TuHURA Biosciences Unveils Delta Opioid Receptor as Novel Target to Overcome Cancer Immunotherapy Resistance
核心洞察
TuHURA Biosciences (搜索) presented groundbreaking research at the 67th ASH Annual Meeting demonstrating that the Delta Opioid Receptor (DOR) is expressed on tumor-associated myeloid-derived suppressor cells and tumor-associated macrophages for the first time.
The company's data showed that DOR inhibition successfully reprograms multiple mechanisms of immunosuppression in these cells, potentially overcoming acquired resistance to cancer immunotherapy.
TuHURA is developing a library of highly selective DOR antagonists with over 1,200-fold selectivity and potency below 1.0 ng/ml for first-in-class antibody drug conjugates.
TuHURA Biosciences (搜索) presented pivotal research at the 67th American Society of Hematology (ASH) Annual Meeting and Exposition in Orlando, Florida, demonstrating the Delta Opioid Receptor (DOR) as a novel target for overcoming resistance to cancer immunotherapy. The company's findings represent the first demonstration that DOR is expressed on tumor-associated myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), opening new avenues for cancer treatment.
Breakthrough Discovery in Immunosuppressive Cell Targeting
In an oral presentation titled "Delta Opioid Receptor (DOR) Expression on Myeloid-Derived Suppressor Cells (MDSCs) Represents a Novel Target to Overcome Resistance to Immune Checkpoint Inhibitors (ICIs)," Dr. Michael Turner, Vice President of Immunology at TuHURA Biosciences (搜索), presented updated data validating DOR expression on MDSCs. The research showed that pharmacological antagonism of DOR reduced the suppressive activity of MDSCs, which are a heterogeneous population of immature myeloid cells that contribute to creating an immunosuppressive tumor microenvironment by suppressing anti-tumor immune responses.
The study demonstrated that antagonism of the DOR with a specific inhibitor modulated a variety of direct and indirect MDSC-mediated immunosuppressive factors and reversed T cell suppression, suggesting the DOR may be a novel target to reprogram MDSC-induced immunosuppression in the tumor microenvironment.
Targeting Tumor-Associated Macrophages
Complementing the MDSC findings, TuHURA's poster presentation revealed that DOR is highly expressed in tumor-infiltrating myeloid cells, particularly TAMs. Dr. Krit Ritthipichai, Director of Immunology at TuHURA Biosciences (搜索), presented results showing that the tumor microenvironment induces DOR upregulation relative to peripheral macrophages. The research indicated that targeting the DOR provides a promising strategy to reprogram suppressive TAMs and MDSCs, alleviate T-cell dysfunction, and potentially overcome resistance to checkpoint blockade and other immunotherapies.
Clinical Implications and Therapeutic Potential
Dr. James Bianco, President and Chief Executive Officer of TuHURA Biosciences (搜索), emphasized the significance of these discoveries: "Our discovery of the expression of the DOR on MDSCs and TAMs, and that its activation is coupled to mechanisms by which these cells contribute to immunosuppression, makes the DOR a compelling target for pharmacologic intervention to overcome acquired resistance to cancer immunotherapy."
The research extends beyond MDSCs and TAMs, with data demonstrating that DOR is also expressed on regulatory T cells (Tregs) and controls the expression of FOXP3, a critical immunosuppressive gene. This provides a shared mechanism by which endogenous opioids, via the DOR, control the immunosuppressive tone of both innate and adaptive immune responses critical in cancer pathology.
Drug Development Pipeline
TuHURA has developed a library of highly selective DOR antagonists with greater than 1,200-fold selectivity and potency below 1.0 ng/ml. The company is positioned to advance first-in-class immune-modulating bi-functional, bi-specific antibody drug conjugates (ADCs). The lead ADC candidate is anticipated to consist of a DOR inhibitor conjugated to the company's VISTA (搜索) inhibiting antibody.
The combination approach leverages VISTA (搜索)'s documented role in being central to how leukemia escapes immune recognition, making it an ideal candidate to link to a DOR inhibitor. According to Dr. Bianco, "Our ADCs have the potential to not only remove the immunosuppressive tone of the tumor microenvironment but to also checkpoint release resting T cells, allowing them to recognize and kill leukemic cells."
Collaborative Research Validation
The Moffitt Cancer Center, under its collaborative work with TuHURA, presented additional supporting data outlining the pathogenic role of DOR-expressing MDSCs in patients with myelodysplastic syndrome (MDS). Dr. Erika Eksioglu from the Department of Immunology at Moffitt Cancer Center presented findings on how delta opioid receptor signaling modulates myeloid suppression in myelodysplastic syndromes, with restoration of stem cell proliferation observed with DOR inhibition.
Broader Therapeutic Applications
Beyond cancer immunotherapy, TuHURA's DOR technology platform shows potential for treating autoimmune and inflammatory diseases. The company's research demonstrates that this single target shares control of the immune suppressive capabilities of multiple cell types, providing a unique position to exploit pharmacologic modulation of the DOR across various therapeutic areas.
TuHURA Biosciences (搜索) continues to advance its comprehensive pipeline, including its Phase 3 innate immune agonist IFx-2.0 for Merkel Cell Carcinoma and TBS-2025 (搜索), a VISTA (搜索) inhibiting monoclonal antibody moving into Phase 2 development for mutNPM1 relapsed/refractory acute myeloid leukemia.