Cancer vaccine combined with immune checkpoint inhibitor and replicating/non-disseminating adenovirus expressing cytosine deaminase:uracil phosphoribosyltransferase prolongs survival and reduces tumor burden in murine BALB-nueT breast cancer model

Identification: Weeratna, Risini


Description

Cancer vaccine combined with immune checkpoint inhibitor and replicating/non-disseminating adenovirus expressing cytosine deaminase:uracil phosphoribosyltransferase prolongs survival and reduces tumor burden in murine BALB-nueT breast cancer model
 
K. Haq, R. Gilbert, M. Elahi, S. MacLean, C. Guilbault, A. Nazemi-Moghadam, L. Krishnan and R. Weeratna
Nations Research Council of Canada, Human Health Therapeutics, Ottawa, ON, Canada
 
Therapeutic cancer vaccines have shown limited efficacy in clinical setting when used as monotherapy. Emerging data shows improved efficacy when cancer vaccines are combined with conventional cancer therapies such as chemotherapy and radiation and/or immune checkpoint inhibitors. This study evaluates replication defective adenoviral vector (AdV) vaccine expressing rat HER2/neu oncogene or rat HER2/neu protein adjuvanted with squalene oil-in-water emulsion (AddaVaxTM) and CpG in combination with immune checkpoint inhibitor anti-CTLA4 monoclonal antibody alone or in combination with a replicative but non-disseminating AdV expressing cytosine deaminase:uracil phosphoribosyltransferase (AdV-CD:UPRT) suicide gene using a transgenic mouse mammary tumor model (BALB/neuT). CD converts non-toxic pro-drug 5-flourocytosine (5-FC) to active cytotoxic agent 5-fluorouracil (5-FU). UPRT converts 5-FU into 5-FU- monophosphate (5-FUM); the first step in activating 5-FU. Intratumoral administration of AdV-CD:UPRT along with the pro-drug 5-FC leads to the generation of high concentration of 5-FU at the tumor site. BALB-neuT mice were injected subcutaneously with rat HER2/neu-expressing tumor cells. Five days later, animals were given AdV-HER2 or adjuvanted rat HER2 protein by intramuscular and anti-CTLA4 by subcutaneous injection. On day 10 and 11, animals were given AdV-CD-UPRT by intratumoral injection followed by 10 daily administration of the 5-FC by intraperitoneal injections. All animals were given a booster immunization with adjuvanted rat HER2/neu protein and anti-CTLA4 on day 19. AdV-HER2/ anti-CTLA4 showed significantly greater anti-tumor activity compared to adjuvanted protein/anti-CTLA4 as shown by prolonged survival and reduced rate of tumor growth. Use of the adjuvanted protein vaccine/anti-CTLA4 in combination with AdV-CD:UPRT significantly enhanced the anti-tumor activity compared to when protein/anti-CTLA4 alone. However, both AdV-HER2 and AdV-CD:UPRT were equal in their anti-tumor capacity. The lack of synergy between AdV-HER2 and AdV-CD:UPRT may be due to decreased efficiency of AdV-CD:UPRT  as a result of inducing AdV neutralizing antibodies  by AdV-HER2 vaccination. Overall, our results demonstrate that combining cancer vaccines with checkpoint inhibitors and chemotherapeutic drugs can enhance vaccine efficacy. Our approach of generating cytotoxic compounds at tumor site may reduce systemic toxicity and enhance therapeutic index of the drug.
 
 

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