Cancer treatment is evolving at a very fast pace and oncolytic virotherapy is one of the most exciting modality. As oncology moves toward precision and immune-based strategies for treatment, oncolytic virotherapy has emerged as a powerful and clinically validated approach. Oncolytic viruses (OVs) are either naturally tumor-selective or genetically engineered and designed to infect, replicate in the cancer cells eventually destroying them, but largely sparing normal tissue.
OVs exploit the inherent weaknesses in cancer cells such as defective interferon signaling, impaired antiviral defenses, dysregulated cell cycle and abnormal oncogenic pathways. Hence, they are explored for selective replication in cancer cells while not harming the normal cells. Several OVs have been widely studied like herpes simplex virus, adenovirus, newcastle disease virus (NDV), reovirus, vaccinia virus and coxsackievirus, each providing unique advantages in genome capacity, immunogenicity and engineering flexibility.
The therapeutic power of OVs comes from two approaches. First is direct oncolysis and second, viral-mediated tumor destruction that triggers a potent immune response. Lysis of cancer cells releases tumor-associated antigens, danger-associated molecular patterns and viral pathogen-associated molecular patterns, effectively converting the tumor into an in situ vaccine. This process enhances antigen presentation, activates dendritic cells and promotes cytotoxic T-cell infiltration. Think of it as a targeted blast inside the tumor, followed by a flare that calls for help.
Engineering OVs for Precision
Some viruses under study are naturally tumor-selective like non engineered strains of NDV. It is nonpathogenic to humans providing natural tumor selectivity, stands out as a cost-effective, safe and scalable OV candidate. But some viruses have to be genetically modified to improve their safety, oncolytic potential or immunostimulatory mechanism. OVs can be personalized to be tailored according to specific tumor profiles of the patients and can be explored for synergistic use along with checkpoint inhibitors, chemotherapy or radiotherapy. As precision oncology is evolving, OVs can be a bridge between virology and immunotherapy for cancer treatment in future.
Common strategies involved for viral genetic modification are, deletion of virulence genes to reduce nonspecific toxicity, insertion of cytokine genes such as GM-CSF or IL-12 to amplify immune responses and the use of tumor-specific promoters to ensure viral replication occurs predominantly in malignant cells. More recently, researchers have begun integrating virotherapy with cellular immunotherapy. An example from study at the Mayo Clinic, where CAR-T cells were engineered to act as carriers for an HSV-1-based oncolytic virus, enabling targeted delivery into solid tumors while combining viral oncolysis with direct T-cell
cytotoxicity.
Clinical translation of oncolytic virotherapy has paved way for various promising therapeutic candidates. Oncorine, an adenovirus-based therapy, was approved in China in 2005 for head and neck cancer, which was the first regulatory approval of an oncolytic virus. In 2015, the US FDA approved Talimogene laherparepvec (T-VEC), an HSV-1 based virus expressing GM-CSF, for the treatment of unresectable metastatic melanoma. In 2021, Japan approved Delytact (G47Δ), a genetically modified HSV for the treatment of malignant glioma.
Clinical trials are ongoing for breast, pancreatic, lung, colorectal and brain cancers with increasing focus on combination strategies. Combination approaches with immune checkpoint inhibitors are also being explored to overcome tumor resistance. Oncolytic viruses can upregulate programmed cell death 1-ligand 1 (PD-L1) expression, increase T-cell infiltration and can remodel the tumor microenvironment, leading to sensitization of tumors to anti-PD-1 and anti-PD-L1 therapies. RP1 (vusolimogene oderparepvec) is a HSV-1-based oncolytic immunotherapy. It stands out as the most promising oncolytic virus therapy in phase III for melanoma (IGNYTE trial), showing 33.6% overall response rate with nivolumab even in PD-1 resistant cases.
AdAPT-001, an adenovirus that neutralizes TGF-β and tested both alone and in combination with immune checkpoint inhibitors, has shown partial responses, stable disease and favorable safety in phase 1/2 trials (BETA PRIME), particularly in tumors resistant to standard immunotherapy. Engineered oncolytic viruses like LOAd703 expressing co-stimulators such as CD40L and 4-1BBL are in phase 1/2 of clinical trials to increase immune activation within the tumor microenvironment. Early data showed response rates up to 44% and disease control in pancreatic cancer. Other constructs are being designed to express immune checkpoint blockers or bispecific immune engagers directly within the tumor to reduce systemic toxicity and enhance efficacy.
Other late-stage clinical candidates like Olvi-Vec (olvimulogene nanivacirepvec), an oncolytic vaccinia virus engineered for safety and tumor selectivity, is in an ongoing phase 3 trial (OnPrime/GOG-3076) for platinum-resistant ovarian cancer, with prior studies demonstrating objective responses, platinum re-sensitization and good tolerability. CG0070 (cretostimogene grenadenorepvec), a modified adenovirus carrying a GM-CSF transgene designed to replicate selectively in tumor cells, is in the phase 3 BOND-003 trial for BCG-unresponsive non-muscle- invasive bladder cancer and has shown high complete response rates, durable high-grade recurrence-free survival and excellent tolerability in interim topline data.
OV therapy can be effectively applied for tumors with defective antiviral defenses, low baseline immune infiltration and resistant to conventional immunotherapy convenient to access via local or targeted viral delivery. A systematic review analyzed 36 trials (Phases II and III) and concluded that OV therapy shows potential in treating solid tumors, improving objective response rate, progression-free survival and overall survival. The benefits were more promising in melanoma and hepatocellular carcinoma. Biomarkers like high tumor mutational burden and CD8+ T cell infiltration were associated with better responses. Incorporating these biomarkers for trial designs is beneficial in patient selection and precision.
OV strategy for targeting cancer is highly promising but also presents several challenges like mode and efficiency of viral delivery, viral clearance by the immune system and tumor heterogeneity. However, advances in biomedical research, nanotechnology and AI modeling can be favorable to combat these barriers. Hopefully the next decade will witness oncolytic virotherapy becoming a focus point in personalized and precised cancer care since we will better understand the tumor microenvironment and immune modalities. From lab experiments to clinical trials, OVs hold a huge potential for development as smarter, safer and personalized cancer care. What’s the goal? Not just to treat cancer but to outsmart it.
Upasana Pathak
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