Experimental models for developing oncolytic virotherapy for metastatic prostate cancer

Abstract

Cancer has remained the second leading cause of death worldwide for over a century. Despite significant advances, effectively targeting cancer cells and overcoming therapeutic challenges remain critical goals. In this review, we focus on advanced metastatic prostate tumors, where the patients' five-year survival rate is less than 35%. While standard androgen deprivation therapy (ADT) has been effective for most prostate cancer patients, recurrence of aggressive tumors is common, emphasizing an urgent need for new treatment strategies. Immunotherapy has gained attention for its potential to harness the immune system against cancer cells. Among these, oncolytic virotherapy stands out for its tumor-specific tropism, its ability to transform or convert the immune-suppressive tumor microenvironment by enhancing immune cell infiltration, and its capacity for therapeutic gene delivery. This review explores the background of commonly used viruses, evaluation models (including cell culture, animal models, ex vivo platforms, and clinical trials), and the anticipated outcomes and challenges of oncolytic virotherapy. By addressing these aspects, we aim to provide a comprehensive overview of the current state and future directions of oncolytic virotherapy models in the treatment of advanced prostate cancer.

Keywords: experimental; immunotherapy; metastatic; models; oncolytic virus; prostate cancer; virotherapy.

Figure 1

Commonly used oncolytic viruses (adenovirus, HSV, and VSV) are used to depict their effects on cancer cells. (1) Selective replication of OVs in cancer cells causes oncolysis (primary effect), and they further infect more cancer cells (secondary effect). (2) Endothelial cell death (anti-angiogenesis; primary effect) is a strategy for OVs to evade the immune system, meanwhile, the reduced vasculature decreases immune cell infiltration, and oxygen and nutrient supply (secondary effect), inhibiting tumor growth. (3) OVs alter the microenvironment by inducing both innate (primary effect) and adaptive immunity (secondary effect) as they respond to PAMPs, TAAs, and DAMPs. HPSGs, Heparan Sulfate Proteoglycans; LDLR, Low-Density Lipoprotein Receptor. Image created with BioRender.

Figure 2

A compilation of oncolytic virus features for a brief comparison across OVs in (A), modified from Ungerechts et al. (57), 2016 (https://pmc.ncbi.nlm.nih.gov/articles/PMC4822647/) and used under the Creative Commons Attribution (CC BY-NC-SA 4.0 International License). (B) A comparison of the survival of pancreatic adenocarcinoma-bearing hamsters treated with different OVs, including Adenovirus, Vaccinia Virus, Herpes Simplex Virus, and Reovirus148. The graph is derived from the original article by Cervera-Carrascon et al. (58).

Figure 3

Immune modulation by oncolytic virus. (A) Upon viral infection, natural protective mechanisms in healthy cells can be activated once viral genetic material is recognized by Toll-like receptors (TLRs) on the endoplasmic reticulum (ER). This recognition triggers downstream signaling pathways, including MyD88/NFĸB and TRIF/IRF, which further lead to the active transcription of type I interferons (IFNs) (Left Panel). Under normal conditions, type I IFNs can initiate a cascade of immune responses through the JAK-STAT pathway to clear pathogens. However, in cancer cells, this response is impaired due to various mutations that allow them to evade detection by the immune system, such as becoming insensitive to IFN stimulation to avoid apoptosis (Right Panel). (B) Evasion of apoptosis facilitates viral replication within cancer cells and ultimately leads to oncolytic cell death. This process releases damage-associated molecular patterns (DAMPs), pathogen-associated molecular patterns (PAMPs), and tumor-associated antigens (TAAs), which enhance immune recognition. Images created with Biorender.