Abstract
Classical Hodgkin lymphoma (cHL) is a hematopoietic malignancy with a characteristic cellular composition. The tumor mass is made up of infiltrated lymphocytes and other cells of hematologic origin but only very few neoplastic cells that are mainly identified by the diagnostic marker CD30. While most patients with early stage cHL can be cured by standard therapy, treatment options for relapsed or refractory cHL are still not sufficient, although immunotherapy-based approaches for the treatment of cHL patients have gained ground in the last decade. Here, we suggest a novel therapeutic concept based on oncolytic viruses selectively destroying the CD30+-positive cHL tumor cells. Relying on a recently described CD30-specific scFv we have generated CD30-targeted measles virus (MV-CD30) and vesicular stomatitis virus (VSV-CD30). For VSV-CD30 the VSV glycoprotein G reading frame was replaced by those of the CD30-targeted MV glycoproteins. Both viruses were found to be highly selective for CD30-positive cells as demonstrated by infection of co-cultures of target and non-target cells as well as through blocking infection by soluble CD30. Notably, VSV-CD30 yielded much higher titers than MV-CD30 and resulted in a more rapid and efficient killing of cultivated cHL-derived cell lines. Mouse tumor models revealed that intratumorally, as well as systemically injected VSV-CD30, infected cHL xenografts and significantly slowed down tumor growth resulting in a substantially prolonged survival of tumor-bearing mice. Taken together, the data support further preclinical testing of VSV-CD30 as novel therapeutic agent for the treatment of cHL and other CD30+-positive malignancies.
Highlights
Classical Hodgkin lymphoma is a malignant disease of the hematopoietic system and occurs with an incidence of 3–4 cases per 100.000 persons per year [1]. cHL is characterized by a unique histological pattern, as tumor cells of cHL are composed of Hodgkin and ReedSternberg (HRS) cells representing a mononucleated or multinucleated subtype, respectively
For measles virus (MV)-CD30 the unmodified MV-H gene was exchanged against the coding sequence of Hmut-CD30scFv, whereas in case of vesicular stomatitis virus (VSV)-CD30 the VSV glycoprotein G gene was replaced by the reading frames of the MV fusion protein (F) and Hmut-CD30scFv (Figure 1A)
After rescue of the oncolytic viruses (OVs), they were propagated on Vero-αHis cells, which are CD30negative but display a Hexa-His-tag (H6)-specific antibody which can be used as entry receptor by both viruses due to a C-terminal H6 fused to Hmut-CD30scFv
Summary
Classical Hodgkin lymphoma (cHL) is a malignant disease of the hematopoietic system and occurs with an incidence of 3–4 cases per 100.000 persons per year [1]. cHL is characterized by a unique histological pattern, as tumor cells of cHL are composed of Hodgkin and ReedSternberg (HRS) cells representing a mononucleated or multinucleated subtype, respectively. The tumor cells are accompanied by a characteristic reactive infiltrate, mainly consisting of activated lymphocytes [2]. CD4+ T cells are involved in the so-called rosetting of tumor cells Their presence correlates with poor progression-free and overall survival [3]. Patients with chemosensitive relapse of cHL are treated by autologous hematopoietic stem cell transplantation (HSCT). This treatment results in long-term progression-free survival in approximately 50% of patients [5]. Further improvement can be expected from the PD1specific immune checkpoint inhibitor nivolumab, which was approved in 2016 for the treatment of patients with cHL that have relapsed or progressed after HSCT and brentuximab vedotin treatment [5]. With a 65% objective response rate there is still need for improvement and alternative concepts
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