge JW, Schlom J: Comparative studies of a retrovirus versus a poxvirus vector in whole tumor-cell vaccines. Cancer Res 59:5106-5111, 1999.