A TCR-mimic antibody to WT1 bypasses tyrosine kinase inhibitor resistance in human BCR-ABL+ leukemias

Abstract

Key Points This study shows the effective anticancer activity of a T-cell receptor mimic antibody targeting WT1 in resistant human Ph+ ALL. In combination with tyrosine kinase inhibitors, ESKM can result in cure of Ph+ ALL in murine models.

CML patients with deep molecular responses to TKI have restored immune effectors and decreased PD-1 and immune suppressors

“…LAAs such as WT1, PRAME, PR3, and BMI-1 in CML patients represent attractive targets for immunotherapy, [23][24][25][26][27][28][29] with efficacy demonstrated in vaccination, including dendritic cell vaccination, [30][31][32][33] and, more recently, T-cell receptor-mimic antibodies. [34][35][36] In support of these studies, we observed maximal restoration of immune recovery, as demonstrated by increased effector NK cell and T-cell immune responses, reduced PD-1 inhibitory molecule expression on CD4 1 and CD8 1 T cells, and reduced numbers of Mo-MDSC in MR 4.5 only, suggesting DMR may be the preferred threshold for future TFR studies to benefit from the improved effector immune responses. Therapeutic methods to enhance NK cell function and immunogenic CTL responses early or blocking aberrant PD-1 signaling may result in greater rate of success in TKI cessation studies.…”

Mechanisms of leukemia resistance to antibody dependent cellular cytotoxicity

“…29 This was confirmed by repeated BV173 harvests after 3 to 5 weeks of ESKM therapy. SET2 cells harvested from mouse BM likewise did not down regulate the target antigen as measured by flow cytometry (Figs.…”

“…BV173 is a Philadelphia positive ALL cell line, whose growth and response to therapy with both TCRm and tyrosine kinase inhibitors (TKIs) was previously described. 29 Lymphomatous relapse, in addition to bone marrow (BM) relapse, was frequently observed with this cell line after mAb therapy in NSG mouse models. Histologic analysis with immunohistochemical staining (IHC) of this leukemia confirmed that BV173 grows in clusters (Figs.…”

“…However, we previously reported that BV173 ALL cells on ESKM therapy harvested from mouse BM did not demonstrate downregulation of surface HLA-A Ã 02:01 or ESKM mAb binding. 29 Thus, antigen loss did not account for treatment failure in this model. We therefore hypothesized that resistance to ADCC could be secondary to mechanisms intrinsic to the target cells, extrinsic factors such as those affecting the pharmacokinetics or biodistribution of the mAb hindering its delivery to the target, or properties of the effector cells or their function in the host.…”

“…29 However, though there are profound anti-leukemia effects, mice are not cured by continued dosing of the mAb alone in these model systems. Unless additional anti-leukemic drugs, such as dasatinib, were used concurrently, the leukemias invariably relapsed within weeks even while on ESKM therapy.…”