Improving CAR T-cell persistence Sample Clauses

Improving CAR T-cell persistence. Another mechanism of disease resistance relates to lack of CAR T-cell persistence, an issue unlikely to be solved by targeting multiple antigens. The use of murine scFvs has been associated with anti-transgene immune responses against CAR T-cells, leading to poor T-cell expansion and persistence. To decrease immunogenicity and improve efficacy, CARs that have been targeted using humanized scFv regions have been developed and tested in the clinic191,192. The intrinsic fitness of CAR T-cells has been implicated as the most important factor shaping the clinical response in patients with advanced CLL, a disease in which response to anti-CD19 CAR T-cell therapy varies from 26-71%119,193,194. In patients responding to anti- CD19 CAR T-cell therapy there was an upregulation of a transcription signature related to early memory differentiation. These patients also had a more robust expansion potential both ex vivo and in vivo. Furthermore, in responding patients the IL-6/STAT3 pathway was upregulated in CAR T-cells while blockade of STAT3 signalling diminished T-cell proliferation. In comparison, CAR T-cells analysed from non-responding patients upregulated genes related to effector T-cell differentiation, exhaustion and glycolysis. The results from this study promote the idea that CAR T-cell fitness may be used as a biomarker to determine likelihood of successful therapeutic efficacy193. A promising strategy to prolong CAR T-cell persistence involves selecting less differentiated T-cell subsets that have a greater proliferative capacity such stem cell memory T-cells (TSCM) and central memory T-cells (TCM)122,195. A preclinical study investigated whether T-cell expansion and function could be improved by culture of the cells in the presence of a phosphatidylinositol 3-kinase δ (PI3Kδ) inhibitor and vasoactive intestinal peptide (VIP) antagonist196. Researchers demonstrated that antagonism of PI3Kδ and VIP signalling pathways ex vivo resulted in the generation of less terminally differentiated T-cells at greater numbers and with enhanced cytotoxic activity. Furthermore, in vivo CAR T-cell persistence was improved after expansion with both inhibitors. Differential costimulatory signalling can influence CAR T-cell persistence and function thereby affecting the durability of anti-tumour activity. As such, engineering strategies to fine tune signalling are being developed, including modifying the costimulatory domain of the CAR. In a recent study, Xxxxxx et al. showed t...