RE:CD8+ TiLs and T-cell exhaustionAugust 29, 2024 - Combo immunotherapy produces distinct waves of cancer-fighting T cells with each dose
Immune checkpoint inhibitors work by unleashing T cells to find and kill cancer cells. It was thought that this type of combination immunotherapy works by equipping an army of T cells to recognize and fight cancer throughout the course of treatment. In a sense, the idea was that if this group of T cells stayed strong for long enough, they would conquer cancer, but if they became too depleted, they would lose the battle. The study, which analyzed data from 36 patients treated with immunotherapy for advanced melanoma, found that the combination therapy produces waves of new T cells—known as a clonal response—with each dose, rather than continually strengthening the same pool of T cells. https://www.pennmedicine.org/news/news-releases/2024/august/combo-immunotherapy-makes-waves-of-cancer-fighting-t-cells
CD8+ TiL cells are critical mediators of cytotoxic effector function in cancer, however, in cancer, CD8+ TiL cells undergo a progressive loss of cytokine production and cytotoxicity, a state termed T-cell exhaustion as well as T-cell dysfuntion, resulting in a failure of T-cells to eradicate tumor cells in the tumor microenvironment (TME).
Also, high levels of PD-1 expression contribute to the characteristic dysfunction seen in exhausted CD8+ TiL cells. Correspondingly, in human tumors, a higher proportion of progenitor exhausted cells was associated with a greater likelihood of response to checkpoint blockade. While PD-1 blockade therapies have been successful in multiple tumor types, their effectiveness has been limited to between 10-20% of the patients treated.
Results from ONCY's AWARE-1 study showed that pelareorep treatment upregulated tumor PD-L1 expression, induced the generation and expansion of T cell clones, promoted tumor infiltration of CD8+ TiL cells, and increased the CelTIL score, a measure of tumor cellularity and inflammation associated with favorable clinical outcomes. Besides being able to overcome an immunosuppressive TME, pelareorp is a critical 'facilitator' in 'priming' the adaptive immune system in advance of PD-1 blockade, thus turning a 'cold' tumor into a 'hot' tumor that is more much conducive for PD-1 blockade, and a more effective I/O therapy than either agent alone.
https://www.newswire.ca/news-releases/oncolytics-biotech-r-and-solti-achieve-primary-endpoint-in-aware-1-study-871181269.html