Department of Medicine and Surgery, University of Parma, Parma, Italy.
Department of Medical-Veterinary Science, University of Parma, Parma, Italy.
J Hematol Oncol. 2020 Jul 11;13(1):89. doi: 10.1186/s13045-020-00919-w.
The oncolytic viruses have shown promising results for the treatment of multiple myeloma. However, the use of human viruses is limited by the patients' antiviral immune response. In this study, we investigated an alternative oncolytic strategy using non-human pathogen viruses as the bovine viral diarrhea virus (BVDV) that were able to interact with CD46.
We treated several human myeloma cell lines and non-myeloma cell lines with BVDV to evaluate the expression of CD46 and to study the effect on cell viability by flow cytometry. The possible synergistic effect of bortezomib in combination with BVDV was also tested. Moreover, we infected the bone marrow mononuclear cells obtained from myeloma patients and we checked the BVDV effect on different cell populations, defined by CD138, CD14, CD3, CD19, and CD56 expression evaluated by flow cytometry. Finally, the in vivo BVDV effect was tested in NOD-SCID mice injected subcutaneously with myeloma cell lines.
Human myeloma cells were selectively sensitive to BVDV treatment with an increase of cell death and, consequently, of apoptotic markers. Consistently, bone marrow mononuclear cells isolated from myeloma patients treated with BVDV, showed a significant selective decrease of the percentage of viable CD138 cells. Interestingly, bortezomib pre-treatment significantly increased the cytotoxic effect of BVDV in myeloma cell lines with a synergistic effect. Finally, the in vitro data were confirmed in an in vivo myeloma mouse model showing that BVDV treatment significantly reduced the tumoral burden compared to the vehicle.
Overall, our data indicate, for the first time, a direct oncolytic effect of the BVDV in human myeloma cells suggesting its possible use as novel alternative anti-myeloma virotherapy strategy.
溶瘤病毒在治疗多发性骨髓瘤方面已显示出良好的效果。然而，由于患者的抗病毒免疫反应，人类病毒的应用受到限制。在这项研究中，我们研究了一种替代的溶瘤策略，使用非人类病原体病毒，如能够与 CD46 相互作用的牛病毒性腹泻病毒（BVDV）。
我们用 BVDV 处理几种人骨髓瘤细胞系和非骨髓瘤细胞系，以评估 CD46 的表达，并通过流式细胞术研究对细胞活力的影响。还测试了硼替佐米与 BVDV 联合使用的协同效应。此外，我们感染了从骨髓瘤患者获得的骨髓单核细胞，并通过流式细胞术评估 CD138、CD14、CD3、CD19 和 CD56 的表达，检查 BVDV 对不同细胞群的影响。最后，在皮下注射骨髓瘤细胞系的 NOD-SCID 小鼠中测试了 BVDV 的体内作用。
人骨髓瘤细胞对 BVDV 治疗具有选择性敏感性，导致细胞死亡增加，继而凋亡标志物增加。一致地，用 BVDV 处理的骨髓瘤患者的骨髓单核细胞显示出有活性的 CD138 细胞百分比明显选择性降低。有趣的是，硼替佐米预处理显著增加了 BVDV 在骨髓瘤细胞系中的细胞毒性作用，具有协同作用。最后，体外数据在体内骨髓瘤小鼠模型中得到证实，与载体相比，BVDV 治疗显著降低了肿瘤负担。
总之，我们的数据首次表明 BVDV 对人骨髓瘤细胞具有直接的溶瘤作用，提示其可能作为新型抗骨髓瘤病毒治疗策略的潜在用途。
