Tarloxotinib targets tumor hypoxia to improve…

Results

Tarloxotinib lowered tumor hypoxia by eightfold in the epidermal growth factor receptor (EGFR)-dependent MB49 syngeneic mouse tumor model of bladder cancer, attracting CD8+ T cells to the tumor, and potentiating checkpoint inhibitor activity. Various methodologies, including CD8+ T cell depletion and exogenous T cell priming, confirmed that tarloxotinib improves the function of activated CD8+ T cells. While anti-programmed death-ligand 1 (anti-PD-L1), anti-programmed death protein-1, and anti-cytotoxic T-lymphocyte antigen-4 treatments were all effective in the remodeled tumor microenvironment, anti-PD-L1 was most responsive to tarloxotinib coadministration, providing a 100% complete response rate with more than 360% improvement in tumor growth delay (p<0.0001) and an increasing CD8+ T cell infiltrate from 8% to 43% of the total CD45+ population in MB49 tumors. RNA transcript analysis of 770 cancer and immune-related genes in naïve and tarloxotinib-treated tumors highlighted the induction of gene clusters related to co-stimulatory signaling, cytokine/chemokine signaling, interferon signaling, immune cell adhesion/migration, antigen presentation, and lymphoid/myeloid compartments. Serum protein analysis confirmed upregulation of several cytokines/chemokines, including interleukin (IL)-6, IL-12p40, interferon-γ, and macrophage inflammatory protein-1β. This broad immunogenic response was dependent on toll-like receptor 9 (TLR9), with the positive interaction between anti-PD-L1 and tarloxotinib being blocked in myeloid differentiation primary response 88- or TLR9-knockout mice. Surprisingly, this observed therapeutic interaction was also evident in EGFR-negative MC38 (and EG7.OVA) syngeneic tumor models, which was associated with suppression of tumor hypoxia rather than TLR9 signaling, indicating two independent mechanisms of action. Consistent with the clinical experience of minimal systemic toxicities related to normal tissue EGFR inhibition (eg, diarrhea, pruritus), mouse body-weight loss was minimal across all in vivo studies.

Tarloxotinib targets tumor hypoxia to improve therapeutic efficacy of immune checkpoint inhibition in a MyD88-dependent manner

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