Enhanced CAR-T activity against established tumors by polarizing human T cells to secrete interleukin-9

Abstract

CAR-T cell therapy is effective for hematologic malignancies. However, considerable numbers of patients relapse after the treatment, partially due to poor expansion and limited persistence of CAR-T cells in vivo. Here, we demonstrate that human CAR-T cells polarized and expanded under a Th9-culture condition (T9 CAR-T) have an enhanced antitumor activity against established tumors. Compared to IL2-polarized (T1) cells, T9 CAR-T cells secrete IL9 but little IFN-γ, express central memory phenotype and lower levels of exhaustion markers, and display robust proliferative capacity. Consequently, T9 CAR-T cells mediate a greater antitumor activity than T1 CAR-T cells against established hematologic and solid tumors in vivo. After transfer, T9 CAR-T cells migrate effectively to tumors, differentiate to IFN-γ and granzyme-B secreting effector memory T cells but remain as long-lived and hyperproliferative T cells. Our findings are important for the improvement of CAR-T cell-based immunotherapy for human cancers.

The Potential of T Cell Factor 1 in Sustaining CD8+ T Lymphocyte-Directed Anti-Tumor Immunity

“…Finally, the significance may extend beyond ICB immunotherapy to also affect chimeric antigen receptor (CAR)-T cell-based therapies. A study exhibiting the potency of IL-9-secreting (T9) CAR-T cells in tumor control demonstrated that such CAR-T cells possess a T CM cell phenotype, are highly proliferative, and capable of generating T EFF cells [ 108 ]. Given the essential nature of TCF1 in generating memory T cells, especially of the T CM subtype, and the proliferative nature of TCF1 + CD8 + T cells and their ability to differentiate into SLECs, it may be plausible to assume that one of the main regulating transcription factors in these T9 CAR-T cells may be TCF1.…”

“…Unfortunately, the scope of this study was not inclusive of TCF1 and further studies should be conducted to confirm the presence and activity of TCF1. Additionally, these T9 CAR-T cells were found to undergo reduced activation-induced cell death, potentially due to their downregulation of Fas and Fas ligands [ 108 ]. This may also suggest a possible mechanism by which TCF1 + CD8 + T cells in general exhibit a higher survivability than other CD8 + subgroups.…”

Targeted Treatment of Follicular Lymphoma

“…There is a need to better understand and overcome mechanisms of resistance using CAR T-cell therapy and strategies to enhance antitumor activity are being explored in the preclinical setting. This includes ex-vivo polarization to IL-9 secreting CAR T-cells, which exert a greater antitumor efficacy compared to standard CAR T-cell constructs [ 93 ]. Other approaches to enhance the antitumor efficacy of CAR T-cells include constitutive expression of the CD40 ligand on CAR T-cells [ 94 ], modifying CAR T-cells to be used as ‘micro-pharmacies’ for local delivery of tumor suppressor proteins [ 95 ], the testing of bivalent CAR constructs that target two domains to mitigate antigen resistance [ 96 ], using novel antigen targets [ 97 ] and the incorporation of immune checkpoint inhibitors with CAR T-cell treatment [ 98 ].…”

How Can We Engineer CAR T Cells to Overcome Resistance?

“…66 Similarly, IL-9 expression in CAR T cells also enhances the pool of central memory cells, with lower expression of exhaustion markers and enhanced in vivo persistence. 67 The addition of constitutively active or inducible IL-18 to CAR T cells can also improve anti-tumour function with enhanced proliferation, IFN-γ production and a reduction in markers of exhaustion compared to IL-12 secreting CAR T cells. 68,69 Furthermore, IL-18 secretion from CAR T cells engaged the local immune response in immunocompetent tumor-bearing mice by inducing an increase in M1polarised macrophages and NK cells and a decrease in T regulatory cells (Tregs), suppressive DCs and M2polarised macrophages within the TME.…”