Memory T cell–driven differentiation of naive cells impairs adoptive immunotherapy

Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8+ T cells for adoptive immunotherapy

“…In this way, late memory and effector T cells can no longer stimulate the differentiation of antigen-specific T cells. 28 Starting with CD8 + T N cells resulted in an elevated CD62L expression in all cultures, though variation remained high. This variation between cultures might be explained by basal donor variation in AKT expression and phosphorylation, 48 showing that optimal dosing is important.…”

“…Since effector T (T EFF ) cells can accelerate the differentiation of naïve T cells 28 and the frequency of T EFF differs per donor, we aimed to increase the robustness of our culture protocol by starting the culture with CD8 + T N cells instead of total CD8 + T cells. Here, we selected the most effective AKT-inhibitors of the allosteric and ATP-competitive group: AktiVIII and GDC, respectively.…”

Improving T-cell expansion and function for adoptive T-cell therapy using ex vivo treatment with PI3Kδ inhibitors and VIP antagonists

“…These results are consistent with the fratricide of naive T cells by T effector memory cells that has been recently described. 5 …”

“…3 Importantly, one of the major off-target effects of these therapies is damage to healthy T cells 4 and loss of the naive and central memory T-cell subsets that have the most potent expansion potential and anticancer activity in vivo. 5 Loss of naive and central memory T cells in previously treated cancer patients is particularly pronounced in adult patients with DLBCL and has been shown to a result of FasL-mediated fratricide from terminally differentiated effector cells. 5 The end result of cellintrinsic deficits in T-cell function in heavily pretreated patients can lead to inadequate ex vivo T-cell expansion, leading to CAR T-cell manufacturing failures and lack of adequate in vivo expansion of reinfused CAR T cells.…”

“…5 Loss of naive and central memory T cells in previously treated cancer patients is particularly pronounced in adult patients with DLBCL and has been shown to a result of FasL-mediated fratricide from terminally differentiated effector cells. 5 The end result of cellintrinsic deficits in T-cell function in heavily pretreated patients can lead to inadequate ex vivo T-cell expansion, leading to CAR T-cell manufacturing failures and lack of adequate in vivo expansion of reinfused CAR T cells. 6 Durable response rates of 30% to 40% have been reported for lymphoma patients treated with CAR T cells, 3,7 with manufacturing failure rates of up to 6%.…”