Intratumoral oncolytic virotherapy in pancreatic cancer: from feasibility to immune priming

Pancreatic ductal adenocarcinoma (PDAC) is often accompanied by substantial weight loss and cancer-associated cachexia at the time of diagnosis (1). PDAC remains among the most lethal malignancies, with a five-year relative survival of 13.3% in the United States (2015–2021) (2) and consistently ranks among the cancers with the poorest prognosis worldwide. This dismal prognosis reflects multiple interlocking barriers, including intrinsic resistance to cytotoxic chemotherapy (3), limited drug delivery due to dense fibrotic stroma (4), and a profoundly immunosuppressive, largely “immune-cold” tumor microenvironment with sparse effector cell infiltration (5). Consequently, immune checkpoint inhibitors (ICIs), which have reshaped treatment paradigms for several gastrointestinal cancers (6,7), have not shown consistent, clinically meaningful benefits in pancreatic cancer.

Against this challenging background, Runcie et al. reported a phase I clinical trial exploring an innovative therapeutic strategy: endoscopic ultrasound (EUS)-guided intratumoral administration of the oncolytic virus talimogene laherparepvec (T-VEC) in nine patients with advanced PDAC (8). In this phase I study of intratumoral administration of T-VEC for PDAC (patients who had progressed on at least one line of systemic therapy), stable disease was achieved in 44% of patients, with a median overall survival of 7.8 months. Notably, one patient experienced durable survival for 28 months. Although no objective responses were observed, the disease control signal in this previously treated population was encouraging. Treatment-related adverse events were generally manageable, and the maximum tolerated dose was established at 10⁸ PFU/mL, consistent with prior experience in melanoma.

The significance of this study lies not only in its clinical efficacy signals—disease stabilization in 44% of previously treated patients and a median overall survival of 7.8 months—but also in its acceptable safety profile and demonstration of technical feasibility and biological plausibility. Intratumoral delivery via EUS has the potential to circumvent one of the central barriers in PDAC therapy, poor drug penetration due to stromal desmoplasia, while simultaneously providing a means to remodel the tumor immune microenvironment. However, the absence of objective responses warrants careful interpretation. T-VEC is designed to induce local viral replication, tumor cell lysis, and antigen release; however, these processes do not necessarily translate directly into measurable tumor shrinkage. In PDAC, even when local oncolysis and immune activation are achieved, these effects may not consistently propagate to a sustained and effective systemic antitumor immune response. This limitation reflects the profound immunosuppressive tumor microenvironment of PDAC, in which T cell expansion, trafficking, and persistence are often impaired. Accordingly, intratumoral oncolytic virotherapy may serve as a rational backbone for combination strategies rather than as a stand-alone treatment.

A deeper understanding of these limitations requires consideration of the unique immunosuppressive tumor microenvironment characteristics of PDAC. The disease is characterized by a dense desmoplastic stroma, low vascular density, and elevated interstitial pressure, all of which severely constrain intratumoral infiltration by immune cells and therapeutic agents. In addition, the phenomenon of “immune exclusion”, whereby cytotoxic T cells are actively prevented from accessing the tumor core, is commonly observed. Even when antigen presentation is successfully induced, mounting evidence indicates that this alone is insufficient to elicit an effective cytotoxic T-cell response in the PDAC microenvironment (9,10). These features collectively help explain why locally generated immunogenic signals may not translate into durable tumor control.

T-VEC is a genetically engineered oncolytic virus derived from herpes simplex virus type 1 (HSV-1) that is designed to preferentially replicate within tumor cells while stimulating antitumor immunity (11). In practical terms, the virus can efficiently enter tumor cells (similar to wild-type HSV-1) via entry receptors such as nectin-1 and herpesvirus entry mediator (HVEM) (12). However, key “virulence” genes have been removed to improve its safety and immunogenicity. Specifically, the deletion of ICP34.5 limits viral replication in normal tissues by reducing the virus’s ability to overcome host antiviral shutoff [the protein kinase R (PKR)-eIF2α pathway], thereby lowering the neurotoxicity risk. Deletion of ICP47 relieves viral suppression of antigen presentation [via transporter associated with antigen processing (TAP)], which can enhance major histocompatibility complex (MHC) class I presentation and facilitate recognition by CD8⁺ T cells. Together, these modifications support tumor-selective oncolysis and immune activation. These modifications are theoretically justified by their ability to enhance tumor antigen presentation in the poorly immunogenic PDAC setting. Beyond direct tumor lysis, T-VEC is an engineered HSV-1 that expresses granulocyte-macrophage colony-stimulating factor (GM-CSF) (13), thereby potentially enhancing local immune activation through dendritic-cell recruitment and improved antigen presentation. Overall, these design features allow T-VEC to function as an in situ cancer vaccine by coupling tumor-selective oncolysis with enhanced antigen presentation and immune priming.

This mechanism has been extensively validated in melanoma, where intratumoral T-VEC has been shown to increase CD8⁺ T-cell infiltration and upregulate interferon-γ-related gene signatures at injection sites, and to induce regression of distant, non-injected lesions (the so-called abscopal effect) (14). Moreover, when combined with ICIs, T-VEC has demonstrated the ability to immunologically “prime” tumors, enhancing responsiveness to checkpoint blockade. Clinical trials combining T-VEC with anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or anti-programmed cell death protein 1 (PD-1) antibodies have reported improved response rates and increased immune infiltration, supporting the concept that T-VEC may function as an immune-conditioning therapy preceding or accompanying ICI therapy (8,15).

Importantly, the present study offers preliminary evidence that immune modulation may not be confined to the tumor microenvironment. RNA profiling of peripheral blood mononuclear cells (PBMCs) from the long-term survivor revealed the upregulation of T helper type 1 (Th1)-associated genes and activation of T- and B-cell receptor signaling pathways (8), suggesting that intratumoral T-VEC administration can induce systemic immunological effects in selected patients. Although this observation is hypothesis-generating, it is noteworthy because it may suggest the potential for intratumoral therapy to influence the peripheral immune system.

Intratumoral oncolytic virotherapy in pancreatic cancer is not without precedent. Prior clinical studies have explored HSV-based approaches, including EUS-guided intratumoral injection of HF10 for unresectable locally advanced pancreatic cancer, supporting the technical feasibility and an acceptable safety profile of local virotherapy in this disease (16). Earlier adenoviral approaches also merit recognition: ONYX-015 was delivered by EUS-guided intratumoral injection in PDAC more than two decades ago (17), and subsequent adenoviral platforms such as VCN-01 have further supported the clinical feasibility of local virotherapy in PDAC (18). In this context, the importance of the present study lies not in being the first intratumoral virotherapy approach in PDAC, but in extending this strategy specifically to T-VEC and revisiting its potential relevance for immune-priming in a highly immunosuppressive tumor.

From a procedural standpoint, gastrointestinal oncology offers a unique advantage of direct tumor access through endoscopic and ultrasound-guided techniques. EUS-guided intratumoral injection enables the precise delivery of therapeutic agents into tumors that are otherwise poorly accessible via systemic routes. This approach is particularly well-suited for oncolytic virotherapy and may have broader applicability across gastrointestinal malignancies beyond pancreatic cancer.

In summary, the report by Runcie et al. is noteworthy not because it establishes a new standard of care but because it provides critical proof of concept for intratumoral immunomodulation in pancreatic cancer. By demonstrating feasibility, acceptable safety, and the possibility of biologically meaningful immune signals, this study lays the groundwork for future trials incorporating rational combination strategies aimed at amplifying and sustaining antitumor immunity. In a disease as refractory as PDAC, such incremental yet conceptually important advances may represent essential steps toward expanding therapeutic horizons.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Gastroenterology and Hepatology. The article has undergone external peer review.

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-2026-0010/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-2026-0010/coif). The authors have no conflicts of interest to declare.

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