Maraba virus-vectored cancer vaccines represent a safe and novel therapeutic option for cats

Abstract

Direct killing of malignant cells combined with induction of tumour-specific immune responses makes oncolytic vaccines attractive for cancer therapy. We previously developed a heterologous cancer immunization strategy that utilized a replication-defective adenovirus-vectored primary vaccine encoding a tumour antigen followed by boosting with a replication-competent Maraba virus expressing the same antigen. To assess the safety of oncolytic Maraba virus-based booster vaccines and inform the design of clinical trials, we conducted translational studies in cats, which have immune systems that are similar to people and spontaneously develop cancers of comparable types and etiologies. A dose of Maraba virus up to 2.5 × 1011 pfu per cat was well-tolerated, with adverse effects limited to mild, transient pyrexia, weight loss, neutropenia, lymphopenia and thrombocytopenia. Maraba viral genomes were present in some urine, stool and most plasma samples up to one week post-infection, but no infectious viruses were recovered. Post-mortem analysis showed one heart, one lung and all spleen samples contained Maraba virus genomes. No replication-competent viruses were recovered from any tissues. Post-mortem histopathological analyses revealed hyperplasia of lymphoid tissues, but no abnormal lesions were attributed to vaccination. This study demonstrated that Maraba virus-vectored cancer vaccines were well-tolerated and supports their use in treating cats.

Use of Precision-Cut Lung Slices as an Ex Vivo Tool for Evaluating Viruses and Viral Vectors for Gene and Oncolytic Therapy

“…We also found that the OVs were mostly found in tumor tissues or the peri-tumoral region in the lung slices ( Figures 5 C and 6 C), as has also been well established in the literature. 53 , 54 , 55 , 56 , 57 , 58 Moreover, we observed a decrease in tumor tissue metabolic activity when in the presence of oncolytic vector MG1-eGFP, using the resazurin assay, a surrogate tool for viability ( Figure S3 ). Therefore, this protocol is a convenient tool to assess the activity of other gene and OV vectors prior to and to complement in vivo work.…”

Development and applications of oncolytic Maraba virus vaccines

“…To further consolidate the immunotherapeutic activity of oncolytic vesiculoviruses, we and others have equipped their genome with transgenes overexpressing tumor antigens. 18 , 20 , 25 , 26 , 33 – 42 The resulting so-called “oncolytic vaccine” aims at potentiating the adaptive arm of antitumor immunity.…”

“… 45 Additionally, with the aim of extending the Ad:MG1 vaccination to the treatment of veterinary cancer patients, we characterized its safety and tolerability profiles in healthy tumor-free outbred cats. 33 …”

“…Five cats were enrolled to evaluate the safety of the Ad prime:MG1 boost strategy. 33 Animals received an intramuscular injection of 1 × 10 10 pfu of replication-defective E1/E3-deleted Ad5 encoding the human placenta-specific 1 (hPLAC1), a cancer/testis antigen reexpressed in multiple malignancies such as breast/mammary tumors. 46 Twenty-one days post-Ad-hPLAC1 prime, the felines were boosted intravenously with one high dose of 2.5 × 10 11 pfu of MG1-hPLAC1.…”

“…Altogether, these preclinical data validated the tolerability and nonpathogenicity of the Ad:MG1 vaccination, thus supporting their use to treat feline patients. 33 …”