Speaker
Description
Resistance to immune checkpoint inhibitors (ICI), including anti-PD-1 and anti-PD-L1 therapies, remains a major limitation in cancer treatment, with most patients relapsing despite initial responses. Previous studies have shown that inhibition of TNF-alpha or TGF-beta overcome resistance to anti-PD-1. Here, we develop a mathematical model to investigate a mechanism of ICI resistance driven by age-associated senescence of CD8+ T cells. In the model, senescent T cells secrete VEGF, thereby promoting tumor growth through enhanced vascular support. To counteract this effect, we incorporate the senolytic drug navitoclax (ABT-263), which selectively eliminates senescent T cells, and assess the efficacy of combined senolytic-ICI therapy in extending tumor remission. Model predictions are validated against independent experimental data from murine studies involving navitoclax and anti-PD-L1 treatment. Using the validated framework, we conduct in silico clinical trials simulating multi-cycle anti-PD-1 treatment in young and old patient cohorts with different timings of senolytic administration. The results demonstrate that the optimal timing of navitoclax depends on immune age: maximal remission extension is achieved when senolytic therapy is initiated in the second treatment cycle in older patients, whereas earlier administration is most effective in younger patients. These findings highlight immune senescence as a key determinant of response to cancer immunotherapy and suggest that age-adapted scheduling of senolytic drugs may improve the durability of ICI-based treatments.
