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Low-dose metronomic cyclophosphamide complements the actions of an intratumoral C-class CpG TLR9 agonist to potentiate innate immunity and drive potent T cell-mediated anti-tumor responses. | LitMetric

AI Article Synopsis

  • The synthetic oligonucleotide SD-101 is a strong agonist for toll-like receptor 9, showing significant anti-tumor effects when injected into tumors, especially when used with PD-1 blockade.
  • Researchers tested the combination of SD-101 with low-dose cyclophosphamide in mouse tumor models and found that this combination leads to greater anti-tumor activity than using either treatment alone.
  • The combination therapy enhances the immune response by producing a favorable environment that reduces regulatory T cells and alters macrophage types, resulting in long-term survival and rejection of both treated and untreated tumors.

Article Abstract

The synthetic oligonucleotide SD-101 is a potent and specific agonist for toll-like receptor 9. Intratumoral injection of SD-101 induces significant anti-tumor immunity in preclinical and clinical studies, especially when combined with PD-1 blockade. To build upon this strategy, we studied the enhancement of SD-101 activities by combination with low-dose cyclophosphamide, a well-characterized agent with potentially complementary activities. In multiple mouse tumor models, we demonstrate substantial anti-tumor activity of the combination, compared to each single agent. Combination therapy generated CD8+ T cell dependent immunity leading to rejection of both non-injected and injected tumors and long-term survival, even in very large tumors. Mechanistic studies encompassing global gene expression changes and characterization of immune cell infiltrates show the rapid, sequential induction of innate and adaptive responses and identify discrete contributions of SD-101 and cyclophosphamide. Importantly, these changes were prominent in tumors not injected directly with SD-101. Combination treatment resulted in creation of a permissive environment for a systemic anti-tumor immune response, including a reduction of intratumoral regulatory T cells (Tregs) and an increase in "M1" versus "M2" tumor-associated macrophage (TAM) phenotypes. Additionally, we observed increased immunogenic cell death as well as antigen processing in response to combination treatment.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944447PMC
http://dx.doi.org/10.18632/oncotarget.27322DOI Listing

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