Augmentation of Antitumor Immunity by Human and Mouse CAR T Cells Secreting IL-18

Abstract

SUMMARY The effects of transgenically encoded human and mouse IL-18 on T cell proliferation and its application in boosting chimeric antigen receptor (CAR) T cells are presented. Robust enhancement of proliferation of IL-18-secreting human T cells occurred in a xenograft model, and this was dependent on TCR and IL-18R signaling. IL-18 augmented IFN-γ secretion and proliferation of T cells activated by the endogenous TCR. TCR-deficient, human IL-18-expressing CD19 CAR T cells exhibited enhanced proliferation and antitumor activity in the xenograft model. Antigen-propelled activation of cytokine helper ensemble (APACHE) CAR T cells displayed inducible expression of IL-18 and enhanced antitumor immunity. In an intact mouse tumor model, CD19-IL-18 CAR T cells induced deeper B cell aplasia, significantly enhanced CAR T cell proliferation, and effectively augmented antitumor effects in mice with B16F10 melanoma. These findings point to a strategy to develop universal CAR T cells for patients with solid tumors.

IL‐18R‐dependent and independent pathways account for IL‐18‐enhanced antitumor ability of CAR‐T cells

“…18 In this study, we investigated the IL-18R-independent pathway and its contribution to biological functions of IL-18 to CAR-T cells. We have demonstrated that IL-18 functions to enhance the antitumor activities of CAR-T cells through both IL-18R-dependent and independent pathways.…”

“…It has also been identified as a pro-inflammatory and immunoregulatory cytokine. 18 Avanzi et al 19 proved that CAR-T cells secreting IL-18 could improve activity in syngeneic hematologic and solid tumor models without prior preconditioning, and enhance the antitumor response of endogenous T cells. 16,17 It has been recently reported that IL-18-secreting CAR-T cells have superior antitumor activity, achieved via the helper effect of CD4 + T cells on the promotion of CD8 + T cells.…”

Programming CAR-T cells to kill cancer

“…119 ), IL-18 (ref. 120 ) and IL-21 (ref. 121 ) can help to promote the cells' proliferation and reshape the tumour microenvironment.…”

Switching on the green light for chimeric antigen receptor T‐cell therapy

“…[26][27][28][29] Strategies to modulate the local TME have led to the generation of 'armored' CAR T cells that provide localised expression of pro-inflammatory cytokines or costimulatory ligands to improve CAR T-cell function within tumors. 33,34 Other systems involving cytokine-mediated enhancement of CAR T cells include the genetic modification of these cells to express a form of membrane-bound chimeric IL-15, which gave rise to a population of CAR T cells that possessed a T memory stem cell phenotype and a better memory potential even in the absence of antigen stimulation. In these studies, CAR T cellsecreted IL-12 augmented their cytotoxic function and alleviated regulatory T cell (Treg)-mediated suppression.…”