PI3K orchestration of the in vivo persistence of chimeric antigen receptor-modified T cells

Abstract

In vivo persistence of chimeric antigen receptor (CAR)-modified T cells correlates with therapeutic efficacy, yet CAR-specific factors that support persistence are not well resolved. Using a CD33-specific CAR in an acute myeloid leukemia (AML) model, we show how CAR expression alters T cell differentiation in a ligand independent manner. Ex vivo expanded CAR-T cells demonstrated decreased naïve and stem memory populations and increased effector subsets relative to vector-transduced control cells. This was associated with reduced in vivo persistence. Decreased persistence was not due to specificity or tumor presence, but to pre-transfer tonic signaling through the CAR CD3ζ ITAMs. We identified activation of the PI3K pathway in CD33 CAR-T cells as responsible. Treatment with a PI3K inhibitor modulated the differentiation program of CAR-T cells, preserved a less differentiated state without affecting T cell expansion, and improved in vivo persistence and reduced tumor burden. These results resolve mechanisms by which tonic signaling of CAR-T cells modulates their fate, and identifies a novel pharmacologic approach to enhance the durability of CAR-T cells for immunotherapy.

Prevention of relapse after allogeneic stem cell transplantation in acute myeloid leukemia: Updates and challenges

“…Excitingly, genome‐editing technologies including clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR‐associated protein 9 (Cas9) and transcription activator‐like effector nucleases (TALEN) may further refine AML CART cell specificity, potency, and prolonged persistence, at the same time reducing “off target” effects . Preclinical studies combining CART therapy with specific kinase inhibitors: CD19 CAR T and ibrutinib in ALL, FLT3 CART with crenolanib in AML, and CD33 or CD19 CAR T cells with PI3K inhibitor LY294002 in AML and ALL, respectively, are underway . Recently, CD4+ and CD8+ HA‐1 T‐cell receptor (TCR) T cells has been studied in a phase I trial for treating HLA‐A*0201 HA‐1‐positive patients with R/R acute leukemia including AML (NCT03326921).…”

Adoptive immunotherapy with CAR modified T cells in cancer current landscape and future perspectives

“…Jetani and colleagues recently reported that the FLT3 inhibitor crenolanib had a synergist activity with FLT3-directed CAR T cells in a FLT3-ITD AML model, at least in part by increasing FLT3 surface expression (79), and similar results were also presented for midostaurin (80). Besides, it was recently reported that PI3K inhibition can enhance CD33-directed CAR T cells durability, thus improving antitumor activity (81).…”

Adoptive CD8+ T cell therapy against cancer:Challenges and opportunities

“…4-1BB, ICOS [75]; 6) altered metabolism status [76,77]. These potentially persistent tumor specific T cells could control cancer and prevent recurrence for a long time [78,79].…”