Additionally, various cytokine combinations have been tested to manipulate metabolic changes and improve the ratio of T SCM and T CM cells during the CAR-T cell expansion phase. IL-2 has been considered the "gold standard" growth factor, though it triggers a shift from OXPHOS to glycolysis . Other cytokine combinations have additionally improved persistence in vivo by promoting OXPHOS and blocking glycolysis. Using IL-7 and IL-15 in clinical studies led to higher proportions of T SCM and T CM than just IL-2, which saw larger amounts of T CM and T EM . A separate study confirmed this, where IL-7 facilitated the highest levels of the T SCM subset compared to other pro-inflammatory cytokines. . A trial in vivo demonstrated that IL-12 modulates the expression of CD62L on activated T cells, resulting in superior persistence and proliferation compared to IL-2. . Additionally, in vivo administration of IL-15 and IL-21 treated T cells exhibited the phenomenal persistence and most effective tumor elimination in vivo. However, it is interesting to note that IL-2 improved the accumulation of CAR-T cells in vitro ( ), even though IL-2-treated CAR-T cells display reduced anti-tumor cytotoxicity.