Mantle cell lymphoma salvage regimen: synergy between a reprogrammed oncolytic virus and two chemotherapeutics.
Measles virus (MV)-PNP H(blind)antiCD20 is a CD20-targeted and prodrug convertase-armed MV that temporarily controls growth of lymphoma xenografts in severe combined immunodeficiency (SCID) mice in combination with fludarabine phosphate (fludarabine). Herein, we examine the replication of this targeted virus and of a vaccine-lineage MV in disease bulks and circulating cells from mantle cell lymphoma (MCL) patients, and show that only the targeted virus is specific for CD20-expressing cells. We then assessed the efficacy of different regimens of administration of this virus in combination with fludarabine and cyclophosphamide (CPA) in an MCL xenograft model. We show that CPA administration before the beginning of virus treatment enhances oncolytic efficacy, likely through temporary immunosuppression. An interval of 1 week between intravenous virus administration and fludarabine treatment further enhanced oncolysis, by synchronizing maximum prodrug convertase expression with fludarabine availability. Finally, three 23-day courses of triple sequential treatment with CPA, virus and fludarabine treatment resulted in complete regression of the xenografts. Secondary disease symptoms interfered with survival, but average survival times increased from 22 to 77 days. These studies document a reprogrammed oncolytic virus, consolidating the effects of two chemotherapeutics, a concept well suited for a phase I clinical trial for MCL patients for whom conventional therapies have failed.
Ungerechts
G
G
Department of Molecular Medicine and Virology and Gene Therapy Track, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Frenzke
M E
ME
Yaiw
K-C
KC
Miest
T
T
Johnston
P B
PB
Cattaneo
R
R
D000818:Animals; D018951:Antigens, CD20 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003520:Cyclophosphamide / Q000627:therapeutic use; D006801:Humans; D053208:Kaplan-Meier Estimate; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D008459:Measles virus / Q000235:genetics; D051379:Mice; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D050504:Oncolytic Viruses / Q000235:genetics*; D016879:Salvage Therapy; D047368:Tumor Burden / Q000187:drug effects; D014709:Vero Cells; D014740:Vidarabine / Q000031:analogs & derivatives / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
D018951:Antigens, CD20; D000970:Antineoplastic Agents; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine