Ex vivo blockade of PI3K gamma or delta signaling enhances the antitumor potency of adoptively transferred CD8⁺ T cells

Abstract

Adoptive T cell transfer therapy induces objective responses in patients with advanced malignancies. Despite these results, some individuals do not respond due to the generation of terminally differentiated T cells during the expansion protocol. As the gamma and delta catalytic subunits in the PI3K pathway are abundant in leukocytes and involved in cell activation, we posited that blocking both subunits ex vivo with the inhibitor IPI‐145 would prevent their differentiation, thereby increasing antitumor activity in vivo. However, IPI‐145 treatment generated a product with reduced antitumor activity. Instead, T cells inhibited of PI3Kγ (IPI‐549) or PI3Kδ (CAL‐101 or TGR‐1202) alone were more potent in vivo. While T cells coinhibited of PI3Kγ and PI3Kδ were less differentiated, they were functionally impaired, indicated by reduced production of effector cytokines after antigenic re‐encounter and decreased persistence in vivo. Human CAR T cells expanded with either a PI3Kγ or PI3Kδ inhibitor possessed a central memory phenotype compared to vehicle cohorts. We also found that PI3Kδ‐inhibited CARs lysed human tumors in vitro more effectively than PI3Kγ‐expanded or traditionally expanded CAR T cells. Our data imply that sole blockade of PI3Kγ or PI3Kδ generates T cells with remarkable antitumor properties, a discovery that has substantial clinical implications.

Kinase inhibitors developed for treatment of hematologic malignancies: implications for immune modulation in COVID-19

“… 92 The PI3K inhibitors described in this review decrease multiple inflammatory cytokines, including IL-1, TNF-α, IL-10, and IFN-γ. 43 , 93 However, idelalisib reduces cytokine production in macrophages, whereas duvelisib polarizes them to an M1 phenotype, leading to a more proinflammatory state. 22 , 50 , 55 Idelalisib and umbralisib reduce exhaustion marker expression on CD8 + T cells, which may assist in preventing lymphocyte dysfunction and depletion.…”

“… 22 , 50 , 55 Idelalisib and umbralisib reduce exhaustion marker expression on CD8 + T cells, which may assist in preventing lymphocyte dysfunction and depletion. 93 Therefore, PI3K inhibitors could be useful in innate response modulation by inhibiting viral replication, improving early macrophage activation, and ameliorating the T-cell dysfunction seen in later stages. However, the last should be approached cautiously because hyperinflammatory side effects (due to a decrease in Tregs) are relatively common.…”

Inhibition of PI3K Isoform p110γ Increases Both Anti-Tumor and Immunosuppressive Responses to Aggressive Murine Head and Neck Squamous Cell Carcinoma with Low Immunogenicity

“…Previously, dual p110δ/γ inhibition with the pharmaceutical IPI-145 has been shown to be ineffective in combination with anti-PD-L1 therapy in murine MOC2 HNSCC [ 26 ]. However, it has also been shown that dual inhibition of p110δ/γ abrogates CD8+ T-cell function while selective inhibition of p110δ or p110γ does not [ 19 ]. Therefore, because our findings indicate PI3K p110γ inhibition alone enhances CD8 + T-cell recruitment and preserves CD8 + T-cell function, this provides a rationale to combine PI3K p110γ inhibition with PD-L1 checkpoint inhibitors against poorly immunogenic HNSCC.…”

“…Such studies indicate that inhibition of PI3K p110γ in combination with other therapies could enhance anti-tumor immune function. For example, a recent study in a murine melanoma model showed that adoptively transferred CD8+ T-cells treated with IPI-549 exhibit increased cytotoxicity [ 19 ]. Further, IPI-549, in conjunction with anti-PD1 therapy, led to a stronger anti-tumor effect than either therapy alone in mouse models of HNSCC, lung, and breast carcinoma [ 20 ].…”

“…For example, it has been shown that in some metastatic breast cancer patients, the use of PI3K inhibitors correlates with depletion of anti-tumor CD8+ T cells and expansion of suppressor cells [ 25 ]. Further, dual inhibition of p110γ and p110δ has been shown to abrogate murine CD8 + activity ex-vivo [ 19 ], while in-vivo demonstrated limited effect on poorly immunogenic HNSCC in a mouse model, even in conjunction with PD-L1 blockade [ 26 ].…”