The advent of tyrosine kinase inhibitors (TKI) targeting BCR-ABL has drastically changed the treatment approach of chronic myeloid leukemia (CML), greatly prolonged the life of CML patients, and improved their prognosis. However, TKI resistance is still a major problem with CML patients, reducing the efficacy of treatment and their quality of life. TKI resistance is mainly divided into BCR-ABL-dependent and BCR-ABL-independent resistance. Now, the main clinical strategy addressing TKI resistance is to switch to newly developed TKIs. However, data have shown that these new drugs may cause serious adverse reactions and intolerance and cannot address all resistance mutations. Therefore, finding new therapeutic targets to overcome TKI resistance is crucial and the ubiquitin-proteasome system (UPS) has emerged as a focus. The UPS mediates the degradation of most proteins in organisms and controls a wide range of physiological processes. In recent years, the study of UPS in hematological malignant tumors has resulted in effective treatments, such as bortezomib in the treatment of multiple myeloma and mantle cell lymphoma. In CML, the components of UPS cooperate or antagonize the efficacy of TKI by directly or indirectly affecting the ubiquitination of BCR-ABL, interfering with CML-related signaling pathways, and negatively or positively affecting leukemia stem cells. Some of these molecules may help overcome TKI resistance and treat CML. In this review, the mechanism of TKI resistance is briefly described, the components of UPS are introduced, existing studies on UPS participating in TKI resistance are listed, and UPS as the therapeutic target and strategies are discussed.
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Chimeric antigen receptor-modified T (CAR-T) cells have shown impressive results against relapsed/refractory B cell malignancies. However, the traditional manufacture of CAR-T cells requires leukapheresis to isolate large amounts of peripheral blood T cells, thus making some patients ineligible for the procedure.
We developed a simple method for CAR-T cell preparation requiring small volumes of peripheral blood. First, CD3+ T cells isolated from 50 mL peripheral blood from patients (B-cell malignancies) were stimulated with immobilized anti-CD3/RetroNectin in 6-well plates and then transduced with CAR-expressing lentiviral vector. After 4 d, the T cells were transferred to culture bags for large-scale CAR-T cell expansion. In vitro and animal experiments were performed to evaluate the activity of the manufactured CAR-T cells. Finally, 29 patients with B-cell acute lymphoblastic leukemia (B-ALL) and 9 patients with B-cell lymphoma were treated with the CAR-T cells.
The CAR-T cells were expanded to 1–3 × 108 cells in 8–10 d and successfully killed B cell-derived malignant tumor cells in vitro and in vivo. For patients with B-ALL, the complete remission rate was 93% 1 month after CAR-T cell infusion; after 12 months, the overall survival (OS) and leukemia-free survival rates were 69% and 31%, respectively. For patients with lymphoma, the objective response rate (including complete and partial remission) was 78% 2 months after CAR-T cell infusion, and after 12 months, the OS and progression-free survival rates were 71% and 43%, respectively. Cytokine-release syndrome (CRS) occurred in 65.51% and 55.56% of patients with B-ALL and B-cell lymphoma, respectively; severe CRS developed in 20.69% of patients with B-ALL and in no patients with lymphoma.
Our novel method can generate sufficient numbers of CAR-T cells for clinical use from 50–100 mL peripheral blood, thus providing an alternative means of CAR-T cell generation for patients ineligible for leukapheresis.
