Chemovirotherapy of Malignant Melanoma with a Targeted and Armed Oncolytic Measles Virus

Abstract

Effective treatment modalities for advanced melanoma are desperately needed. An innovative approach is virotherapy, in which viruses are engineered to infect cancer cells, resulting in tumor cell lysis and an amplification effect by viral replication and spread. Ideally, tumor selectivity of these oncolytic viruses is already determined during viral cell binding and entry, which has not been reported for melanoma. We engineered an oncolytic measles virus entering melanoma cells through the high molecular weight melanoma-associated antigen (HMWMAA) and proved highly specific infection and spread in melanoma cells. We further enhanced this oncolytic virus by inserting the FCU1 gene encoding the yeast-derived prodrug convertases cytosine deaminase and uracil phosphoribosyltransferase. Combination treatment with armed and retargeted MV-FCU1-αHMWMAA and the prodrug 5-fluorocytosine (5-FC) led to effective prodrug conversion to 5-fluorouracil, extensive cytotoxicity to melanoma cells, and excessive bystander killing of noninfected cells. Importantly, HMWMAA-retargeted MV showed antitumor activity in a human xenograft mouse model, which was further increased by the FCU1/5-FC prodrug activation system. Finally, we demonstrated susceptibility of melanoma skin metastasis biopsies to HMWMAA-retargeted MV. The highly selective, entry-targeted and armed oncolytic virus MV-FCU1-αHMWMAA may become a potent building block of future melanoma therapies.

MicroRNA-mediated multi-tissue detargeting of oncolytic measles virus

“…3 In addition, we and others have developed strategies to enhance the natural oncotropism as well as to optimize tumor cell killing, immune evasion and stimulation of an anti-tumor immune response. [4][5][6][7][8][9][10][11][12][13][14][15] Simultaneously, the maximum feasible dose of recombinant MV has been raised from 10 9 TCID 50 administered in the first 1 to 10 11 TCID 50 administered in the most recently reported clinical phase I trial. 2 However, clinical translation of more potent oncolytic vectors and systemic administration of increased viral doses may uncover severe adverse reactions limiting the therapeutic index.…”

Viral Oncolysis — Can Insights from Measles Be Transferred to Canine Distemper Virus?

“…New approaches for melanoma therapy combine measles virus targeted against melanoma-associated antigen (high molecular weight melanoma-associated antigen HMWMAA) and an insertion of the FCU1 gene (MV-FCU-1-α-HMWMAA) [140]. The latter encodes the yeast-derived prodrug convertases cytosine deaminase and uracil phosphoribosyltransferase [140].…”

“…The latter encodes the yeast-derived prodrug convertases cytosine deaminase and uracil phosphoribosyltransferase [140]. The aim of the study was to enhance virus specificity for tumor cells in combination with an increased efficacy of chemotherapy by local prodrug conversion [140].…”

“…The latter encodes the yeast-derived prodrug convertases cytosine deaminase and uracil phosphoribosyltransferase [140]. The aim of the study was to enhance virus specificity for tumor cells in combination with an increased efficacy of chemotherapy by local prodrug conversion [140]. In a human melanoma xenograft model (A375M cells) tumors, that had reached a volume of 50 mm³, were treated intratumorally on five consecutive days with 1.44 × 10 5 cell infectious units MV-FCU-1-α-HMWMAA followed by intraperitoneal administration of 5-fluorouracile twice daily on five consecutive days, starting three days after the last virus application [140].…”

“…The aim of the study was to enhance virus specificity for tumor cells in combination with an increased efficacy of chemotherapy by local prodrug conversion [140]. In a human melanoma xenograft model (A375M cells) tumors, that had reached a volume of 50 mm³, were treated intratumorally on five consecutive days with 1.44 × 10 5 cell infectious units MV-FCU-1-α-HMWMAA followed by intraperitoneal administration of 5-fluorouracile twice daily on five consecutive days, starting three days after the last virus application [140]. This treatment scheme resulted in a significant growth retardation of treated tumors accompanied by a significantly prolonged survival time compared to controls [140].…”