Correction to: Changes in expression of lysosomal membrane proteins in leucocytes of cancer patients treated with tyrosine kinase inhibitors

Abstract Abstract 1733 Targeted therapies with tyrosine kinase inhibitors (TKI) have significantly improved the treatment of cancer patients. Ex vivo generated dendritic cells (DC) are commonly used in immunotherapeutic strategies due to their unique ability to initiate adaptive immune responses, and multiple approaches presently aim to combine targeted therapies with immunotherapy. However, as many kinases targeted by TKI are, besides governing tumor cell growth, also involved in the activation of DC, TKI therapy may cause immunoinhibitory side effects. Osteoactivin (GPNMB, DC-HIL) is a type I transmembrane glycoprotein that is detected abundantly in DC but not in monocytes. Its expression on antigen-presenting cells can inhibit T cell activation by binding syndecan-4 (SD-4) on T cells. Here we investigated the effect of the BCR/ABL TKI imatinib, dasatinib and nilotinib, which are approved for the treatment of CML, on the expression of osteoactivin and DC functions. DC were generated from blood monocytes by plastic adherence and exposure to GM-CSF and IL-4. Imatinib, nilotinib or dasatinib were added to the culture medium every second day starting from the first day of culture. In some experiments, toll-like receptor (TLR) ligands (L) (LPS (TLR4L), pam3Cys (TLR2L), poly I:C (TLR3L) or R848 (TLR7/8L) were added on day 6 of culture for maturation of DC. We found that DC generated in the presence of therapeutic concentrations of all three TKI displayed an altered phenotype. Imatinib caused significantly reduced expression of the typical DC markers CD1a, CD83 and the co-stimulatory molecule CD86. Nilotinib reduced the expression of CD1a, CD83, CD86 and the DC-specific C-type lectin receptor DC-SIGN (CD209). Dasatinib impaired expression of CD1a, CD83, CD86, CD80 and DC-SIGN. Most notably, we observed excessive up-regulation of osteoactivin on DC upon treatment with all three TKI. Interestingly, incubation with the immunosuppressive and anti-inflammatory cytokine IL-10 also resulted in osteoactivin over-expression. In line with osteoactivin up-regulation, exposure to TKI resulted in reduced stimulatory capacity of DC in MLR with allogenic T cells that could be restored by addition of blocking anti-osteoactivin antibody. In summary, our data demonstrate that up-regulation of osteoactivin is critically involved in the inhibition of DC function upon TKI exposure. These findings are of great importance for future combinatory approaches using TKI and DC-based immunotherapy and indicate that inhibition of osteoactivin expression or function may serve as a novel strategy to enhance the efficacy of immunotherapeutic interventions in cancer patients. Disclosures: No relevant conflicts of interest to declare.

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Risk of QTc interval prolongation among cancer patients treated with tyrosine kinase inhibitors.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.3033 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 3033-3033

Author(s):

Anan Abdelmoti Abu Rmilah ◽

Grace Lin ◽

Joerg Herrmann

Keyword(s):

Tyrosine Kinase ◽

Cancer Patients ◽

Tyrosine Kinase Inhibitors ◽

Kinase Inhibitors ◽

Complication Rates ◽

Qtc Interval ◽

Interval Prolongation ◽

Qtc Prolongation ◽

Qtc Interval Prolongation ◽

Life Threatening

3033 Background: QTc interval prolongation can lead to life-threatening complications such as torsade de pointes (TdP), ventricular tachycardia (VT), and sudden cardiac death (SCD). It can occur with various tyrosine kinase inhibitors (TKIs) but comparative analyses on the incidence and complication rates are scarce. We thus conducted a comprehensive analysis of TKI use and QTc prolongation in clinical practice. Methods: We retrospectively reviewed the electronic medical records of all cancer patients who were treated with TKI between 01/2005 and 12/2018 at our institution. QTc prolongation was defined as a QTc ≥ 450 ms or 460 ms among male or female patients, respectively. For each type of TKIs, we determined the administration rate and incidence of QTc interval prolongation. We also studied the frequency of QTc prolongation ≥ 500 ms, rate of increase of the QTc interval by ≥ 60 ms, and the development of complications (VT, TdP and SCD). Results: In the present study, we analyzed the data of 685 cancer patients (431 male and 254 female), including 299 patients with RCC, 188 with chronic leukemia, 55 with acute leukemia, 65 with thyroid cancer, 48 with lung cancer and 39 with GIST. These patients received 902 TKI administrations and QTc prolongation was reported in 1/3 of these (289 administrations). The highest frequency was seen with imatinib, nilotinib and dasatinib (30, 40 and 50%). Among cases of QTc prolongation, a QTc interval ≥ 500 ms was documented in 53 (18.3%) and QTc progression ≥ 60 ms in 72 (25%). Complications were found in 14 cases (5%) including VT in 9, TdP in 2 and SCD in 3 administrations. Conclusions: The current findings suggest that TKI therapy leads to QTc prolongation in 1/3 of patients on average and most commonly with the Bcr-Abl TKIs, imatinib, nilotinib and dasatinib. While SCD is rare (1%) it can still evolve and in 5% of all QTc prolongations with TKIs are potentially life-threatening. These data support recommendations for serial ECGs in cancer patients undergoing TKI therapy. [Table: see text]

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