Advances in cell-based delivery of oncolytic viruses as therapy for lung cancer

Abstract

Lung cancer's intractability is enhanced by its frequent resistance to (chemo)therapy and often high relapse rates that make it the leading cause of cancer death worldwide. Improvement of therapy efficacy is a crucial issue that might lead to a significant advance in the treatment of lung cancer. Oncolytic viruses are desirable combination partners in the developing field of cancer immunotherapy due to their direct cytotoxic effects and ability to elicit an immune response. Systemic oncolytic virus administration through intravenous injection should ideally lead to the highest efficacy in oncolytic activity. However, this is often hampered by the prevalence of host-specific, anti-viral immune responses. One way to achieve more efficient systemic oncolytic virus delivery is through better protection against neutralization by several components of the host immune system. Carrier cells, which can even have innate tumor tropism, have shown their appropriateness as effective vehicles for systemic oncolytic virus infection through circumventing restrictive features of the immune system and can warrant oncolytic virus delivery to tumors. In this overview, we summarize promising results from studies in which carrier cells have shown their usefulness for improved systemic oncolytic virus delivery and better oncolytic virus therapy against lung cancer.

Keywords: antibody neutralization; cell-mediated carrier; lung cancer; oncolytic viral therapy; target delivery.

Graphical abstract

Figure 1

Pie chart illustrating the overall prevalence of common lung cancer (sub)types About 80% of SCLC patients are ever-smokers vs. only 16% never-smokers. This differs significantly for NSCLC where about 40% are never-smokers compared with 60% ever-smokers. Especially lung adenocarcinoma (90% vs. 35%) was higher among never-smokers than among ever-smokers, suggesting fundamental differences in lung cancer ontology between these two different groups of patients.

Figure 2

Strategies for improving oncolytic virus efficacy Oncolytic viruses (OVs) are designed for distinct expansion within the tumor niche. At least seven important modes of action can be elicited in tumor cells after infection with optimized, genetically engineered OVs. The introduction of three types of transgenic payloads in OV genomes results in the expression of angiogenesis inhibitors, immunostimulatory factors, and pro-drug converting enzymes. Direct genetic manipulation of the OV genome might alter its intrinsic capacity to transduce host cells and affect the viral replicative life cycle through alternations in transcription, translation, and induction of pro-apoptosis activities. The latter intrinsic OV genome mutation can also affect the maintenance and viral life cycle of OVs in various carrier cell types.

Figure 3

Mechanisms of OV therapy (A) OVs either naturally or after genetic manipulation selectively multiply in cancerous cells. Due to viral clearance, normal cells are unaffected. Lysis of tumor cells is caused by viral replication and the activation of cell death mechanisms. By releasing viral offspring, oncolysis makes it possible for fresh tumor cells to become infected. (B) Immuno-stimulating effects. Oncolysis, which is brought on by virus replication, results in the production of pathogen- and damage-associated molecular pattern molecules (PAMPs and DAMPs, respectively), as well as antigens associated with tumors (TAAs) and viruses. These antigens are subsequently absorbed by antigen-presenting cells (APCs) such as dendritic cells, which then induce the formation of tumor- and virus-specific T cells. At the same time, viral infection and replication trigger an inflammatory response, which results in the production of chemokines and thereby attracts T cells. The latter action facilitates tumor- and virus-specific T lymphocytes to infiltrate into the tumor and perform their immune function. (C) OVs as a platform for transgene delivery. Adenovirus and vaccinia virus are two examples of OVs that may be altered to carry transgenes (armed OVs), after which transgene products can be specifically delivered to the tumor microenvironment and further stimulate an anticancer immune response.

Figure 4

Carrier cells deliver their replicating OV load via a three-stage kinetic model (A) Typical kinetics of OV delivery using permissive cancer cells (CCs). OV-infected cellular carriers undergo an eclipse phase after the virus is ex vivo added at time zero (t = 0), which comes before the release phase in which viral protein production, exponential amplification, and the release of offspring virions take place. (B) Three stages of CC/OV delivery that are delivered sequentially and are mapped to the duration of the viral development cycle depicted in (A) at the optimal times. Slower replicating OVs in specific CCs can elongate the eclipse phase significantly but might also produce a lower number of virions. The eclipse and release periods are therefore critically dependent on the OV life cycle in its CC and unique for every specific CC/OV combination. The complete eclipse period must be long enough to facilitate a proper stealth delivery. The release phase on the other hand should be fast enough to prevent a long time expression of viral proteins by the CCs to successfully evade adaptive barriers such as antiviral antibody-dependent cellular clearance.

Figure 5

Advantage of systemic delivery of an MSC-shielded OV Systemically injected unprotected OVs, such as the virus, cause an antiviral response through innate (NK cells, cytokines, mononuclear phagocyte system (MPS), complement activation) and eventual adaptive (antibodies, T cell mediated) immunity, which clears the virus and prevents any oncolytic effects. On the other hand, efficient transport to the tumor bed and oncolytic activity are made possible by viruses being protected by an appropriate protective carrier, such as mesenchymal stem cells (MSCs). The therapeutic system, or "Trojan horse," consists of MSCs infected with OVs, which improves oncolysis and raises the acquired anti-tumor immune response, enhancing the total anticancer impact. This figure is adapted from Hadryś et al.