Emerging Trends in Oncolytic Viral Therapy: Innovations from Preclinical to Translational Research

Highlights from the 2025 American Association for Cancer Research (AACR) Meeting

Oncolytic Viruses: Engineered Agents for Tumor-Selective Therapy

Oncolytic viruses (OVs) are natural or engineered viruses that selectively infect and kill cancer cells while sparing healthy tissue. They also trigger immune responses, making them promising cancer immunotherapies. OVs replicate in tumor cells by targeting cancer-specific features like abnormal receptors or faulty antiviral defenses. This replication causes cancer cell lysis and releases tumor antigens and danger signals that stimulate immunity.

OVs are used alone or with other therapies. For example, T-VEC (a modified herpes virus) is injected into tumors to kill cells and boost immune activity. OVs also enhance immunotherapy by triggering immune cell activation and improving responses to checkpoint inhibitors like anti-PD-1. Some OVs are designed to deliver therapeutic genes (e.g., cytokines) directly into tumors. Others, like adenovirus or vaccinia virus, can reach metastatic sites through systemic delivery. OVs are also effective against treatment-resistant tumors by using different killing mechanisms.

T-VEC (Imlygic®) is FDA-approved for melanoma (2015), and Delytact (Teserpaturev/G47∆) is approved in Japan for glioblastoma (2021). Other candidates, including Reolysin and Pexa-Vec, are in trials. Challenges include delivery limits, safety risks like cytokine storms, and complex production and regulation.

Advantages of Oncolytic Virotherapy over AAV and Immunotherapy

Compared to adeno-associated virus (AAV)-based gene therapy, OVs offer dynamic, self-amplifying platforms that can simultaneously deliver multiple payloads, induce immunogenic cell death, and serve as adjuvants. Unlike AAVs, which are non-replicating and have limited packaging capacity, OVs propagate within tumors, providing sustained therapeutic impact and tumor-specific spread.

Against checkpoint immunotherapy, which relies heavily on the pre-existence of T cell infiltrates, OVs can prime the immune response de novo, particularly in ‘cold’ tumors. Moreover, the inclusion of immune modulators (e.g., IL-12, IFN-gamma) within OVs provides direct immune stimulation, converting immune-desert tumors into responsive ones. Additionally, several engineered viruses now support diagnostic imaging, enabling theranostic applications—a feature not inherent to monoclonal antibody-based immunotherapies.

Evolving Strategies and Innovations in Oncolytic Viral Therapeutics

Oncolytic viral therapy (OVT) is rapidly evolving from a novel concept into a multi-pronged clinical strategy aimed at transforming cancer treatment. Recent studies presented at the 2025 American Association for Cancer Research (AACR) meeting highlight a broad spectrum of engineered viruses featuring enhanced tumor selectivity, immune modulation, and innovative delivery approaches. Based on these abstracts, several emerging trends are shaping the current landscape of OVT: combinatorial immunotherapy, rational vector engineering, stromal reprogramming, systemic delivery, and diagnostic integration.

1. Immunostimulatory Payloads and Combination Strategies

A defining trend is the strategic arming of viruses with cytokines and immune modulators. IL-12, GM-CSF, IL-18 muteins, CCL21, TGF-β inhibitors, and novel checkpoint synergy have been incorporated across various platforms. For instance, Kalivir’s VET3-TGI and Tottori University’s FUVAC-IL12/CCL21 potentiate Th1 immunity and memory T cell responses, respectively, suggesting a systemic reshaping of the tumor-immune microenvironment. Furthermore, researchers at Allegheny and Hanyang University revealed that localized cytokine expression or co-treatment with immune-modulatory drugs (e.g., GSK3β inhibitors) enhances both local and systemic immune responses.

Several studies emphasized combining OVT with immune checkpoint inhibitors, CAR-T cells, or radiation therapy. Notably, oAd and CAR-T synergy in pancreatic cancer, and IGF1R blockade combined with oHSV and radiation in glioblastoma, demonstrate that virus-induced inflammation can be harnessed and redirected for therapeutic gain.

2. Tumor-Specific and Immune-Evasive Vector Design

Vector design has advanced significantly. Diverse adenovirus serotypes (Ad6, Ad34, Ad35) and synthetic VSV glycoprotein libraries are used to escape neutralizing antibodies and increase re-administration feasibility. Mayo Clinic’s CRAd657-CD40L and synthetic VSV platforms exemplify immune-evasive yet immunogenic systems. City of Hope’s GPC3-encoding virus also highlights antigen sensitization as a strategy to broaden CAR-T and antibody therapy applicability to GPC3-negative tumors.

Additionally, promoter tuning and capsid modifications such as hTERT or ASCL1-driven replication allow tumor-specific transgene expression. These design elements are central in targeting resistant subtypes like neuroblastoma and colorectal cancer stem cells (CD133+), as seen in multiple University of Minnesota studies.

3. Targeting and Remodeling the Tumor Stroma

A significant barrier in solid tumors is the dense extracellular matrix (ECM). Vesiculoviruses expressing collagenase and hyaluronidase (UAMS) and relaxin-armed adenoviruses (Hanyang University) successfully degrade ECM, increasing immune and therapeutic infiltration. Meanwhile, Emory University’s exploration of stromal reprogramming with AVID-317 uncovered dose-dependent activation of reparative and pro-tumorigenic signatures, advocating for precise dosing and intelligent combinations.

4. Systemic and Localized Delivery Innovations

Effective systemic delivery is critical. Kalivir’s VET3-TGI and Mayo Clinic’s synthetic VSV pseudotypes demonstrated repeatable intravenous administration. Conversely, localized strategies include intranasal photothermal adenovirus therapy for glioblastoma (Hanyang), and MSC-based adenovirus delivery in prostate cancer (Purdue), both bypassing traditional delivery limitations.

City of Hope’s CF33-hNIS and UMN’s OAd-NIS integrate sodium iodide symporter (NIS) to enable real-time imaging of viral distribution, enabling “theranostic” applications—therapeutics with built-in diagnostics. Such dual-function platforms bridge efficacy monitoring and treatment in real time.

5. Novel Platforms and Tools for Rapid Development

Tools like CytoEvolvR (UC Berkeley) and ultra-diverse adenovirus libraries (UMN) offer scalable platforms for high-throughput vector evolution and AI-based discovery. These technologies support accelerated screening for tumor selectivity, immune activation, and resistance circumvention, promising faster translation from bench to clinic.

The following Table 1 summarizes current trends in oncolytic viral therapy (based on the AACR meeting abstracts)

Table 1: Emerging trends in oncolytic viral therapy

Conclusion

The current trends in oncolytic virotherapy reflect a convergence of genetic engineering, immunology, and systems biology. By combining rational vector design with advanced delivery and immune-modulatory strategies, OVT is poised to become a cornerstone of personalized cancer therapy. As these preclinical advances transition into clinical pipelines, the field moves toward integrated, multi-modal regimens capable of reshaping cancer immunotherapy paradigms.

Source

Proceedings: AACR Annual Meeting 2025; April 25-30, 2025; Chicago, Illinois.

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