Treating Solid Tumors With Effective Viral Immunotherapies

Lung cancer remains the leading cause of cancer-related mortality worldwide[1]. In the United States, an estimated 229,410 new cases of lung and bronchus cancer are expected in 2026 [2]. Non-small cell lung cancer (NSCLC) accounts for approximately 80% to 85% of lung cancer diagnoses[3].

Despite advances in early detection, molecular profiling, targeted therapies, and immunotherapy, many patients still present with advanced or metastatic disease. For patients with advanced NSCLC without actionable driver mutations, standard treatment commonly includes immune checkpoint inhibitors, either alone or in combination with platinum-based chemotherapy, depending on tumor and patient characteristics. Surgery, radiotherapy, systemic therapy, and immunotherapy are used in earlier-stage settings depending on disease stage and resectability [4].

While immune checkpoint inhibitors have improved outcomes for some patients, many do not achieve durable benefit. Outcomes remain particularly challenging for patients with low or absent PD-L1 expression, immunologically “cold” tumors, certain oncogenic driver alterations, or disease that is refractory to immune checkpoint blockade. Among patients with advanced NSCLC who progress after immunotherapy or are ineligible for it, currently available subsequent therapies often provide limited clinical benefit.

The 5-year relative survival rate for patients with distant-stage lung and bronchus cancer remains approximately 10%, underscoring the need for new treatment strategies for patients who do not derive durable benefit from current therapies [5].

References
[1] International Agency for Research on Cancer. Lung cancer.
[2] American Cancer Society. Cancer Facts & Figures 2026.
[3] American Cancer Society. What Is Lung Cancer?
[4] National Comprehensive Cancer Network. NCCN Guidelines for Patients: Metastatic Non-Small Cell Lung Cancer.
[5] National Cancer Institute, SEER Program. Cancer Stat Facts: Lung and Bronchus Cancer.

NCT04495153 is a phase 2, open-label, multicenter clinical trial evaluating aglatimagene besadenovec plus valacyclovir in combination with standard-of-care immune checkpoint inhibitor (ICI) therapy, with or without chemotherapy (as indicated), in patients with unresectable stage III or IV non-small cell lung cancer (NSCLC) who have experienced an inadequate response to first-line anti-PD-1 or anti-PD-L1 treatment.

Eligible patients were assigned to protocol-defined cohorts according to response status and time on ICI therapy: patients with stable disease after at least 18 weeks of treatment were enrolled in cohort 1 and patients who progressed after at least 18 weeks of ICI were enrolled in cohort 2.

Patients received two courses of intratumoral aglatimagene besadenovec followed by 14 days of oral valacyclovir while continuing background ICI therapy.

Study endpoints included overall survival, overall response rate, duration of response, progression-free survival, safety, and immunologic biomarker analyses.

• Aglatimagene exhibited a generally favorable safety and tolerability profile throughout an extended follow-up period, with no new safety signals identified.
• Aglatimagene demonstrated a median overall survival of 25.4 months in patients with advanced NSCLC who have had inadequate response to ICI therapy and 21.5 months in patients with progressive disease at baseline despite ICI therapy. Among evaluable patients with progressive disease at baseline despite prior ICI therapy (cohort 2, n=41), mOS was 21.5 months.
• Long tail of survival observed in 50% of patients (per protocol population) who remained alive for more than 2 years after aglatimagene administration at the time of data cutoff (March 2, 2026).
• Histologic analysis of available baseline and tumor biopsies demonstrated that among evaluable patients surviving beyond 24 months and with PD-L1 status available, (17/20) 85% had baseline PD-L1 TPS below 50% (a population typically less responsive to ICI). These findings highlight the ability of aglatimagene to convert immunologically “cold,” ICI-resistant tumors into immune-active microenvironments.
• Molecular profiling of paired baseline and post-treatment tumor biopsies revealed that long-term survivors exhibited robust upregulation of genes associated with sustained immune activation and antigen presentation. Enhanced interferon signaling and activation of myeloid and antigen-presenting cell programs were observed, including a significant increase in the expression of IFNγ CSF1, CX3CL1, and IL1β (p = 0.010, 0.026, 0.013, and 0.034, respectively). These findings reflect increased local inflammation and recruitment of immune effector populations within the tumor microenvironment following aglatimagene treatment and may have contributed to the durable anti-tumor immune responses observed in long-term survivors.
• Decrease in size of uninjected tumors was observed in 69% of patients with multiple lesions (n=35), indicating that local injection may induce a systemic anti-tumor immune response (abscopal effect).
• Patients with non-squamous histology predominated among the long-term survivors: 14/15 patients with an overall survival greater than 24 months and 9/9 patients with an overall survival greater than 30 months had non-squamous NSCLC.
• Patients with non-squamous histology exhibited more pronounced changes in T cells, B cells, and dendritic cells after aglatimagene administration compared to patients with squamous NSCLC.
• Median overall survival of 25.4 months was observed in non-squamous NSCLC patients with progressive disease, despite ICI treatment.
• These outcomes compare favorably with historical reference mOS of 9.8–11.8 months, reported for patients with progressive disease following ICI treatment receiving standard-of-care docetaxel^1,2, representing approximately a two-fold improvement in mOS in this difficult-to-treat population.

References
[1] Paz-Ares LG et al. J Clin Oncol. 2024;42:2860-2872.
[2] Ahn MJ et al. J Clin Oncol. 2025;43:260-272.

The phase 2 clinical trial NCT04495153 is active but no longer recruiting participants.
A phase 3 clinical trial evaluating aglatimagene besadenovec in combination with immunotherapy in patients with metastatic, non-squamous NSCLC whose disease has progressed during immunotherapy is planned to begin recruitment in the second quarter of 2026.

Pancreatic cancer is one of the most lethal solid malignancies and remains a major public health challenge. In the United States, an estimated 67,530 new pancreatic cancer cases are expected in 2026 [1]. Pancreatic ductal adenocarcinoma (PDAC) accounts for more than 90% of pancreatic cancer diagnoses [2].

Because early-stage disease is often clinically silent and effective population-level screening is not available for most individuals, many patients are diagnosed with locally advanced or metastatic disease. Standard treatment may include surgical resection when feasible, combined with systemic chemotherapy and, in selected cases, radiotherapy.

Despite extensive clinical investigation, outcomes for pancreatic cancer have improved only modestly over time. Immunotherapy approaches, including immune checkpoint inhibitors, have generally not demonstrated clinically meaningful benefit for most patients, with the exception of rare molecular subgroups such as microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) tumors.

The 5-year relative survival rate for patients with distant-stage pancreatic cancer remains approximately 3%, reflecting early systemic dissemination, profound tumor-mediated immunosuppression, low tumor mutational burden, and a dense stromal microenvironment[3]. As a result, pancreatic cancer remains an area of high unmet medical need with few durable therapeutic options for most patients.

References
[1] American Cancer Society. Cancer Facts & Figures 2026.
[2] Johns Hopkins Medicine. Pancreatic Cancer Types.
[3] National Cancer Institute, SEER Program. Cancer Stat Facts: Pancreatic Cancer.

NCT02446093 is a randomized, open-label, multicenter phase 2 clinical trial evaluating aglatimagene besadenovec plus prodrug in combination with standard-of-care neoadjuvant chemoradiation or stereotactic body radiation therapy, followed by surgery when feasible, in patients with borderline resectable pancreatic ductal adenocarcinoma (PDAC).

The study randomized patients in a 2:1 ratio to receive standard of care with or without aglatimagene besadenovec plus prodrug after completion of at least 4 months of FOLFIRINOX-based induction chemotherapy. Borderline resectable status was confirmed by central radiologic review following induction therapy.

Eligible patients received three planned courses of study treatment timed with different phases of therapy: prior to chemoradiation or stereotactic body radiation therapy, concurrent with chemoradiation or just after completion of stereotactic body radiation therapy, and at the time of surgical resection. Up to two additional courses were permitted at recurrence, if feasible.

The study was designed to characterize safety, preliminary efficacy, and immune biologic activity. Key endpoints included adverse events, survival outcomes, resection-related outcomes, and exploratory biomarker analyses.

• Aglatimagene showed a favorable safety and tolerability profile.

• Aglatimagene plus valacyclovir demonstrated remarkable survival benefits with a median overall survival of 31.4 months versus 12.5 months in the standard of care control arm.

• Three out of seven patients treated with aglatimagene were still alive at the time of data cut-off (February 20, 2025), with survival of 66.0, 63.6, and 35.8 months after enrollment, respectively.

• Previous analysis at 24 months showed survival rates of 71.4% in patients treated with aglatimagene compared to 16.7% in the control group.

The phase 2 clinical trial NCT02446093 is active and no longer recruiting participants.

High-grade gliomas are rare but highly aggressive primary brain tumors. Glioblastoma is the most common malignant primary brain tumor in adults and accounts for approximately 52% of malignant brain and other central nervous system tumors in the United States [1].

Initial treatment typically consists of maximal safe surgical resection followed by radiotherapy with concurrent and adjuvant temozolomide. Despite aggressive multimodal therapy, glioblastoma remains associated with poor long-term survival and a high likelihood of recurrence.

At recurrence, prognosis is poor, with median overall survival commonly reported as less than 6 to 9 months. There is no universally accepted standard of care for recurrent glioblastoma, and management may include repeat surgery, re-irradiation, systemic therapy, bevacizumab, tumor treating fields, clinical trials, or best supportive care, depending on patient and disease characteristics. While bevacizumab is approved in the United States for recurrent glioblastoma [2] and can improve radiographic response and progression-free survival, it has not demonstrated an overall survival benefit in randomized glioblastoma studies [3].

Numerous immunotherapy approaches, including immune checkpoint inhibitors, vaccines, and cell-based therapies, have been evaluated in glioblastoma, but results to date have been limited and inconsistent.

Contributing factors include profound tumor-mediated immunosuppression, low neoantigen burden, marked intratumoral heterogeneity, and barriers to effective drug and immune-cell trafficking within the central nervous system. Recurrent glioblastoma therefore remains an area of substantial unmet medical need.

References
[1] Central Brain Tumor Registry of the United States (CBTRUS). CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States.
[2] Cohen MH, Shen YL, Keegan P, Pazdur R. FDA drug approval summary: bevacizumab (Avastin) as treatment of recurrent glioblastoma multiforme. Oncologist. 2009;14:1131-1138.
[3] Wick W, Gorlia T, Bendszus M, et al. Lomustine and bevacizumab in progressive glioblastoma. N Engl J Med. 2017;377:1954-1963.

NCT03152318 is an open-label phase 1b clinical trial evaluating intratumoral linoserpaturev in patients with recurrent high-grade glioma, including glioblastoma. The primary objective of the study is to determine the maximum tolerated dose and characterize the safety and tolerability of intratumoral linoserpaturev. Secondary and exploratory objectives include assessment of preliminary antitumor activity, radiographic changes, and evaluation of viral shedding, viremia, antibody responses, and immunologic biomarkers in tumor tissue and peripheral blood.

• Linoserpaturev was well tolerated without dose-limiting toxicities.

• Updated median overall survival data (as of August 2025): mOS was 11.8 months (CI: 8.3–14.9) for arm A (n=41) and 12.0 months (CI: 10.0–NA) for arm B (n=9) after a single injection of linoserpaturev.

• Responses were observed in both injected and uninjected lesions in patients with multifocal disease.

• Transformative patient case studies observed in arm A and arm B.

• Positive HSV-1 serology, before or after linoserpaturev injection, was a predictor of response and was associated with improved survival in 66% of patients who had 14.2 mOS, which is twice the expected median overall survival in this therapy-resistant population.

• Approximately 30% of seronegative patients at baseline seroconverted after linoserpaturev treatment. Those patients also exhibited increased survival, suggesting the possibility of leveraging this mechanism and further improving survival upon multiple injections.

• The activation of both local and systemic immune response, including the expansion of the T-cell repertoire diversity, as well as HSV-1 immune status correlate with survival, suggesting that linoserpaturev can enhance anti-cancer immune responses even in immunosuppressive tumor microenvironments.

• Additional extensive biomarker studies including histology, transcriptomics, and single cell sequencing are ongoing.

• Long-term survival observed: At time of data cutoff, one patient from arm A and one patient from arm B remained alive after prolonged follow-up (59.2 and 42.4 months, respectively, after linoserpaturev administration).

• Arm C interim data: 9 patients have received multiple administrations of linoserpaturev (ranging from 4-6 injections). At time of data cutoff, 4 out of 9 patients were alive (range 3.1-28.2 months after treatment initiation), with 3 of the 5 deceased patients surviving more than one year after treatment (range 5.5-21.8 months).

• No clear evidence that >4 injections resulted in better clinical outcomes than 4 injections, informing potential pivotal trial design.

The phase 1b clinical trial (NCT03152318) is active and no longer recruiting participants.