Oncolytic Adenovirus Loaded with L-carnosine as Novel Strategy to Enhance the Antitumor Activity

Abstract

Oncolytic viruses are able to specifically replicate, infect, and kill only cancer cells. Their combination with chemotherapeutic drugs has shown promising results due to the synergistic action of virus and drugs; the combinatorial therapy is considered a potential clinically relevant approach for cancer. In this study, we optimized a strategy to absorb peptides on the viral capsid, based on electrostatic interaction, and used this strategy to deliver an active antitumor drug. We used L-carnosine, a naturally occurring histidine dipeptide with a significant antiproliferative activity. An ad hoc modified, positively charged L-carnosine was combined with the capsid of an oncolytic adenovirus to generate an electrostatic virus-carnosine complex. This complex showed enhanced antitumor efficacy in vitro and in vivo in different tumor models. In HCT-116 colorectal and A549 lung cancer cell lines, the complex showed higher transduction ratio and infectious titer compared with an uncoated oncolytic adenovirus. The in vivo efficacy of the complex was tested in lung and colon cancer xenograft models, showing a significant reduction in tumor growth. Importantly, we investigated the molecular mechanisms underlying the effects of complex on tumor growth reduction. We found that complex induces apoptosis in both cell lines, by using two different mechanisms, enhancing viral replication and affecting the expression of Hsp27. Our system could be used in future studies also for delivery of other bioactive drugs. Mol Cancer Ther; 15(4); 651-60. Ó2016 AACR.

Combination of immunogenic oncolytic adenovirus ONCOS-102 with anti-PD-1 pembrolizumab exhibits synergistic antitumor effect in humanized A2058 melanoma huNOG mouse model

“…Oncolytic viruses have been tested in preclinical studies and in numerous clinical trials against various tumor types, have a tolerable safety profile, and show varying degrees of efficacy. 8,[10][11][12][31][32][33][34][35][36][37][38][39][40] Their advantages include lysis of infected tumor cells, release of tumor antigens in an immunogenic milieu, and viral infection of adjacent tumor cells. In addition, Figure 5.…”

Extracellular vesicles enhance the targeted delivery of immunogenic oncolytic adenovirus and paclitaxel in immunocompetent mice

“…Therapies aimed at activating the host immune response [9] have been proven useful as monotherapy or in combination with other anti-neoplastic agents [10][11][12][13][14], particularly when tumors acquire resistance to standard therapies and become metastatic [15,16]. Among the novel therapeutic strategies aiming at targeting the host immune response against the tumor, treatment with OVs is one of the most promising approach [17][18][19][20] since it combines the cytolytic activity with the ability of the virus to activate the immune system [21,22]. OVs can exhibit natural tumor-selective tropism or be genetically modified for cancer cellrestricted replication (adenovirus, poliovirus, herpes simplex) [23].…”

Antitumor‐specific T‐cell responses induced by oncolytic adenovirus ONCOS‐102 (AdV5/3‐D24‐GM‐CSF) in peritoneal mesothelioma mouse model

“…Their antitumor activity is based on the direct lysis of cancer cells and the induction of systemic antitumor immunity . Oncolysis leads to the release of tumor epitopes that can be processed by antigen‐presenting cells to activate antigen‐specific CD4+ and CD8+ T‐cell responses. Immunogenic cell death leads to changes in cell surface structure, such as exposure of calreticulin in the outer plasma membrane and subsequent release of high‐mobility group box 1 protein and adenosine triphosphate .…”