New Ideas for Tumor Immunotherapy: Research Progress on Oncolytic Viruses

Oncolytic viruses (OVs) are a type of natural or recombinant viruses that can selectively infect and kill tumor cells without damaging normal cells. Oncolytic viruses have the advantages of good targeting, few adverse reactions, multiple ways to kill tumors, and are not prone to drug resistance. And oncolytic virus combined with chemotherapy, radiotherapy and immunotherapy has a synergistic effect. In recent years, with the continuous development of technology and the deepening of research, the selectivity and effectiveness of oncolytic virus products on tumor cells have been continuously improved, while the impact on normal cells has been further reduced, and they have gradually become a research and development hotspot.

Overview of Oncolytic Virus

Oncolytic virus immunotherapy is a new type of anti-tumor treatment that uses natural viruses or gene-edited viruses to selectively replicate in tumor cells. It exerts anti-tumor effects through the dual mechanism of directly dissolving tumor cells and inducing anti-tumor immune responses.

The Anti-tumor Mechanism of Oncolytic Virus

The mechanism of action of oncolytic virus includes directly lysing tumor cells, inducing systemic anti-tumor immune responses, acting on the tumor microenvironment, and affecting tumor blood vessels.

Directly lyse tumor cells: Oncolytic virus selectively infects tumor cells, replicates and dissolves them in tumor cells, without damaging normal cells. Normal cells can clear viruses by activating signal transduction pathways. These signal transduction pathways can be activated by locally released interferons (IFNs) or intracellular Toll-like receptors (TLRs), and viral components can activate TLRs. However, the above-mentioned processes of tumor cells are impaired, allowing the virus to replicate within the tumor cells and then dissolve the tumor cells.

Figure 1. Oncolytic viruses can exploit cancer immune evasion pathways. (Kaufman H L, et al., 2015)

Induction of local and systemic anti-tumor immune responses: OVs can induce innate immune responses and tumor-specific adaptive immune responses. After the death of OV-infected tumor cells, the released tumor-associated antigens can promote adaptive immune responses and shrink tumors in distant sites not exposed to OVs. In addition, it can also release PAMP, DAMP and cytokines to promote APC maturation and activate antigen-specific CD4+ and CD8+ T cell responses. Activated CD8+ T cells expand into cytotoxic effector cells and mediate anti-tumor immune responses through antigen recognition.

Figure 2. The induction of local and systemic anti-tumor immunity by oncolytic viruses. (Kaufman H L, et al., 2015)

Acting on the tumor microenvironment: Tumor cells have evolved complex immune evasion mechanisms. Oncolytic viruses modulate the immunosuppressive tumor microenvironment by changing the cytokine environment and immune cell types in the tumor microenvironment. This change promotes immune-mediated recognition and clearance of tumor cells and can induce tumor-associated antigens and epitope spreading. In addition, killing tumor cells by oncolytic viruses can lead to the release of tumor neoantigens, which can be taken up by local APCs and induce immune responses.

Influence on tumor blood vessels: Oncolytic virus can infect and lyse vascular endothelial cells (VEC) in the tumor vascular bed. OV HSV-1716 was the first to be reported to have a direct anti-angiogenic effect on ovarian cancer.

Currently Approved Oncolytic Virus Treatment Products Globally

Approved oncolytic virus therapeutic products include T-VEC, ECHO-7, H101 and Teserpaturev.

H101 (Ankerui®) is a recombinant human adenovirus type 5 that was approved for marketing in China in 2005 for the treatment of advanced nasopharyngeal cancer. H101 is currently the only oncolytic virus drug approved for marketing in China. Phase III clinical trials show that intratumoral injection of H101 combined with chemotherapy in the treatment of head and neck or esophageal squamous cell carcinoma has an ORR of 72.7%, compared with 40.3% in the chemotherapy alone group.

T-VEC is a genetically engineered herpes simplex virus type 1 (HSV-1) that causes cell lysis by secreting the cytokine GM-CSF within tumor cells. T-VEC is the first oncolytic virus drug approved by the US FDA in 2015. A prospective randomized trial showed that the sustained response rate (DRR) of T-VEC in the treatment of unresectable melanoma was 16.3%, compared with 2.1% for GM-CSF in the control group. T-VEC improved overall survival (23.3 vs 18.9 months).

ECHO-7 is a recombinant enterovirus that was first approved in Latvia in 2004 and later in Georgia and Armenia for the treatment of melanoma.

Teserpaturev is a recombinant type I herpes simplex virus and was approved in Japan in 2021 for the treatment of glioblastoma. Glioblastoma is highly malignant. From 2009 to 2015, the 5-year survival rate of glioblastoma patients in the United States was only 7%. A study published in Nature Medicine in 2022 included 19 adult patients with residual or recurrent supratentorial glioblastoma after radiotherapy and temozolomide treatment. The median overall survival of Teserpaturev treatment reached 28.8 months, far exceeding the data of previous treatments. In addition, in a phase 2 clinical trial, the one-year survival rate of glioblastoma patients treated with Teserpaturev was as high as 92.3%. The 1-year survival rate of standard treatment with postoperative radiotherapy and chemotherapy (temozolomide) is only 15%.

Oncolytic Virus Clinical Research

The efficacy of OV alone is limited, and clinical studies usually observe OV combined with other anti-tumor treatments, including chemotherapy, immunotherapy, radiotherapy and targeted therapy. Among them, the most popular one is OV combined with immune checkpoint inhibitor (ICI) or adoptive T cell therapy (ACT).

Only 12.5% of patients treated with immune checkpoint inhibitors (ICIs) benefit. A common reason for primary resistance to ICI is that tumor cells do not express or express PD-L1 at low levels. OV can significantly increase the expression level of PD-L1. In addition, OV therapy can convert immunologically "cold tumors" into "hot tumors", especially by causing tumor-infiltrating lymphocytes (TILs) to accumulate in tumor tissues. Some OVs can change the tumor microenvironment into one that promotes inflammatory response and enhance the efficacy of ICI.

The reasons for the insufficient efficacy of adoptive T cell therapy (such as CAR-T and TCR-T) in solid tumors include insufficient T cell transport to the tumor, antigen loss or heterogeneity, and poor matching with the tumor immune microenvironment. From a mechanism perspective, OV can increase T cell transport to tumors, support T cell survival and expansion, reduce antigen loss, and reduce CAR-T cell and TCR-T cell exhaustion. In general, oncolytic virus products are highly innovative and develop rapidly, and they are expected to play a greater role in anti-tumor treatment in the future.

References

Kaufman H L, et al. Oncolytic viruses: a new class of immunotherapy drugs. Nature reviews Drug discovery, 2015, 14(9): 642-662.

Chen L, et al. Oncolytic virotherapy in cancer treatment: challenges and optimization prospects. Frontiers in Immunology, 2023, 14: 1308890.

Tian Y, et al. Engineering strategies to enhance oncolytic viruses in cancer immunotherapy. Signal Transduction and Targeted Therapy, 2022, 7(1): 117.

Yun C O, et al. Current clinical landscape of oncolytic viruses as novel cancer immunotherapeutic and recent preclinical advancements. Frontiers in Immunology, 2022, 13: 953410.