Introduction
Cancer remains a significant global cause of mortality, highlighting the urgent need for inventive and successful treatment methods. A groundbreaking avenue in cancer therapy is the utilization of oncolytic viruses, which leverage viral infection to target and eliminate cancer cells specifically. This approach has gained substantial momentum in oncolytic virotherapy, with a surge in clinical trials showcasing encouraging outcomes regarding safety, effectiveness, and the capacity to provoke enduring immune responses against tumors.
What Is Oncolytic Virus?
Oncolytic viruses (OVs) have emerged as promising cancer treatments, offering advantages over standard therapies. They can selectively kill cancer cells and enhance anti-tumor immunity. OVs overcome the limitations of conventional treatments and have shown efficacy against drug-resistant tumors. Genetic engineering enables the development of personalized OVs tailored to individual tumor types and driver mutations. Predictive tests help identify patients likely to benefit from OV treatment. Combining OVs with other therapies in a synergistic manner has yielded successful outcomes. OVs hold great potential in the field of cancer treatment.
What Are The Mechanisms Of Tumor-mediated Immune Tolerance?
Cancer cells undergo genetic mutations and epigenetic changes to evade growth suppressors and promote their growth and spread. They also employ various strategies to evade the immune system, creating an immune-tolerant environment within the tumor. These strategies include altering antigen presentation, releasing immunosuppressive cytokines like TGF-β (transforming growth factor-beta), inducing factors that promote T cell exhaustion and inhibit proliferation, recruiting immune suppressive cells such as Tregs and myeloid-derived suppressor cells, and up-regulating inhibitory receptors on T cells.
Inhibitory receptors like PD-1, CTLA-4, Tim-3, and LAG-3 play essential roles in immune regulation to prevent autoimmunity. However, in the context of tumor growth, their expression can hinder T-cell responses and contribute to immune evasion. Recent clinical developments have focused on therapies targeting CTLA-4 and PD-1, and this review will specifically explore the combination of these therapies with oncolytic viruses.
What Are The Challenges And Considerations In The Development And Translation Of Oncolytic Viruses To Clinical Practice?
Developing oncolytic viruses (OVs) for clinical use poses challenges. Only a few OVs have been approved, and many discontinued due to limited efficacy or toxicity concerns.
Selection Of An OV:
Selecting the right viral backbone is crucial, with DNA and RNA viruses being the main options. DNA viruses allow easier genetic engineering but have lower immunogenicity than RNA viruses. Adenovirus, HSV-1, and reovirus are commonly used. The measles vaccine virus has also shown promise. Other viral backbones of interest include parvovirus, vaccinia virus, Newcastle disease virus, Maraba virus, VSV, poliovirus, and coxsackievirus. Careful consideration of genetic engineering, combination therapies, and administration routes is essential for successful OV development.
Genetic Engineering:
Genetic engineering is vital in developing oncolytic viruses (OVs). Most clinical trials use genetically engineered OVs, which involve deleting non-essential viral genes for selective tumor replication and reduced toxicity. Genetic modifications induce immune responses and reduce innate toxicity. OVs can be made more tumor-specific by incorporating ligands for tumor cell receptors. Genetic modifications also enhance anti-tumor activity by inhibiting angiogenesis and altering tumor cell signaling. These strategies improve the effectiveness and safety of OVs for cancer therapy.
Resistance to OV Therapy:
The antiviral immune response poses challenges in OV therapy, hindering viral replication and promoting clearance. Strategies aim to minimize antiviral responses while promoting tumor-targeting immune responses. Adenoviruses, especially serotype 5, face obstacles due to pre-existing immunity. Modifications in adenoviral vectors are needed to reduce immunogenicity and bypass innate antiviral immune responses. Transient suppression of early immune responses has been explored, enhancing OV potency and survival in animal models of hepatocellular carcinoma.
OVs as Combination Therapy:
Combining oncolytic viruses (OVs) with other cancer therapies improves treatment outcomes. OVs can be designed to enhance the effectiveness of existing treatments, such as making immune-resistant tumors responsive to immunotherapy. OVs release immunomodulatory molecules that convert "cold" tumors into "hot" tumors, increasing their susceptibility to immunotherapy. Genetic modifications in OVs can overcome chemoresistance and increase tumor cell sensitivity to radiation therapy. Combination approaches with immune checkpoint inhibitors (ICIs) and T-cell therapies have shown promise in preclinical and clinical studies. OVs can enhance the efficacy of ICIs by promoting T-cell infiltration into tumor tissues. Combining OVs with T-cell therapy improves their anti-tumor efficacy by providing activation signals for T cells and increasing their bioavailability at the tumor site. OVs can complement traditional cancer therapies by encoding prodrug enzyme genes or sensitizing cells to radiation therapy. Additionally, OVs can be combined with senescence-inducing agents to eradicate senescent tumor cells. Combining OVs and chemotherapy has shown improved tumor reduction and enhanced viral replication.
What Are The Considerations In Targeting Specific Tumor Types And Selecting Routes Of Administration For Oncolytic Viruses?
Oncolytic viruses (OVs) target specific signaling pathways to replicate and destroy tumor cells. The choice of OV depends on the tumor type, as intact pathways in tumor cells can lead to resistance. Melanoma, gastrointestinal, and solid tumors are extensively studied for OV treatment, primarily due to the accessibility of melanoma for local injection. Common indications for OV trials include melanoma, liver, colorectal, non-small-cell lung cancer, and treatment-resistant glioblastoma. Hematologic malignancies are less explored due to limitations in intravenous administration. Intratumoral injection directly delivers the virus to the tumor site, but it may not be feasible for all tumors. T-VEC, the approved OV, is limited to intratumoral applications but is being evaluated for other methods in non-cutaneous tumors. Intravenous delivery allows for widespread distribution and potential metastases treatment, but the immune system poses a challenge in clearing foreign pathogens. Stealth viral vectors and carrier cells are investigated to protect OVs and enhance tumor targeting.
What Is A Personalized Medicine Approach For Oncolytic Virus Therapy?
Personalized approaches to cancer treatment are gaining interest due to the heterogeneity of tumors. Human organoids, 3D tissue constructs that mimic organs, have been proposed for drug screening in individual patients. Organoids offer a realistic model with histological and genetic patterns of the patient's tumor. In oncolytic virotherapy, organoids have been used to study virus selectivity and efficacy. For example, the Zika virus showed selective replication in patient-derived glioblastoma stem cells without infecting normal cells. Creating patient-specific "virograms" involves testing different oncolytic viruses or combinations of compounds on tumor-derived organoids to determine the most effective treatment for an individual patient.
Conclusion
Oncolytic viruses have great promise as targeted treatments for cancer. Scientists are making progress in utilizing viruses' tumor-selective and destructive properties to eliminate tumors effectively. Although there are challenges, ongoing research and clinical trials are advancing the development of more powerful and precise oncolytic viral therapies. This brings hope for better outcomes and the potential to revolutionize cancer treatment.
