Ideally, an oncolytic virus will replicate preferentially in malignant cells, have the ability to treat disseminated metastases, and ultimately be cleared by the patient. Here we present evidence that the attenuated vesicular stomatitis strains, AV1 and AV2, embody all of these traits. We uncover the mechanism by which these mutants are selectively attenuated in interferon-responsive cells while remaining highly lytic in 80% of human tumor cell lines tested. AV1 and AV2 were tested in a xenograft model of human ovarian cancer and in an immune competent mouse model of metastatic colon cancer. While highly attenuated for growth in normal mice, both AV1 and AV2 effected complete and durable cures in the majority of treated animals when delivered systemically.

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Oncolytic viruses capable of tumor-selective replication and cytolysis have shown early promise as cancer therapeutics. However, the host immune system remains a significant obstacle to effective systemic administration of virus in a clinical setting. Here, we demonstrate the severe negative impact of the adaptive immune response on the systemic delivery of oncolytic vesicular stomatitis virus (VSV) in an immune-competent murine tumor model, an effect mediated primarily by the neutralization of injected virions by circulating antibodies. We show that this obstacle can be overcome by administering virus within carrier cells that conceal viral antigen during delivery. Infected cells were delivered to tumor beds and released virus to infect malignant cells while sparing normal tissues. Repeated administration of VSV in carrier cells to animals bearing metastatic tumors greatly improved therapeutic efficacy when compared with naked virion injection. Whole-body molecular imaging revealed that carrier cells derived from solid tumors accumulate primarily in the lungs following intravenous injection, whereas leukemic carriers disseminate extensively throughout the body. Furthermore, xenogeneic cells were equally effective at delivering virus as syngeneic cells. These findings emphasize the importance of establishing cell-based delivery platforms in order to maximize the efficacy of oncolytic therapeutics.

Multiple myeloma is a radiosensitive malignancy that is currently incurable. Here, we generated a novel recombinant vesicular stomatitis virus [VSV(⌬51) - IntroductionMultiple myeloma is a malignancy of antibody-secreting plasma cells that reside predominantly in bone and bone marrow and secrete a monoclonal immunoglobulin. 1 The disease responds initially to alkylating agents, corticosteroids, and thalidomide, but eventually becomes refractory. 2 Multiple myeloma remains incurable causing more than 10 000 deaths each year in the United States. 3 Although cultured myeloma cells are relatively resistant to radiotherapy in vitro, 4,5 the malignancy is highly radiosensitive and radiation therapy is routinely used for palliation of pain, neurologic compromise, or structural instability from focal myeloma deposits. Efforts to use radiation as a systemic modality for definitive therapy of myeloma, however, have been problematic because of collateral toxicity to normal tissues especially the bone marrow progenitor cells. 6,7 Developing novel therapies for multiple myeloma based on the targeted delivery of radioisotopes to sites of active disease may have important clinical implications for myeloma therapy.Gene transfer using the thyroidal sodium iodide symporter (NIS) gene offers a novel strategy for delivery of radionuclides to disseminated cancer cells. 8 NIS is a transmembrane protein in thyroid follicular cells that actively mediates iodide uptake to a concentration gradient more than 20 to 40-fold. 9 Cloning the human NIS cDNA has aided in imaging and therapy of dedifferentiated thyroid cancer and nonthyroid cancers such as glioma, neuroblastoma, melanoma, multiple myeloma, and ovarian, breast, cervix, lung, liver, and colon carcinoma. 10 Tissue-specific NIS expression has been achieved in various cancer xenografts with minimal toxicity to normal organs by using promoters and enhancers from genes encoding immunoglobulins, prostate-specific antigen, probasin, and mucin-1. [11][12][13][14][15][16] Cancer therapy using oncolytic viruses (oncolytic virotherapy) requires agents that amplify efficiently through replication and spread causing rapid tumor lysis, yet are safe causing minimal toxicity to normal tissue enabling systemic inoculations to treat metastatic cancers. 17,18 We previously engineered the NIS gene into a lymphotropic, replication-competent attenuated strain of measles virus (MV-NIS) 19 that was subsequently used for oncolytic virotherapy of myeloma xenografts. Intratumoral spread of MV-NIS could be monitored noninvasively by radioiodine imaging and virus-resistant tumors were ablated after administration of 131 I. 20 A phase I clinical trial to evaluate the targeting properties of MV-NIS in patients with recurrent or refractory myeloma is ongoing at our institution. Several RNA viruses other than measles virus, including reovirus, Newcastle disease virus, mumps virus, and vesicular stomatitis virus (VSV), are being developed as systemic oncolytic agents for cancer therapy. 18,21 Each of these viruses ...