A precision medicine tool 'Knowledge Frames' to explain poor results of STING agonist trials
| Autor: | Al Blunt, Steve Gyorffy, Gerald L. Messerschmidt |
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| Rok vydání: | 2020 |
| Předmět: | |
| Zdroj: | Journal of Clinical Oncology. 38:e15632-e15632 |
| ISSN: | 1527-7755 0732-183X |
| DOI: | 10.1200/jco.2020.38.15_suppl.e15632 |
| Popis: | e15632 Background: STING activating cyclic-di-nucleotides result in the production of interferons, activating immune cells. We show that “Precision Medicine Knowledge Frames” (PMKF) are analyses inherently involving 2 processes: Frame 1 – Bench Science - biochemical functions of the experimental product, and Frame 2 - Human Organism Level - actions from product biochemical effects to tumor cell killing. Methods: STING agonists meet this PMK frame1 and activate STING (step 1) effectively. Activated STING binds TBK1 (step 2), then phosphorylates IRF3 (step 3), enters the nucleus (step 4), dimerizes (step 5) and binds specific regions of the DNA (step 6) for interferon transcription (step 7), which are secreted (step 8). Frame 2, the Human Organism Level - final common pathway requires many additional actions: Interferon must interact with immune cells (step 9) [within tumor or peripheral locations]. Very warm or hot tumors [contain functional immune cells] actively allow trafficking (homing) to the tumor (step 10) and infiltrating the tumor microenvironment (step 11). An activated immune cell can kill the tumor cell(s) (step 12). Cold tumors may not allow homing (step 10) to the tumor and/or infiltration (step 11) of the microenvironment. Results: PMKF modeling was applied to STING administration public data. Lack of efficacy was predicted if one of the critical pathway steps to tumor cell death are dysfunctional. Early steps (Frame 1) to interferon production and excretion into the environment occur within normal cells (antigen presenting cells) predictably. However, in the setting of malignancy, Frame 2 steps are often aberrant at the Organism Level. Cold tumors do not allow immune cell homing (step 10) and inhibit tumor infiltration (Step 11), tumor cell localization and killing of the tumor cell (step 12). Conclusions: STING Agonist are cutting edge therapies that perform PMKF Frame 1 well and increase interferon production. Application of the PMKF - Frame 2 demonstrate poor clinical activity may be explained by poor immune cell homing, infiltration and functional killing within the cold tumor microenvironment (dysfunctional steps 10, 11 and 12). Population selection may improve these results. |
| Databáze: | OpenAIRE |
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