Oncolytic herpes simplex virus type 1 (HSV‐1) in combination with lenalidomide for plasma cell neoplasms

Abstract

Oncolytic viruses exert an anti-tumour effect through two mechanisms: direct oncolytic and indirect immune-mediated mechanisms. Although oncolytic herpes simplex virus type 1 (HSV-1) has been approved for melanoma treatment and is being examined for its applicability to a broad spectrum of malignancies, it is not known whether it has an anti-myeloma effect. In the present study, we show that the third-generation oncolytic HSV-1, T-01, had a direct oncolytic effect on five of six human myeloma cell lines in vitro. The anti-tumour effect was enhanced in the presence of peripheral blood mononuclear cells (PBMCs) from healthy individuals and, to a lesser extent, from patients with myeloma. The enhancing effect of PBMCs was abrogated by blocking type I interferons (IFNs) or by depleting plasmacytoid dendritic cells (pDCs) or natural killer (NK) cells, suggesting that pDC-derived type I IFNs and NK cells dominated the anti-tumour effect. Furthermore, the combination of T-01 and lenalidomide exhibited enhanced cytotoxicity, and the triple combination of T-01, lenalidomide and IFN-a had a maximal effect. These data indicate that oncolytic HSV-1 represents a viable therapy for plasma cell neoplasms through direct oncolysis and immune activation governed by pDCs and NK cells. Lenalidomide is likely to augment the anti-myeloma effect of HSV-1.

Oncolytic herpes simplex virus infects myeloma cells in vitro and in vivo

“…Furthermore, it has been recently reported that oncolytic HSV-1, T-01, induces direct oncolysis and immune activation governed by plasmacytoid dendritic cells (pDCs) and natural killer (NK) cells in plasma cell neoplasms. 11 Additionally, oHSV-1 also induced apoptosis in primary MM cells. It was observed to be higher in the total cellular fraction isolated from BM aspirates of patients with MM, compared to that isolated from PB, and also in the BM CD138 + cellular fraction compared to the BM CD138 À cellular fraction.…”

“…Furthermore, it has been recently reported that oncolytic HSV-1, T-01, induces direct oncolysis and immune activation governed by plasmacytoid dendritic cells (pDCs) and natural killer (NK) cells in plasma cell neoplasms. 11 …”

“…While this manuscript was in communication, two recent reports highlighted that the third-generation oncolytic HSV-1, T-01, could infect and kill human cell lines and primary cells derived from various lineages of hematological malignancies 10 and that the oncolytic effect of T-01 could be augmented by the immunomodulatory drug lenalidomide in the treatment of plasma cell neoplasms. 11 However, we had first reported on the possibility of using HSV-1 in OV therapy of MM. 12 Since herpes virus entry mediator (HVEM, CD270, tumor necrosis factor receptor superfamily member 14 [TNFRSF14]) is overexpressed not only on myeloid and lymphoid cells, but also on primary MM cells and plasma cell leukemias, 13 in this work, we decided to investigate whether this receptor could be used by oHSV-1 to infect and kill MM cells.…”

The Use of Oncolytic Viruses in the Treatment of Multiple Myeloma

“…In a subcutaneous xenograft myeloma model, HSV-1 treatment decreased tumour volume after intratumoral injection [ 42 ]. Another study reported similar findings in vitro and examined if the presence of an immune cell population would enhance the cytotoxic effect of HSV-1 [ 43 ]. Co-cultures of myeloma cell lines and PBMC cells (from healthy donors or myeloma patients) were treated with HSV-1.…”

Intratumoral cancer immunotherapy exploiting anti-viral immunity

“…HSV-1 killed various lineages of hematological tumor cells. 36,37 Notably, intratumoral injection of T-VEC into primary cutaneous B-cell lymphoma in a phase I trial induced 6 complete responses and 5 partial responses out of 13 patients in injected lesions. 38 Two out of 3 patients with non-injected lesions showed an abscopal effect on these lesions.…”