Siren Biotechnology presented groundbreaking preclinical data for its Universal AAV Immuno-Gene Therapy at the American Society of Gene & Cell Therapy (ASGCT) 26th Annual Meeting in Los Angeles. The novel treatment approach combines adeno-associated virus (AAV) gene therapy and cytokine immunotherapy into a single modality, showing remarkable efficacy against high-grade gliomas in multiple experimental models.
The San Francisco-based company, which officially emerged from stealth mode coinciding with the presentation, revealed compelling results from studies evaluating AAV9 vectors expressing 12 different engineered immunomodulatory interferon (IFN) cytokine payloads, including IFN-α, IFN-β, IFN-λ, and various combinations.
Impressive Efficacy in Preclinical Models
In primary human high-grade glioma (HGG) organoids, Siren's AAV immuno-gene therapies demonstrated rapid and selective reduction in tumor size. This stands in stark contrast to control treatments, including phosphate buffered saline, dimethyl sulfoxide diluent, and AAV9-GFP (green fluorescent protein), which had no impact on tumor growth. Notably, the current standard of care for HGG, temozolomide chemotherapy, not only failed to adequately control tumor growth but also significantly damaged healthy cerebral cells.
The in vivo results were equally compelling across three different HGG mouse models comprising 450 treated mice. Following intratumoral administration via convection-enhanced delivery (CED), the treatment resulted in:
- Tumor regression and significantly prolonged survival in human GBM6 xenografts (P<0.2-0.001), with 31-60% complete responses
- Significant tumor reduction in mouse GL261 allografts (P<0.0009)
- Meaningful responses in human patient-derived xenografts (P<0.04), with 30% complete responses
Rapid Tumor Destruction Mechanism
Detailed examination of tumor-bearing mouse brains revealed the treatment's remarkable speed and precision. Within just 48 hours of administration, local intratumoral expression of Siren's engineered IFNs triggered widespread tumor cell apoptosis and activated brain-resident macrophages (microglia), which help clear dying cells.
By day 7 post-treatment, researchers observed:
- Reproducible tumor eradication
- No evidence of residual proliferating tumor cells
- No remaining engineered cytokine payload expression
- Only residual microglial activity
Single-cell sequencing on syngeneic mouse brain tumors following treatment confirmed that tumor cells exhibited significant upregulation of genes linked to IFN responses and other classic immune response genes. Importantly, these responses were specific to the IFN payload expression and not to the AAV vector itself.
A New Paradigm for Cancer Treatment
"We're excited to present these potentially transformative data as we simultaneously introduce Universal AAV Immuno-Gene Therapy and Siren Biotechnology," said Dr. Nicole Paulk, Founder and Chief Executive Officer of Siren, who presented the findings at ASGCT. "This novel approach represents a new, big, bold idea to fight cancer by combining the potential of AAV gene therapy and cytokine immunotherapy into a single modality."
Dr. Paulk, a renowned AAV gene therapy expert, outlined the company's strategic focus on brain and eye cancers, areas where systemic drug treatments have historically failed. "The unmet need for these patients is dire, and our opportunity to help is massive," she emphasized.
Future Directions
Siren Biotechnology's vision extends beyond their initial focus areas. The company aims for Universal AAV Immuno-Gene Therapy to eventually become the standard of care for a wide range of solid tumor cancers.
The technology's ability to selectively target and destroy cancer cells while sparing healthy tissue, combined with its rapid action and durable response, positions it as a potentially transformative approach in oncology. The complete clearance of both the tumor and the therapeutic payload by day 7 also suggests a favorable safety profile that warrants further investigation in additional tumor types and eventually in clinical trials.
As Siren continues to develop this platform, the oncology community will be watching closely to see if this innovative combination of gene therapy and immunotherapy can deliver on its early promise and address the significant unmet needs in solid tumor treatment.
