Oncolytic viruses may meet criteria as ideal purging agents for hematological malignancies. Specifically, certain oncolytic viruses selectively target malignant hematopoietic cells such as multiple myeloma and leukemia cells while sparing normal HSPCs [51
]. This capacity to purge autologous HCT grafts makes oncolytic viruses particular attractive for potential use in the clinical transplant setting (). A few oncolytic viruses have already been translated into the clinic ().
Proposed treatment schema of oncolytic virotherapy for patients with hematological malignancies undergoing high-dose chemotherapy and autologous HCT.
Oncolytic viruses for the treatment of hematological malignancies.
One potential purging agent is coxsackievirus A21 (CVA21) based on its ability to selectively target hematological malignant cells [52
]. CVA21, a common enterovirus, exhibited a potent cytostatic and cytocidal effect against three MM cell lines with reduced cytotoxicity against normal human peripheral blood mononuclear cells (PBMCs) [53
]. CVA21 specificity is believed to be related to expression of intercellular adhesion molecule-1 (ICAM-1) and decay accelerating factor (DAF) on the surface of target cells. While the immunocompromised status of MM patients receiving chemotherapy poses a concern for the use of virotherapy, it may be in these patients that CVA21 virotherapy will have the most successful outcome due to the lack of antiviral immunity. Disseminated CVA21 infection can be controlled by antiviral compounds, such as pleconaril [54
] or immunoglobulin [55
]. CVA21 has already been administered to end-stage melanoma patients without adverse effects [56
], and further human trials are currently underway to evaluate safety.
Another potential oncolytic virus for the treatment of hematological malignancies is reovirus [57
]. Reovirus is a double-stranded RNA virus that is replication competent and preferentially infects cells with hyperactivated signaling, for example, in the Ras pathway. When reovirus was used to ex vivo
purge MM cells from admixtures of apheresis products, purging was incomplete: only 50% of the MM cells were effectively purged. Also, reovirus was unable to purge follicular lymphoma and Burkitt's lymphoma cells [58
]. A major advantage with reovirus is that it does not affect normal HSPCs. Therefore, reovirus may have potential in certain hematological malignancies, but it remains to be defined how clinically effective the virus is at eliminating each type of cancer.
Vesicular stomatitis virus (VSV) is another virus with oncolytic potential [59
]. This negative strand RNA virus lacks toxicity for HSPCs in culture and has oncolytic activity against AML cell lines. Moreover, VSV can purge MM from mobilized PBSC CD34+ cells [60
The Edmonston-B vaccine strain of measles virus (MV-Edm) also has reported oncolytic activity against MM. Using six clinical MM samples and a transplant model into immunodeficient mice, this measles virus successfully purged myeloma cells [61
]. The intrinsic tumor selective cytotoxicity is an attractive feature of this agent. They also noted that administration of MV-Edm into MV-susceptible transgenic mice expressing the human CD46 receptor resulted in infection of macrophages in spleen, lymph nodes, and peritoneal cavity [62
]. To enhance virus specificity, they generated an anti-CD38 scFv and demonstrated that display of scFv redirected virus binding and entry into CD38 receptor positive cells that were devoid of natural measles receptors [63
]. The MV-Edm virus is currently in a phase I clinical study for recurrent or refractory MM where it is administered systemically via intravenous route along with cyclophosphamide chemotherapy (http://www.ClinicalTrials.gov
ID NCT00450814) [64
]. In this trial, the investigators are using the MV-NIS Edmonston lineage which was genetically engineered to express the human sodium iodide symporter (NIS). Insertion of the NIS protein into MV enables pharmacokinetic monitoring of the virus by means of radioactive iodine (123
I) administration. Cells infected with MV-NIS will show increased uptake of the radioactive iodine, and this uptake can be serially tracked in real time. The patient's normal thyroid function is protected by coadministration of a normal thyroid hormone, triiodothyronine (T3).
Live attenuated measles virus (MV) has potent oncolytic activity against MM tumor xenografts. The virus is tumor selective and preferentially targets cells that express high levels of CD46 receptors [65
]. A vaccine strain of MV causes regression of large established human lymphoma xenografts in immunodeficient mice. MV is a negative-strand RNA virus, and, interestingly, the presence of anti-MV antibodies does not compromise the oncolytic effect of MV [66
Adachi et al. reported a midkine promoter based conditionally replicative adenovirus (Ad) for the treatment of pediatric solid tumors and bone marrow tumor purging. A conditionally replicative Ad in which the expression of E1 is controlled by the MK promoter achieved high levels of viral replication in neuroblastoma or Ewing's sarcoma cells and induced tumor cell killing. No damage to CD34+ cells was seen, even after three hours of infection at 1000 MOI [67
]. Adenovirus serotype 5 (Ad5) and other low-seroprevalence adenoviruses may have utility as oncolytic agents against MM and other hematological malignancies [68
Tumor-specific double-deleted Vaccinia virus has also been tested in multiple myeloma [69
]. Esfandyari et al. were the first to document permissiveness of lymphoma cells to oncolytic herpes viruses and introduced ELK as a suitable factor for predicting tumor susceptibility to novel anticancer agents [70
Oncolytic rat parvovirus, H-1PV, may be a potential candidate for the treatment of some non-Hodgkin's B-cell lymphomas, including those resistant to apoptosis induction by rituximab. H-1PV efficiently killed through necrosis while sparing normal B lymphocytes [71
Recently, we showed that myxoma virus (MYXV) has the capacity to selectively target primary human leukemia cells while spare normal HSPCs [51
]. Poxviruses such as MYXV can bind and initiate entry into most mammalian cells but then discriminates permissive versus nonpermissive cells by virtue of the cell signaling circuitry of the infected cell. We have shown that upregulated AKT signaling, either as constitutive phosphorylation or induced by virus infection [72
], regulates MYXV permissiveness in a wide variety of human solid tumor cell lines [73
]. Considering the complexity and heterogeneity of cancer cells, this pathway is likely not the only mechanism for cancer cell specificity and there may be other mechanisms to explain the virus' discrimination between leukemia cells and normal HSPC. For example, when normal macrophages are infected with MYXV, the cells rapidly coinduce two antiviral cytokines (tumor necrosis factor and type I interferon) by a RIG-I-dependent signaling mechanism, which then aborts MYXV infection in normal somatic cells in a paracrine-like manner [74
]. Thus, it could be that normal HSPCs are competent for this synergy, whereas malignant HSPCs, such as AML cells, are defective in some aspect of the tumor necrosis factor/interferon pathway. The mechanism for selective killing of cancer is still being studied, but two important factors include (1) most human cancer cells lack type I IFN and TNF synergy responses [75
] and (2) most cancer cells have excessive levels of activated Akt, which facilitates MYXV replication [73