Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of hematologic cancers, providing durable responses and even complete remissions. However, its efficacy in solid tumors, such as prostate cancer, remains limited. The tumor microenvironment (TME), composed of a dense extracellular matrix, low oxygenation, acidity, and immunosuppressive metabolites, forms a physical and functional barrier to CAR-T cell infiltration and persistence. In this context, oncolytic viruses emerge as strategic allies, not only for selectively destroying tumor cells but also for remodeling the TME and promoting a more favorable immune response.
What is Ad-CXCL9-IL15 and how does it work?
A recent study introduces an innovative approach that combines viral engineering with cellular immunotherapy. Lin Fang and colleagues developed a genetically modified oncolytic adenovirus (OAV) designed to express the chemokine CXCL9 and the cytokine IL-15, resulting in the vector Ad-CXCL9-IL15. This combination aims to increase the infiltration of activated T cells into the tumor via CXCL9-mediated attraction and to promote their expansion and persistence through IL-15 support. The vector is engineered to preferentially infect tumor cells, ensuring localized release of immunomodulatory molecules and minimizing systemic side effects.
Robust preclinical data in prostate cancer
DU145 model: complete regression
In the DU145 prostate cancer model, intratumoral administration of Ad-CXCL9-IL15 combined with CAR-T cells targeting the B7H3 antigen led to complete tumor regression in all treated animals. The combined therapy not only controlled tumor growth but also significantly prolonged survival. Mice that achieved complete regression developed resistance to tumor rechallenge, suggesting the establishment of durable immune memory.
Bilateral model: abscopal effect
In a bilateral renal OSRC-2 tumor model, the vector was injected into only one tumor, yet its combination with CAR-T cells resulted in regression of both tumors, indicating an abscopal effect. This supports the hypothesis that TME modulation at one tumor site can trigger a systemic immune response.
PANC-1 model: overcoming “cold” tumors
Even in cold tumor models (non-immunogenic, with little or no T-cell infiltration) such as pancreatic PANC-1, which are traditionally resistant to immunotherapy, the Ad-CXCL9-IL15 plus CAR-T combination showed significant clinical benefits, including complete tumor regression and substantial survival improvement.
Immunological evidence
Immunological analysis revealed a marked increase in CD45⁺CD3⁺ and CD8⁺ T-cell infiltration within the tumors, along with a reduction in regulatory T cells (Tregs), which are known to suppress antitumor immunity. In the spleen, there was an increase in CD44⁺CD62L⁺ memory T cells, indicating that the treatment not only promoted local responses but also strengthened systemic immune surveillance. Moreover, combined therapy extended the persistence of circulating CAR-T cells for up to five weeks post-infusion, a critical factor for long-term therapeutic success.
Comparative analysis with other viral approaches
While other vectors engineered to express IL-7, CCL19, or IFN-γ have also yielded promising results, the specific combination of CXCL9 and IL-15 demonstrated superior outcomes in tested models, striking a balance between cell recruitment and immune support. This type of viral engineering may represent a new generation of “armored” vectors, capable of priming the tumor microenvironment for cellular therapies.
Study limitations and next clinical steps
Despite encouraging results, the preclinical models lack the immunological complexity of human physiology. Next steps include validating the safety and efficacy of Ad-CXCL9-IL15 in immunocompetent models and, subsequently, in clinical trials. Assessing systemic toxicity and the risk of exacerbated inflammatory responses will be critical for safe clinical translation.
A leap toward personalized CAR-T and oncolytic therapies
Beyond technical advances, the Ad-CXCL9-IL15 strategy has direct implications for personalized cancer treatment. By tailoring the viral vector to different tumor profiles and integrating it with CAR-T cells directed against specific antigens, this platform opens the door to customized therapies, especially for patients resistant to conventional approaches.
The discovery also enhances understanding of how the tumor microenvironment can be reprogrammed in real time through bioengineered tools. Localized release of CXCL9 and IL-15 by the adenovirus not only increases effector cell infiltration but also activates immune memory mechanisms capable of preventing tumor recurrence. This dual effect—immediate immunity and long-term surveillance—is particularly valuable in refractory solid tumors, where relapse is common. The armoring strategy proposed by the researchers may further be expanded with additional immunoregulatory molecules, paving the way for modular and highly customizable viral platforms.
This research offers a new perspective on how the tumor microenvironment can be strategically manipulated to enhance cellular therapy outcomes. Armoring oncolytic adenoviruses with CXCL9 and IL-15 not only strengthens immune responses but also appears to boost CAR-T activity, promoting durable systemic effects and complete responses even in cold tumors.
Read also on our blog: How to generate potent and persistent antitumor immunity through affinity-tuned CAR-T cells targeting mesothelin.
