Friday, May 9, 2025
5/9/2025
Systemic/Abscopal Anti-Tumor Immune Responses during IAP Antagonism and Radiation - PROJECT SUMMARY Radiotherapy (RT) is used for locally advanced head and neck cancer either as primary/definitive therapy or in the adjuvant (post-surgical) setting to improve local control rates. However, RT may occasionally improve distant tumor control due to immune stimulation. Tumor regression outside the radiation field (distant effect) is termed the abscopal effect. RT mediates this, in part, by acting as in-situ vaccine, liberating tumor antigens, and generating an inflammatory milieu that enhances the CD8+ T-cell anti-tumor response. RT can synergize with immune checkpoint blockade (ICB) to enhance the abscopal effect, but this has rarely been seen in the clinical setting. Inhibitor of apoptosis proteins (IAPs) regulate the extrinsic and intrinsic apoptotic pathways, which can be induced by radiation. IAP antagonists can enhance these apoptotic pathways and are under active study as anti-cancer therapeutics. We have shown that the efficacy of RT + IAP antagonism can be further enhanced with the addition of anti-PD-1 ICB. Our prior preclinical work in head and neck cancer models showed that the when the IAP antagonist tolinapant was added to RT, local tumor control was enhanced, and T-cell stimulation was noted in the tumor draining lymph node (TDLN). This combination also enhanced several other components of the anti-tumor immune response, including antigen presentation, immunogenic cell death, and dendritic cell activation. Using biospecimens from our first-in-human clinical trial of tolinapant + RT (without platinum chemotherapy), we have seen dramatic increases in circulating, activated T cells in 50% of patients. These results suggest that tolinapant + RT can induce systemic anti-tumor immunity. RT stimulates a tumor-specific stem-like CD8+ T cell subset within the tumor and TDLN, which is critical for responses to ICB and abscopal responses. IAP antagonism can also promote T-cell costimulation, which is important for reinvigoration of stem-like CD8+ T cells. Thus, we hypothesize that tolinapant will enhance the RT-stimulated abscopal response by stimulating stem-like CD8+ T-cells. In Aim 1, we will use innovative, orthotopic abscopal murine models of oral cancer to determine whether tolinapant can enhance anti-tumor immune responses outside of the radiation field by increasing stem-like CD8+ T cells within the TLDN. In Aim 2, we will take a more in-depth look at blood and tissue biospecimens from our innovative clinical trial to determine if IAP antagonists combined with RT, in the absence of platinum chemotherapy, can induce systemic anti- tumor immunity. We will perform single-cell RNA sequencing on blood samples of patients who have had increased CD38+HLA-DR+ T cells in the blood and compare results with samples from patients who have not had these increases. Spatial transcriptomics will be used on baseline tissue samples to determine what tumor cell and immune cell features are associated with robust peripheral immune responses. With multiple large clinical trials of RT + IAP antagonism under development for HNSCC, these studies will be critical for advancing the field and improving our understanding of how IAP antagonists can be best utilized to enhance the effects of RT.
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