title: Verapamil results in increased blood levels of oncolytic adenovirus in treatment of patients with advanced cancer.
abstract: Calcium channel blockers including verapamil have been proposed to enhance release and antitumor efficacy of oncolytic adenoviruses in preclinical studies but this has not been studied in humans before. Here, we studied if verapamil leads to increased replication of oncolytic adenovirus in cancer patients, as measured by release of virions from tumor cells into the systemic circulation. The study was conducted as a matched case-control study of advanced cancer patients treated with oncolytic adenoviruses with or without verapamil. We observed that verapamil increased mean virus titers present in blood after treatment (P < 0.05). The frequency or severity of adverse events was not increased, nor were cytokine responses or neutralizing antibody levels different between groups. Signs of possible treatment-related clinical benefits were observed in both groups, but there was no significant difference in responses or survival. Thus, our data suggests that the combination of verapamil with oncolytic adenoviruses is safe and well tolerated. Moreover, verapamil treatment seems to result in higher virus titers in blood, indicating enhanced overall replication in tumors. A randomized trial is needed to confirm these findings and to study if enhanced replication results in benefits to patients.
authors: Cancer Gene Therapy Group, Transplantation Laboratory, Haartman Institute and Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland.
authors: Anniina
authors: A
authors: Koski
authors: Mari
authors: M
authors: Raki
authors: Petri
authors: P
authors: Nokisalmi
authors: Ilkka
authors: I
authors: Liikanen
authors: Lotta
authors: L
authors: Kangasniemi
authors: Timo
authors: T
authors: Joensuu
authors: Anna
authors: A
authors: Kanerva
authors: Sari
authors: S
authors: Pesonen
authors: Ramon
authors: R
authors: Alemany
authors: Akseli
authors: A
authors: Hemminki
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology; D000293:Adolescent; D000328:Adult; D000368:Aged; D057134:Antibodies, Neutralizing / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology; D002121:Calcium Channel Blockers / Q000009:adverse effects / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D004279:DNA, Viral / Q000097:blood; D004357:Drug Synergism; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D050130:Oncolytic Virotherapy / Q000009:adverse effects; D050504:Oncolytic Viruses / Q000235:genetics* / Q000276:immunology; D016019:Survival Analysis; D016896:Treatment Outcome; D014700:Verapamil / Q000009:adverse effects / Q000627:therapeutic use*; D019562:Viral Load / Q000187:drug effects; D055815:Young Adult
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D002121:Calcium Channel Blockers; D004279:DNA, Viral; D018836:Inflammation Mediators; D014700:Verapamil