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Purpose Methods and materials Results Conclusion Personal information and conflict of interest References, Purpose: Coronary artery aneurysms (CAAs) are focal, localized dilatation of a coronary artery segment more than 1.5 times than the adjacent normal sorounding segment and more common in adult male patients. Aneurysms can be further divided into saccular -...

e19003 Background: Preclinical data indicate that anti-PD-1 agents can facilitate activity of bispecific T-cell engager (BiTE) molecules. Here we assess the combination of the anti-CD19 BiTE molecule blinatumomab with the anti-PD-1 antibody AMG 404 in adults with R/R ALL (NCT04524455). Methods: Eligible adults with R/R ALL (Ph+ disease included) received 2-5 treatment cycles. Each cycle was 42 days, consisting of 4 weeks of cIV blinatumomab and a 2-week treatment-free interval as per label. In Cohort 1, AMG 404 was dosed IV at 240 mg every 4 weeks (Q4W); first dose was Day (D) 11 of Cycle (C) 1. Primary endpoints were dose-limiting toxicities (DLTs) and other adverse events (AEs). Results: As of 20 Dec 2021, patients (pts) from Cohort 1 (n=8) had median age of 57 (range: 24-73) y, 6/8 male, 6/8 Caucasian, 1 with extramedullary disease (duodenum), 2 with prior blinatumomab, and a median of 5 (2-15) prior treatment lines. Two pts remain on study and 2 completed the study; 4 pts discontinued the study due to death (n=3) or consent withdrawn (n=1). No DLTs were reported for the 3 evaluable pts. Of the 5 pts not evaluable for DLTs, in C1, 4 had disease progression and 1 an unrelated fatal pneumonia. Treatment-related grade (Gr) ≥3 and/or serious AEs in all 8 pts included cytokine release syndrome (CRS) (1 pt Gr 2, 1 pt Gr 1 and 3), Gr 3 increases in ALT and AST, Gr 3 fever, Gr 3-4 neutropenia, Gr 4 neutropenia/Gr 3-4 thrombocytopenia (same pt), Gr 2 sensorimotor polyneuropathy, Gr 3 hypertension, Gr 3 encephalopathy, and in 1 pt Gr 3-4 decreases in white blood cells, lymphocytes, and neutrophils. One pt developed Gr 3 SARS-COV-2 pneumonia on C2D25, resolving without clinical sequelae. C3 start was delayed by 12 days but protocol treatment resumed uneventfully. All 3 DLT-evaluable pts had a complete response (CR) or CR with partial hematologic recovery (CRh), 2/3 without measurable residual disease (MRD), within 2 cycles; the 3rd pt had an MRD response at the end of C3. Preliminary pharmacokinetic results for the combination of blinatumomab and AMG 404 demonstrated that their exposures were consistent with those observed for each as monotherapy and did not indicate any drug-drug interactions. To date, all samples tested for anti-blinatumomab antibodies have been negative. Conclusions: In this ongoing phase 1b study, the combination of blinatumomab with AMG 404 was tolerated with a manageable safety profile. No DLTs were reported. Enrollment continues in Cohort 2 in which AMG 404 is dosed Q4W at 480 mg starting on C1D1, 48 hours prior to blinatumomab. Clinical trial information: NCT04524455. [Table: see text]

Whereas Edwardian male-authored Wildeana tends to represent the Wildean character as a solipsistic bachelor, whose tarnished reputation could affect only his bachelor friends, Mary Elizabeth Braddon’s The Rose of Life (1905) and Julia Frankau’s The Sphinx’s Lawyer (1906) place the Wildean character within the family unit. This allows them to examine the consequences the character’s legal prosecution and stigmatisation could have on his wife. Braddon’s and Frankau’s novels shift the focus from homoeroticism and homosexuality to the catalysing role male influence plays in the development of innate queerness. At the same time, they critically engage with the contemporary belief that female influence might “cure” queerness. Braddon and Frankau avoid demonising and/or oversimplifying the Wildean character’s feelings and note that queerness and the family are by no means oppositional or antithetical units. To achieve this effect, they invariably sacrifice women’s happiness, which allows us to read their novels as more anti-feminist than anti-queer.

Acute lymphoblastic leukaemia (ALL) is the most common cause from death of disease in children. Whilst cure rates over the last 30 years have drastically improved, the children that do go on and relapse have a very poor prognosis. Additionally, the ones that do survive can have significant long term side effects from existing treatments. Understanding the molecular mechanisms of the relationship between leukaemia and its microenvironment is essential for the identification of novel targets for treatment and/or the manipulation of existing treatments. The role that vascular endothelial growth factor (VEGF), an integral component of both neovascularisation and normal haematopoiesis, plays in the progression and invasiveness of solid tumours is well established. However, its function in haematological malignancies has been a more recent and thus less considered observation. Human leukaemia cells secrete VEGF, which may act in a paracrine manner with the bone marrow microenvironment to promote the survival and proliferation of leukaemia cells. In addition to VEGF being produced by leukaemias, it also increases vascularity in the bone marrow and lymph nodes of patients. Our previous work has established a panel of 10 childhood acute lymphoblastic leukaemia xenografts from patient biopsies in NOD/SCID mice. Several of these secrete VEGF, and express the FMS-like tyrosine kinase-3 (FLT-3). FLT 3, a receptor tyrosine kinase (RTK), and its ligand, play an essential role in regulating normal haematopoiesis. This thesis builds on the previous work by examining the relationship between VEGF and FLT 3, two widely, yet independently studied molecules in leukaemia, with the aberrant expression of either having adverse outcomes for patients. The results show that the high expression and activation of FLT 3, significantly increases the secretion VEGF. To assess whether VEGF secretion is triggered by FLT-3 signalling, we measured VEGF in the absence and presence of a class III receptor tyrosine kinase (RTK) inhibitor (SU11657), humanised anti-FLT 3 blocking antibodies as well as decreasing the receptors with siRNA. All of these manipulations were able to decrease the secretion of VEGF in leukaemia cells. To further investigate this relationship, we examined the phosphorylation status of FLT-3 and the downstream signalling pathway. Our results indicate that FLT 3 signalling may be an important factor in the induction of VEGF secretion in a sub-type of leukaemia cells and in turn, VEGF secretion can be attenuated by an FLT-3 specific inhibitor. Two separate microarray studies were also used to assess simultaneous gene expressions between the leukaemia and bone marrow microenvironment, and to examine the effects of FL on ALL xenograft cells. The results of the microarray studies confirm the previously observed results regarding the manipulation of the microenvironment by the leukaemic cells. Inhibition of the FLT-3/VEGF pathway may disrupt paracrine signalling between leukaemia cells and the bone marrow microenvironment, and future studies into how this disruption may influence leukaemia cell responses to conventional chemotherapy are warranted.