Combining nilotinib and PD-L1 blockade reverses CD4+ T-cell dysfunction and prevents relapse in acute B-cell leukemia

Abstract

Patients with acute lymphoblastic leukemia have experienced significantly improved outcomes due to the advent of chimeric antigen receptor T-cells and bispecific T-cell engagers, although a proportion of patients still relapse despite these advances. T-cell exhaustion has been recently suggested to be an important driver of relapse in these patients. Indeed, phenotypic exhaustion of CD4+ T-cells is predictive of relapse and poor overall survival in B-ALL. Thus, therapies that counter T-cell exhaustion, such as immune checkpoint blockade, may improve leukemia immunosurveillance and prevent relapse. Here, we used a murine model of Ph+ B-ALL as well as human bone marrow biopsy samples to assess the fundamental nature of CD4+ T-cell exhaustion and the preclinical therapeutic potential for combining anti-PD-L1 based checkpoint blockade with tyrosine kinase inhibitors targeting the BCR-ABL oncoprotein. scRNA-seq analysis revealed that B-ALL induces a unique subset of CD4+ T-cells with both cytotoxic and helper functions. Combination treatment with the tyrosine kinase inhibitor nilotinib and anti-PD-L1 dramatically improves long-term survival of leukemic mice. Depletion of CD4+ T-cells prior to therapy completely abrogates the survival benefit, implicating CD4+ T-cells as key drivers of the protective anti-leukemia immune response. Indeed, treatment with anti-PD-L1 leads to clonal expansion of leukemia-specific CD4+ T-cells with the afore-mentioned helper/cytotoxic phenotype, as well as reduced expression of exhaustion markers. These findings support efforts to utilize PD1/PD-L1 checkpoint blockade in clinical trials and highlight the importance of CD4+ T-cell dysfunction in limiting the endogenous anti-leukemia response.

Positive regulators of T cell proliferation as biomarkers for predicting prognosis and characterizing the immune landscape in lung adenocarcinoma

“…Consistent with previous reports, patients in cluster 2 with a high TMB (>10 Mb) and low TIDE score had a better response to PD-1/PD-L1 blockade therapy (Figures 4G-J) (Chan et al, 2019). In addition, the low-risk group was more susceptible to ipifarnib and nilotinib, both of which inhibit PD-1/PD-L1 directly or indirectly (Jackson et al, 1986;Tracy et al, 2022). Altogether, our results confirmed that TPCs are a valuable tool for predicting drug sensitivity and immunotherapy responses in patients with LUAD.…”

AARS2as a novel biomarker for prognosis and its molecular characterization in pan‐cancer

“…For instance, the small‐molecule inhibitor of ABL named GNF‐2 overcomes off‐target toxicities in solid malignancies, improving clinical efficacy 31 . Combining anti‐PD‐L1 drug and nilotinib, a tyrosine kinase inhibitor targeting BCR‐ABL, markedly increases survival of leukemic mice 32 . These potential drugs and targeted pathways brought a new direction for cancer therapy.…”

“… 31 Combining anti‐PD‐L1 drug and nilotinib, a tyrosine kinase inhibitor targeting BCR‐ABL, markedly increases survival of leukemic mice. 32 These potential drugs and targeted pathways brought a new direction for cancer therapy.…”

T-cell exhaustion and stemness in antitumor immunity: Characteristics, mechanisms, and implications

“…Anti-PD-L1 antibodies can also block the binding of PD-L1 to PD-1, thereby inhibiting the exhaustion of T cells. Combination therapy with anti-PD-L1 and the tyrosine kinase inhibitor nilotinib can reduce T-cell exhaustion markers in leukemia and significantly improve the long-term survival rate of mice with leukemia ( 189 ). Anti-PD-1 and anti-PD-L1 therapies can reduce T-cell exhaustion and achieve superior treatment outcomes.…”