Abstract
Prime-boost vaccination employing heterologous viral vectors encoding an antigen is an effective strategy to maximize the antigen-specific immune response. Replication-deficient adenovirus serotype 5 (Ad5) is currently being evaluated clinically in North America as a prime in conjunction with oncolytic rhabdovirus Maraba virus (MG1) as a boost. The use of an oncolytic rhabdovirus encoding a tumor antigen elicits a robust anti-cancer immune response and extends survival in murine models of cancer. Given the prevalence of pre-existing immunity to Ad5 globally, we explored the potential use of DEC205-targeted antibodies as an alternative agent to prime antigen-specific responses ahead of boosting with an oncolytic rhabdovirus expressing the same antigen. We found that a prime-boost vaccination strategy, consisting of an anti-DEC205 antibody fused to the model antigen ovalbumin (OVA) as a prime and oncolytic rhabdovirus-OVA as a boost, led to the formation of a robust antigen-specific immune response and improved survival in a B16-OVA tumor model. Overall, our study shows that anti-DEC205 antibodies fused to cancer antigens are effective to prime oncolytic rhabdovirus-boosted cancer antigen responses and may provide an alternative for patients with pre-existing immunity to Ad5 in humans.
Highlights
As knowledge of the important role played by the immune system in preventing tumor growth in healthy individuals has expanded over the last decades, immunotherapy has emerged as a viable treatment option for cancer.[1]
In addition to Imlygic, an intratumorally delivered oncolytic herpes simplex virus 1 (HSV-1) strain approved for treatment of late-stage melanoma, many different viruses have been clinically evaluated for their potential as oncolytic viruses (OVs), including many that can be delivered intravenously (i.v.), such as measles virus,[5] coxsackie virus,[6] and rhabdoviruses, like vesicular stomatitis virus (VSV) and the closely related Maraba virus (MG1).[7]
Oncolytic rhabdoviruses are attenuated by deletion of the matrix protein in VSV and mutation of components of the matrix and glycoproteins in MG1.8 In addition, OVs can be genetically manipulated to encode proteins that either help to establish a productive infection of cancer cells or encode cytokines and/or immunogenic antigens, such as cancer antigens
Summary
As knowledge of the important role played by the immune system in preventing tumor growth in healthy individuals has expanded over the last decades, immunotherapy has emerged as a viable treatment option for cancer.[1]. OVs are live, replicating viruses selected or genetically modified to preferentially target and kill cancer cells while leaving healthy cells relatively unharmed.[2] This is possible owing to the fact that cancers exhibit many characteristics that are conducive to successful viral replication, such as resistance to apoptosis, increased nucleotide synthesis, and an impaired antiviral response.[3] OVs elicit their anti-cancer effects through multiple mechanisms and following tumor cell lysis and immunogenic cell death, can trigger anti-cancer immune responses.[4] In addition to Imlygic, an intratumorally delivered oncolytic herpes simplex virus 1 (HSV-1) strain approved for treatment of late-stage melanoma, many different viruses have been clinically evaluated for their potential as OVs, including many that can be delivered intravenously (i.v.), such as (but not limited to) measles virus,[5] coxsackie virus,[6] and rhabdoviruses, like vesicular stomatitis virus (VSV) and the closely related Maraba virus (MG1).[7] Additional attenuating genetic modifications are generally introduced into OVs in order to increase their safety profile. Oncolytic rhabdoviruses are attenuated by deletion of the matrix protein in VSV (termed VSVD51) and mutation of components of the matrix and glycoproteins in MG1.8 In addition, OVs can be genetically manipulated to encode proteins that either help to establish a productive infection of cancer cells or encode cytokines and/or immunogenic antigens, such as cancer antigens
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