Oncolytic Viruses: A Novel Approach to Cancer Immunotherapy

Abstract:

Cancer immunotherapy has revolutionized cancer treatment by leveraging the immune system to fight tumors. Oncolytic viruses (OVs) are genetically modified viruses specifically designed to infect and replicate within cancer cells. This replication process directly destroys cancer cells while simultaneously stimulating an anti-tumor immune response. This article explores the potential of combining OVs with other established immunotherapies to improve treatment efficacy for a broader range of cancers.

Oncolytic Viruses and Their Mechanism of Action:

OVs are engineered to target and infect cancer cells selectively. Once inside, they replicate, causing the cancer cell to burst (lyse), leading to direct tumor cell death. Additionally, OVs trigger a specific type of cell death (immunogenic cell death) that releases tumor antigens and danger signals. These signals alert the immune system to the presence of cancer cells, promoting an immune response against the tumor.

Mechanism of oncolytic virus immunotherapy. Oncolytic viruses infect cancer cells and induce the immunogenic cell death and release of infectious viral progeny that infect nearby cancer cells. Tumour-associated antigens and cellular DAMPs, such as CRT, HMGB1 and cellular ATP, stimulate the host antitumour immune responses. Cellular detection of viral infection and the products of oncolysis trigger the rapid activation of host antiviral responses and influx of immune cells that mediate the destruction of residual infected and uninfected tumour cells. The direct recognition and killing of tumour cells is primarily mediated by natural killer cells of the innate immune system and tumour antigen-specific CD8+ cytotoxic and CD4+ helper T lymphocytes of the adaptive immune system. The effects of OVs reflect on MDSCs, TAMs and Treg cells inhibition and modify the suppressive microenvironment altering the cytokine milieu (red lines) OVs: oncolytic viruses; ATP: adenosine triphosphate; HMGB1: high mobility Group Box 1; CRT: calreticulin; DAMPs: damage-associated molecular pathways; CD: cluster differentiation; TLR4: Toll-like receptor 4; P2RX7: Purin 2 Receptor X7; DC: dendritic cell; MCH I: major histocompatibility complex Class I; Treg: T regulatory; TAMs: tumour-associated microenvironment; MDSCs: myeloid-derived suppressor cells.

Synergy with Immunotherapy:

The ability of OVs to activate the immune system creates a unique opportunity for combination therapy with existing immunotherapies:

  • Immune Checkpoint Inhibitors (ICIs): ICIs, such as anti-PD-1 and anti-CTLA-4 antibodies, work by removing inhibitory signals within the tumor microenvironment (TME), allowing immune cells to attack the tumor. OVs can enhance the effectiveness of ICIs by:
    • Increasing the number of activated T cells infiltrating the tumor.
    • Converting tumors with low immune cell infiltration ("cold" tumors) into tumors with high immune cell infiltration ("hot" tumors), making them more susceptible to ICI therapy.
  • CAR T-cell Therapy: Chimeric antigen receptor (CAR) T-cell therapy utilizes genetically engineered T cells to target and eliminate cancer cells. OVs can:
    • Improve the expansion and persistence of CAR T cells within the TME.
    • Enhance the migration of CAR T cells towards tumors.
  • Cytokines: Cytokines, such as IL-2, stimulate the proliferation and activation of immune effector cells. OVs can work together with cytokines by creating a more favorable environment within the TME for cytokine action.

The effect of combining CAR T cell therapy and oncolytic virotherapy in tumor microenvironment (TME). CAR T cells have instant potent activity to kill cancer cells expressing tumor-associated antigens (TAAs) on cell surface, but are susceptible to TME with immune suppressive modulators, such as immunosuppressive cytokines (e.g., IL-10, TGFβ), immune checkpoint coinhibitory receptors and ligands (e.g., PD-1, PD-L1, CTLA-4), M2 phenotype tumor-associated macrophages (TAMs), etc. Oncolytic viruses (OVs) remodel the TME through upregulating proinflammatory cytokines (e.g., IFNγ, IL-6, TNFα, IL-12), immune checkpoint costimulatory receptors and ligands (e.g., OX40, OX40L, 4-1BB, 4-1BBL), mature dendritic cells (DCs), nature killer (NK) cells, M1 phenotype TAMs, etc. The oncolysis and immune activation mediated by OVs promote antigen spread, resulting in proliferation of cytotoxic lymphocytes (CTLs) targeting other TAAs presented by major histocompatibility complex (MHC) in addition to CAR T cells. The combination therapy takes advantage of the instant potent activity of CAR T cells and immune activation by OVs, leading to more effective lysis of the heterogeneous cancer cell populations to mitigate tumor relapse encountered by CAR T cell therapy due to antigen escape.

Optimizing Oncolytic Virus Therapy:

Researchers are actively investigating methods to improve the effectiveness of OV therapy. This includes optimizing viral design for:

  • Enhanced tumor specificity: Ensuring that the virus only infects cancer cells and minimizes infection of healthy cells.
  • Increased potency: Improving the efficiency of viral replication and subsequent tumor cell death.

Oncolytic viruses delivering target for CAR-T cells. Unique antigens can be delivered to tumor cells using oncolytic virus, and CAR-T cells specific for that unique antigen can be used in combination to destroy tumors.

Reliable Research Reagents are Essential:

High-quality research reagents are crucial throughout the development process for successful OV therapy. Companies like Maxanim provide researchers with essential tools for OV design, vector engineering, and pre-clinical testing.

Clinical Trials and Future Directions:

Several clinical trials are underway to evaluate the safety and efficacy of combining OVs with various immunotherapies. Early results are promising, showing improved patient outcomes compared to using either therapy alone.

Future research directions include:

  • Identifying biomarkers to predict which patients will respond best to combination therapy.
  • Developing strategies to overcome potential limitations, such as pre-existing immunity to the chosen OV.

Clinical trials of oncolytic viruses in breast cancer. Oncolytic viruses selectively infect tumor tissue, undergo viral replication and cause tumor cell lysis. Currently, 14 different oncolytic viruses have been investigated in 18 published clinical trials. These oncolytic viruses fall into three different groups; (i) oncolytic viruses with natural anti-neoplastic properties; (ii) oncolytic viruses designed for tumor-selective replication; (iii) oncolytic viruses modified to activate the immune system. All published trials demonstrate that oncolytic viruses are well tolerated and safe for use in patients.

Conclusion:

The combination of OVs with immunotherapy represents a promising new approach for cancer treatment. By exploiting the complementary mechanisms of each therapy, this strategy has the potential to overcome resistance to current therapies and improve outcomes for a wider range of cancer patients.


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Oncolytic Viruses: A Novel Approach to Cancer Immunotherapy
Gen store June 25, 2024
Tags
Biology Cancer Biology Cellular Biology Immunotherapy
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Immunotherapy Combinations for Enhanced Cancer Treatment