CD30-targeted oncolytic viruses as novel therapeutic approach against classical Hodgkin lymphoma

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.

High-Affinity DARPin Allows Targeting of MeV to Glioblastoma Multiforme in Combination with Protease Targeting without Loss of Potency

“…By exchanging the gfp marker gene against the prodrug convertase SCD encoding scd gene via the DNA fragment also containing the MeV N gene cassette by Mlu I/ SbfI (NEB), plasmid p(+)PolII-MV NSe -MMPA1-SCD(N)-E.01 was generated. The expression plasmid pCG-F-IRES-Puro allowing selection of MeV-F expression by coupling F mRNA to puromycin resistance was generated by blunt end insertion of the IRES-Puromycin cassette released from pH-HCD30-IP-LTR 41 via Spe I and Acc65 I 3′ to the F gene by linearization of pCG-F 42 using XbaI (NEB) and subsequent Klenow (NEB) digestion to generate blunt ends and allowing ligation. EGFRvIII sequence was obtained by RNA isolation from U87MG.ΔEGFR cells that express EGFRvIII as a transgene.…”

Oncolytic Viruses and Immune Checkpoint Inhibition: The Best of Both Worlds

“…VSV is an enveloped virus of size 70 × 200 nm belonging to the Rhabdoviridae family containing an 11 kb single-stranded-RNA of negative sense 94 . VSV in particular is an attractive vector because of (1) its effectiveness against a variety of tumor models,95, 96, 97, 98, 99, 100, 101, 102 including leukemia 103 and lymphoma, 104 and (2) its sensitivity to type I IFNs, an innate immune mechanism found in normal cells but not in tumor cells, thus making the virus tumor selective and able to boost CD8 T cell responses 105, 106. In clinical trials, recombinant VSV expressing IFNβ has been tested against refractory multiple myeloma, acute myeloid leukemia, T cell lymphoma (ClinicalTrials.gov: NCT03017820) and refractory hepatocellular carcinoma (ClinicalTrials.gov: NCT01628640).…”

The emerging role of oncolytic virus therapy against cancer

“…The best studied oncolytic rhabdovirus Vesicular Stomatitis Virus (VSV) uses the low-density lipoprotein (LDL) receptor for cell entry, allowing VSV to infect nearly all cell types and cause lytic infection in a wide variety of permissive cells (57). Oncolytic VSV cell entry has been made tumor selective through retargeting strategies, involving replacing the VSV G with a more selective entry G as the measles F and H (hemagglutinin) proteins (58), receptor targeted measles H and F proteins (59,60), the lymphocytic choriomeningitis virus WE54-strain glycoprotein (LCMV-GP) (61) and Lassa virus G (62).…”