•Antibody-based therapeutics have demonstrated substantial activity in AML.•Combinations of antibodies with novel agents will hopefully be even more effective.•Checkpoint inhibitors, bispecifics and ...immunocytokines open up a new avenue for the immunotherapy of AML.
The development of antibody-based therapeutics for patients with acute myeloid leukemia (AML) has long been hampered due to the shared expression of antigens on leukemic blasts and hematopoietic stem and progenitor cells (HSPC). Nevertheless, the first antibody-drug conjugate has been approved for the treatment of AML in the recent years. In addition, multiple antibody-based therapeutics including antibody-drug conjugates, bispecific antibodies and immunocytokines are currently being developed in clinical trials with some of them demonstrating encouraging results alone and/or in combination with current standard therapies. In this review we discuss current concepts of antibody-based therapies and results from emerging antibody-based therapeutics for the treatment of AML.
Summary
Acute myeloid leukaemia (AML) is a haematological malignancy characterized by a poor prognosis. Bone marrow mesenchymal stromal cells (BM MSCs) support leukaemic cells in preventing ...chemotherapy‐induced apoptosis. This encouraged us to investigate leukaemia‐BM niche‐associated signalling and to identify signalling cascades supporting the interaction of leukaemic cells and BM MSC. Our study demonstrated functional differences between MSCs originating from leukaemic (AML MSCs) and healthy donors (HD MSCs). The direct interaction of leukaemic and AML MSCs was indispensable in influencing AML cell proliferation. We further identified an important role for Notch expression and its activation in AML MSCs contributing to the enhanced proliferation of AML cells. Supporting this observation, overexpression of the intracellular Notch domain (Notch ICN) in AML MSCs enhanced AML cells’ proliferation. From a therapeutic point of view, dexamethasone treatment impeded Notch signalling in AML MSCs resulting in reduced AML cell proliferation. Concurrent with our data, Notch inhibitors had only a marginal effect on leukaemic cells alone but strongly influenced Notch signalling in AML MSCs and abrogated their cytoprotective function on AML cells. In vivo, dexamethasone treatment impeded Notch signalling in AML MSCs leading to a reduced number of AML MSCs and improved survival of leukaemic mice. In summary, targeting the interaction of leukaemic cells and AML MSCs using dexamethasone or Notch inhibitors might further improve treatment outcomes in AML patients.
We conducted a phase I trial in newly diagnosed acute myeloid leukaemia (AML) to investigate the combination of two novel targeted agents, gemtuzumab ozogamicin (GO) and midostaurin, with intensive ...chemotherapy in FLT3-mutated AML and CBF leukaemia. Three dose levels of midostaurin and one to three sequential doses of 3 mg/m
GO in combination with '7 + 3' induction were evaluated. Based on safety findings in 12 patients, our results show that 3 mg/m
GO on Days 1 + 4 and 100 mg midostaurin on Days 8-21 can be safely combined with IC in newly diagnosed AML.
Summary
The low‐density lipoprotein receptor (LDLR) is a membrane receptor that mediates the endocytosis of low‐density lipoprotein (LDL). Uptake of LDL has been proposed to contribute to ...chemotherapy resistance of acute myeloid leukaemia (AML) cell lines in vitro. In the present study, we analysed LDLR expression and survival using bone marrow biopsies from 187 intensively treated patients with AML. Here, increasing LDLR expression was associated with decreasing overall (58·4%, 44·2%, and 24·4%; P = 0·0018), as well as event‐free survival (41·7%, 18·1%, and 14·3%; P = 0·0077), and an increasing cumulative incidence of relapse (33·9%, 55·1%, and 71·4%; P = 0·0011). Associations of LDLR expression with survival were confirmed in 557 intensively treated patients from two international validation cohorts. In the analytic and validation cohorts, LDLR expression remained associated with outcome in multivariable regression analyses including the European LeukemiaNet genetic risk classification. Thus, LDLR predicts outcome of patients with AML beyond existing risk factors. Furthermore, we found low expression levels of LDLR in most healthy tissues, suggesting it as a promising target for antibody‐based pharmacodelivery approaches in AML.
Chimeric antigen receptor (CAR) engineering of T cells allows one to specifically target tumor cells via cell surface antigens. A candidate target in Ewing sarcoma is the ganglioside G
, but ...heterogeneic expression limits its value. Here we report that pharmacological inhibition of Enhancer of Zeste Homolog 2 (EZH2) at doses reducing H3K27 trimethylation, but not cell viability, selectively and reversibly induces G
surface expression in Ewing sarcoma cells. EZH2 in Ewing sarcoma cells directly binds to the promoter regions of genes encoding for two key enzymes of G
biosynthesis, and EZH2 inhibition enhances expression of these genes. G
surface expression in Ewing sarcoma cells is not associated with distinct in vitro proliferation, colony formation, chemosensitivity, or in vivo tumorigenicity. Moreover, disruption of G
synthesis by gene editing does not affect its in vitro behavior. EZH2 inhibitor treatment sensitizes Ewing sarcoma cells to effective cytolysis by G
-specific CAR gene-modified T cells. In conclusion, we report a clinically applicable pharmacological approach for enhancing efficacy of adoptively transferred G
-redirected T cells against Ewing sarcoma, by enabling recognition of tumor cells with low or negative target expression.
Oncogenesis of Ewing sarcoma (EwS), the second most common malignant bone tumor of childhood and adolescence, is dependent on the expression of chimeric EWSR1‐ETS fusion oncogenes, most often ...EWSR1‐FLI1 (E/F). E/F expression leads to dysregulation of focal adhesions (FAs) enhancing the migratory capacity of EwS cells. Here, we show that, in EwS cell lines and tissue samples, focal adhesion kinase (FAK) is expressed and phosphorylated at Y397 in an E/F‐dependent way involving Ezrin. Employing different EwS cell lines as in vitro models, we found that key malignant properties of E/F are mediated via substrate‐independent autophosphorylation of FAK on Y397. This phosphorylation results in enhanced FA formation, Rho‐dependent cell migration, and impaired caspase‐3‐mediated apoptosis in vitro. Conversely, treatment with the FAK inhibitor 15 (1,2,4,5‐benzenetetraamine tetrahydrochloride (Y15) enhanced caspase‐mediated apoptosis and EwS cell migration, independent from the respective EWSR1‐ETS fusion type, mimicking an anoikis‐like phenotype and paralleling the effects of FAK siRNA knockdown. Our findings were confirmed in vivo using an avian chorioallantoic membrane model and provide a first rationale for the therapeutic use of FAK inhibitors to impair metastatic dissemination of EwS.
In Ewing sarcoma (EwS) cells, EWSR1‐FLI1‐dependent expression of Ezrin contributes to autophosphorylation of focal adhesion kinase (FAK) on tyrosine 397. This impairs apoptosis and detachment‐dependent cell death (anoikis) and enhances focal adhesion formation and migratory capacity of EwS. Since Y397 autophosphorylation can effectively be targeted by FAK inhibitor 15 (1,2,4,5‐benzenetetraamine tetrahydrochloride (Y15), FAK might represent a valuable target for antimetastatic pharmacotherapy in EwS.
Immunotherapy can become a crucial therapeutic option to improve prognosis for lung cancer patients. First clinical trials with therapies targeting the programmed cell death receptor PD-1 and its ...ligand PD-L1 have shown promising results in several solid tumors. However, in lung cancer the diagnostic, prognostic and predictive value of these immunologic factors remains unclear.
The impact of both factors was evaluated in a study collective of 321 clinically well-annotated patients with non-small lung cancer (NSCLC) using immunohistochemistry.
PD-1 expression by tumor infiltrating lymphocytes (TILs) was found in 22%, whereas tumor cell associated PD-L1 expression was observed in 24% of the NSCLC tumors. In Fisher's exact test a positive correlation was found for PD-L1 and Bcl-xl protein expression (p = 0.013). Interestingly, PD-L1 expression on tumor cells was associated with improved overall survival in pulmonary squamous cell carcinomas (SCC, p = 0.042, log rank test), with adjuvant therapy (p = 0.017), with increased tumor size (pT2-4, p = 0.039) and with positive lymph node status (pN1-3, p = 0.010). These observations were confirmed by multivariate cox regression models.
One major finding of our study is the identification of a prognostic implication of PD-L1 in subsets of NSCLC patients with pulmonary SCC, with increased tumor size, with a positive lymph node status and NSCLC patients who received adjuvant therapies. This study provides first data for immune-context related risk stratification of NSCLC patients. Further studies are necessary both to confirm this observation and to evaluate the predictive value of PD-1 and PD-L1 in NSCLC in the context of PD-1 inhibition.
Summary
Considering the unsatisfactory results of salvage therapies for patients with relapsed/refractory acute myeloid leukaemia (R/R‐AML), their value before allogeneic haematopoietic stem cell ...transplantation (HSCT) remains questionable. However, direct allogeneic HSCT following established conditioning regimens applied in patients with R/R‐AML during active disease has been equally disappointing. In this retrospective observational study, high‐dose melphalan, as part of a sequential preparative regimen, followed by a total body irradiation (4 × 2 Gy)‐based or a treosulfan‐based dose‐adapted conditioning therapy for allogeneic HSCT was administered to 292 adult patients (median age 56 years, range 17–74) with primary refractory (144 patients), secondary refractory (97 patients) or relapsed AML (51 patients). Overall survival rates at 3 years were 34%, 29% and 41%, respectively. Risk factors associated with an inferior survival were higher age, transplantation from a human leucocyte antigen‐mismatched donor and high disease burden. Patients transplanted with blast infiltration <20% showed a notable survival rate of 51% at 3 years. In particular, patients with primary refractory AML showed a more favourable outcome when transplanted early during their disease course. Thus, high‐dose melphalan‐based sequential conditioning chemotherapy followed by an allogeneic HSCT is feasible and enables long‐term remission to be achieved in a substantial proportion of patients with active R/R‐AML.
Synovial sarcoma is a soft tissue malignancy characterized by a reciprocal t(X;18) translocation. The chimeric SS18-SSX fusion protein acts as a transcriptional dysregulator representing the major ...driver of the disease; however, the signaling pathways activated by SS18-SSX remain to be elucidated to define innovative therapeutic strategies.
Immunohistochemical evaluation of the Hippo signaling pathway effectors YAP/TAZ was performed in a large cohort of synovial sarcoma tissue specimens. SS18-SSX dependency and biological function of the YAP/TAZ Hippo signaling cascade were analyzed in five synovial sarcoma cell lines and a mesenchymal stem cell model
. YAP/TAZ-TEAD-mediated transcriptional activity was modulated by RNAi-mediated knockdown and the small-molecule inhibitor verteporfin. The effects of verteporfin were finally tested
in synovial sarcoma cell line-based avian chorioallantoic membrane and murine xenograft models as well as a patient-derived xenograft.
A significant subset of synovial sarcoma showed nuclear positivity for YAP/TAZ and their transcriptional targets FOXM1 and PLK1. In synovial sarcoma cells, RNAi-mediated knockdown of
led to significant reduction of YAP/TAZ-TEAD transcriptional activity. Conversely, SS18-SSX overexpression in SCP-1 cells induced aberrant YAP/TAZ-dependent signals, mechanistically mediated by an IGF-II/IGF-IR signaling loop leading to dysregulation of the Hippo effectors LATS1 and MOB1. Modulation of YAP/TAZ-TEAD-mediated transcriptional activity by RNAi or verteporfin treatment resulted in significant growth inhibitory effects
and
.
Our preclinical study identifies an elementary role of SS18-SSX-driven YAP/TAZ signals, highlights the complex network of oncogenic signaling pathways in synovial sarcoma pathogenesis, and provides evidence for innovative therapeutic approaches.
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