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Lundstrom, K. Alphaviruses in Immunotherapy and Anticancer Therapy. Encyclopedia. Available online: https://encyclopedia.pub/entry/29967 (accessed on 19 May 2024).
Lundstrom K. Alphaviruses in Immunotherapy and Anticancer Therapy. Encyclopedia. Available at: https://encyclopedia.pub/entry/29967. Accessed May 19, 2024.
Lundstrom, Kenneth. "Alphaviruses in Immunotherapy and Anticancer Therapy" Encyclopedia, https://encyclopedia.pub/entry/29967 (accessed May 19, 2024).
Lundstrom, K. (2022, October 18). Alphaviruses in Immunotherapy and Anticancer Therapy. In Encyclopedia. https://encyclopedia.pub/entry/29967
Lundstrom, Kenneth. "Alphaviruses in Immunotherapy and Anticancer Therapy." Encyclopedia. Web. 18 October, 2022.
Alphaviruses in Immunotherapy and Anticancer Therapy
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This entry is adapted from the peer-reviewed paper 10.3390/biomedicines10092263

Alphaviruses have been engineered as expression vectors for vaccine development and gene therapy. Due to the feature of RNA self-replication, alphaviruses can provide exceptional direct cytoplasmic expression of transgenes based on the delivery of recombinant particles, naked or nanoparticle-encapsulated RNA or plasmid-based DNA replicons.

alphavirus vectors recombinant particles RNA delivery

1. Introduction

During the last decade, immunotherapy has become an attractive alternative for cancer therapy [1]. In this context, viral vectors have also proven useful for immunotherapeutic applications [2]. Alphaviruses have frequently been engineered for the overexpression of suitable antigens and immunostimulatory genes for vaccine development and cancer therapy [3]. Additionally, the expression of cytotoxic and antitumor genes has been used for cancer therapy applications. Semliki Forest virus (SFV) [4], Sindbis virus (SIN) [5] and Venezuelan equine encephalitis virus (VEE) [6] are most commonly used for the engineering of expression systems. Additionally, the naturally occurring oncolytic alphavirus M1 [7] and engineered oncolytic versions based on SFV and SIN vectors [8] have been utilized for cancer therapy. The evaluation of efficacy in appropriate animal models has provided proof of concept before conducting clinical trials.

2. Alphavirus Lifecycle and Expression Vector Systems

Alphaviruses possess an enveloped structure of capsid and spike proteins encapsulating a single-stranded RNA (ssRNA) genome of positive polarity [9]. Upon the infection of host cells, the alphavirus ssRNA is released into the cytoplasm, where translation can immediately occur requiring no delivery of RNA to the nucleus as is the case for other RNA viruses such as the influenza virus and DNA viruses (Figure 1). In the cytoplasm, efficient self-replication occurs through a minus-strand RNA template leading to the accumulation of approximately 106 copies of subgenomic RNA per cell. Together with the utilization of the highly efficient 26S subgenomic promoter, high-level expression of viral proteins occurs [10]. The RNA self-replication and high-level expression of alphavirus structural proteins generate high-titer virus progeny. Nucleocapsids comprising the capsid protein harboring full-length alphavirus RNA are transported to the cell surface, where the envelope proteins are attached, and mature viral particles are released by budding.
Figure 1. Schematic presentation of the lifecycle of alphaviruses. Alphaviruses infect host cells by endocytosis through endosomal fusion with the plasma membrane. The positive sense ssRNA is released into the cytoplasm for translation of viral proteins and RNA replication. Full-length ssRNA genomes are packaged into nucleocapsids. The alphavirus envelope proteins are transported to the plasma membrane through the endoplasmic reticulum and Golgi. The nucleocapsids are encircled by the envelope proteins at the plasma membrane and released by budding. ER, endoplasmic reticulum.
In the case of expression systems, the focus is on the expression of heterologous genes (Figure 2). In the context of replication-deficient alphavirus particles, the structural protein genes have been replaced by the gene of interest (GoI), and a helper vector is engaged in providing the structural proteins in trans (Figure 2A). Co-transfection of in vitro transcribed RNA from expression and helper vectors into baby hamster kidney (BHK) cells leads to the production of recombinant particles. As the RNA packing signal is located in one of the genes coding for the non-structural proteins (nsPs), in the nsP2 gene of SFV and nsP1 of SIN [11], uniquely RNA from the expression vector is packaged into viral particles, providing expression of the GoI but not the structural protein genes and thereby, eliminating any production of viral progeny. In contrast, introduction of a second 26S subgenomic promoter and the GoI into the full-length alphavirus RNA genome, either downstream of the nsP or the structural protein genes, generates replication-competent particles capable of both high-level GoI expression and viral progeny production (Figure 2B). In addition to the application of recombinant particles, RNA replicons can also be used for GoI expression. As has been demonstrated for the recent BNT162b2 [12] and mRNA-1273 [13] COVID-19 vaccines, RNA-based delivery is highly efficient. However, in contrast to this conventional mRNA approach, alphavirus RNA replicons provide the additional advantage of RNA self-amplification leading to superior expression levels. Moreover, replacement of the SP6 RNA polymerase promoter by a CMV promoter, DNA replicon vectors for GoI expression (Figure 2C) have been engineered for the transfection of cell lines and in vivo administration [14]. The use of DNA replicons eliminates any risk of the production of new virus particles but relies on the less efficient delivery of DNA compared to viral vectors. Moreover, DNA molecules must be delivered to the nucleus for the in vivo transcription of RNA (Figure 2C).
Figure 2. Schematic presentation of SFV expression systems. (A) Replication-deficient recombinant particles. In vitro transcribed RNA molecules from the SFV expression vector carrying the non-structural protein (nsP) genes, replicase genes (replicon) and the gene of interest (GoI) and the structural protein genes (capsid, 6K, envelope E1, E2 and E3) from the helper vector are electroporated or transfected into BHK-21 cells. After RNA replication, only the RNA from the expression vector containing the packaging signal is packaged into nucleocapsids and transported to the plasma membrane, where budding of mature viral particles takes place. Although the generated particles are capable of infecting new host cells, no viral progeny is produced due to the absence of the structural protein genes. However, high-level expression of the recombinant protein of interest (rPoI) takes place (B) Replication-competent recombinant particles. The in vitro transcribed full-length RNA genome with the GoI introduced either downstream of the nsP genes or the structural protein genes is electroporated or transfected into host cells for production of replication-competent viral particles and rPoI expression. (C) DNA replicon vectors. The replacement of the SP6 RNA polymerase promoter by a CMV promoter upstream of the nsP genes allows for direct transfection of host cells for rPoI expression. DNA replicons in the form of DNA plasmids are transfected into host cells, and DNA replicons are delivered to the nucleus. Transcribed ssRNA molecules of positive polarity are delivered to the cytoplasm for RNA replication and expression of the rPoI.

3. Alphavirus-Based Immunotherapy for Cancer

In the context of cancers, alphaviruses have been frequently used for prophylactic and therapeutic applications. Immunization with alphavirus vectors overexpressing tumor-associated antigens (TAAs) has been a common approach for cancer vaccine development. This approach has been used to provide both prevention against tumor challenges and tumor regression and eradication. Moreover, overexpression of cytotoxic and antitumor genes has been evaluated for cancer therapy. The delivery of immunostimulatory genes from alphavirus vectors has served the means of cancer immunotherapy. Moreover, alphaviruses induce apoptosis through activation of caspases in infected cells [15], which has resulted in tumor regression after administration of alphaviruses carrying no therapeutic genes and has allowed the use of vectors with reporter genes to verify and localize expression in animal tumor models. Finally, engineered or naturally occurring oncolytic alphaviruses have demonstrated tumor cell-specific killing in animal models [16]. Examples of cancer vaccinations, cancer therapy and immunotherapy are given below and summarized in Table 1.
Table 1. Examples of alphavirus-based vaccines against cancer.
Cancer Vector Finding Ref
Reporter Genes      
Lung SFV-EGFP Tumor regression in mice [17]
Colon SIN-LacZ Complete tumor remission [18]
  SFV-LacZ RNA Tumor regression, protection [19]
TAAs      
Cervical VEE-HPV-16 E7 Protection against tumor challenges in mice [20]
  SFVenh-HPV E6-E7 Tumor eradication, long-lasting CTL in mice [21]
  SFV-sHELP-E7SH Tumor regression, protection in mice [22]
  SFV-HPV E6-E7 DNA 85% of immunized mice tumor-free [23]
  SFVenh-HPV E6-E7 Phase I: Immunogenicity in all patients [24]
Colon SFV-VEGFR-2 Inhibition of tumor growth, metastatic spread [25]
  SFV-VEGR-2 + SFV-IL-4 Prolonged survival after coadministration [25]
  VEE-CEA Phase I: Ag-specific response, long-term survival [26]
Pancreatic VEE-CEA Phase I: Prolonged survival [27]
Melanoma VEE-TRP-2 + DNA Superior to plasmid DNA vaccine in mice [28]
  VEE-TRP-2 Humoral immune responses, protection in mice [29]
  VEE-TRP-2 + CTLA-4 mAbs Tumor regression in 50% of mice [30]
  VEE-TRP-2 + GITR mAbs Tumor regression in 90% of mice [30]
  SFV-VEGFR-2/IL-12 DNA Synergistic antitumor activity from combination of [31]
  + SFV-Survivin/β-hCG DNA DNA replicons  
Ovarian SFV-OVA + VV-OVA Immune responses, enhanced antitumor activity [32]
Prostate VEE-PSMA Th1-biased immune responses [33]
  VEE-PSMA Phase I: Good safety, weak immunogenicity [34]
  VEE-PSA PSA-specific Abs, delay in tumor growth [35]
  VEE-mSTEAP + pcDNA Prolonged survival, tumor challenge protection [36]
  VEE-PSCA Long-term survival of mice [37]
Cytotoxic and Antitumor Genes      
Glioblastoma SFV–Endostatin Tumor growth inhibition, reduced vascularization [38]
Breast SIN-HER2/neu DNA Significant tumor growth inhibition, protection [39]
  SIN-HER2/neu DNA 80% less DNA needed compared to plasmid DNA [40]
  VEE-HER2/neu ECD/TM Complete prevention of tumors in mice [41]
  VEE-HER2/neu ECD/TM Safe, PR in 1 patient, SD in 2 patients [42]
Immunostimulation      
Glioblastoma SFV-IL-18 + rec IL-12 Superior therapeutic effect of combination [43]
Glioma SFV-IL-12 70–97% tumor volume reduction in rats [44]
Brain SIN-gp100 + SIN-IL-12 DNA Superior antitumor activity, prolonged survival [45]
Breast SFV-IL-12 + LV101 Superior antitumor activity of combination [46]
Colon SFVenh-IL-12 Complete tumor regression, long-term survival [47]
  SFV-IL-12 + anti-PD1 Superior combination therapy in mice [48]
  VEE-IL-12 + VEE-CEA Superior combination therapy in mice [49]
Melanoma SFV-IL-12 + anti-PD1 Superior combination therapy in mice [48]
  LSFV-IL-12 Phase I: Good safety and tolerability [50]
Ovarian SIN-IL12 + Irinotecan Long-term survival in 35% of mice [51]
Oncolytic Viruses      
Glioblastoma SFV-VA-EGFP Long-term survival in 16 out of 17 mice [52]
Prostate SFV-VA-EGFP Complete tumor eradication in mice [53]
Lung SFV-VA-EGFP Long-term survival in mice [8]
Liver M1 Liver tumor targeting in mice [54]
Glioma M1 Replication in tumors [55]
Bladder M1 Tumor growth inhibition, prolonged survival [56]
Breast M1 + Doxorubicin Reduced tumor growth in mice [7]
Pancreatic M1 + IRE Tumor growth inhibition, prolonged survival [57]
Cervical SIN AR339 Regression of established tumors in mice [58]
Ovarian SIN AR399 Ascites formation in metastasis mouse model [59]
Abs, antibodies; anti-PD1, immune checkpoint inhibitor; CEA, carcinoembryonic antigen; CTLA-4, CTL antigen-4; GITR, glucocorticoid-induced tumor necrosis factor; HPV, human papilloma virus; IRE, irreversible electroporation; LV101, Salmonella typhimurium AroC strain; mAbs, monoclonal antibodies; mSTEAP, mouse six-transmembrane epithelial antigen of the prostate; OVA. Ovalbumin; PR, partial response; PSA, prostate-specific antigen; PSMA, prostate-specific membrane antigen; rec IL-12, recombinant IL-12; SD, stable disease; SFV, Semliki Forest virus; SIN, Sindbis virus; TRP-2, tyrosine-related protein-2; VEE, Venezuelan equine encephalitis virus; VEGFR-2, vascular endothelial growth factor receptor-2; VV, vaccinia virus.

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Subjects: Virology
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Kenneth Lundstrom
View Times: 361
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Update Date: 19 Oct 2022
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