MD/PhD Candidate Vanderbilt University Nashville, Tennessee, United States
Disclosure(s):
Neil C. Chada, BS: No financial relationships to disclose
Introduction/Rationale: Adoptive cell therapy (ACT) has demonstrated efficacy in hematologic malignancies but remains limited in solid tumors due to an immunosuppressive tumor microenvironment (TME) that restricts T cell infiltration, activation, and persistence. Activation of the stimulator of interferon genes (STING) pathway can reprogram the TME toward inflammation; however, systemic STING agonist delivery is hindered by poor tumor accumulation and dose-limiting toxicity. We hypothesized that targeted systemic delivery of a STING agonist using an albumin-hitchhiking nanobody platform could safely enhance ACT efficacy in solid tumors by reversing the immunosuppressive TME.
Methods: We developed albumin-hitchhiking nanobody–STING agonists (AHNSA) and evaluated them as an adjuvant to ACT in a TCR-transgenic OTI T cell transfer model using MC38-OVA tumors. Dosing and timing of AHNSA relative to ACT were optimized. Tumor-infiltrating immune cells and transferred T cells were analyzed by flow cytometry and IHC to assess activation, proliferation, exhaustion, and cytotoxic potential, as well as global changes in TME composition.
Results: Systemic AHNSA administration following OTI T cell transfer significantly improved survival compared to ACT alone. AHNSA treatment increased infiltration of both innate immune cells and adoptively transferred T cells into tumors. Transferred T cells displayed enhanced activation and proliferation with reduced expression of exhaustion markers. Bulk tumor immune profiling revealed enrichment of pro-inflammatory populations, including M1 macrophages, dendritic cells, and CD8⁺ T cells, alongside depletion of immunosuppressive subsets such as myeloid-derived suppressor cells, M2 macrophages, and regulatory T cells. These findings indicate effective reversal of TME immunosuppression. Ongoing studies are extending this approach to a fully immunocompetent CAR-T model.
Conclusion: AHNSA represents a promising strategy to overcome TME-mediated resistance and enhance ACT efficacy in solid tumors.
