Allogeneic Anti-BCMA CAR T Cells Are Superior to Multiple Myeloma-derived CAR T Cells in Preclinical Studies and May Be Combined with Gamma Secretase Inhibitors.

Multiple myeloma remains an incurable plasma cell malignancy despite the rapidly evolving treatment landscape. Chimeric antigen receptor T cells targeted against BCMA have recently shown great promise in relapsed refractory multiple myeloma; however, all patients ultimately still progress from their disease. Lack of CAR T-cell persistence, impaired T-cell fitness in autologous CAR T-cell products and the presence of an immunosuppressive bone marrow (BM) microenvironment are contributory factors to treatment failure. We generated anti-BCMA CAR T cells from healthy donors (HD) and patients with multiple myeloma at different stages of disease to compare their T-cell profile, fitness, and cytotoxic activity in preclinical studies. We also used an ex vivo assay with multiple myeloma BM biopsies from distinct genomic subgroups to test the efficacy of HD-derived CAR T cells in a clinically relevant model. HD volunteers showed increased T-cell counts, higher CD4/CD8 ratio, and expanded naïve T-cell population compared with patients with multiple myeloma. After anti-BCMA CAR T-cell production, patients with relapsed multiple myeloma had lower frequencies of CAR+ T cells, decreased central memory phenotype, and increased checkpoint inhibitory markers compared with HD-derived products, which compromised their expansion and cytotoxicity against multiple myeloma cells in vitro. Importantly, HD-derived CAR T cells efficiently killed primary multiple myeloma cells within the BM microenvironment of different multiple myeloma genomic subgroups and their cytotoxic activity could be boosted with gamma secretase inhibitors. In conclusion, allogeneic anti-BCMA CAR T cells are a potential therapeutic strategy for patients with relapsed multiple myeloma and should be further developed in the clinic. Significance: Multiple myeloma is an incurable cancer of the plasma cells. A new therapy with anti-BCMA CAR T cells - the patient's own T cells genetically engineered to find and kill myeloma cancer cells - has shown encouraging results. Unfortunately, patients still relapse. In this study, we propose to use T cells from HD volunteers, which have a stronger T-cell fitness, higher cancer killing capacity, and are ready to be administered when needed.

Thermostable small-molecule inhibitor of angiogenesis and vascular permeability that suppresses a pERK-FosB/ΔFosB-VCAM-1 axis.

Vascular permeability and angiogenesis underpin neovascular age-related macular degeneration and diabetic retinopathy. While anti-VEGF therapies are widely used clinically, many patients do not respond optimally, or at all, and small-molecule therapies are lacking. Here, we identified a dibenzoxazepinone BT2 that inhibits endothelial cell proliferation, migration, wound repair in vitro, network formation, and angiogenesis in mice bearing Matrigel plugs. BT2 interacts with MEK1 and inhibits ERK phosphorylation and the expression of FosB/ΔFosB, VCAM-1, and many genes involved in proliferation, migration, angiogenesis, and inflammation. BT2 reduced retinal vascular leakage following rat choroidal laser trauma and rabbit intravitreal VEGF-A165 administration. BT2 suppressed retinal CD31, pERK, VCAM-1, and VEGF-A165 expression. BT2 reduced retinal leakage in rats at least as effectively as aflibercept, a first-line therapy for nAMD/DR. BT2 withstands boiling or autoclaving and several months' storage at 22°C. BT2 is a new small-molecule inhibitor of vascular permeability and angiogenesis.

Language dysfunction-associated EEG findings in patients with CAR-T related neurotoxicity.

Chimeric antigen receptor-modified T cells (CAR-T) have emerged as a promising immunotherapeutic approach in relapsed/refractory haematolgical malignancies. Broader application is limited by unique toxicities, notably, neurotoxicity (NTX). Language dysfunction is among the most frequent symptoms of NTX, the underlying mechanisms of which remain to be elucidated. Electroencephalogram (EEG) is an important tool to monitor for NTX and may provide insights into language dysfunction. AIM: We aimed to characterise language dysfunction and define electroencephalographic signatures after CAR-T cell therapy. METHODS: We reviewed the clinical presentation and EEG findings of 20 adult patients presenting with language dysfunction after CAR-T cell infusion. The cohort included a subset of patients treated with investigational CD19-directed CAR-T cells for non-Hodgkin's lymphoma (n=17), acute lymphoblastic leukaemia (n=1), follicular lymphoma (n=1) and chronic lymphocytic leukaemia (n=1). RESULTS: Language dysfunction presented within 14 days of CAR-T cell infusion in 16 (84%) patients. Ten (50%) patients had mild word-finding difficulties and 10 (50%) had marked dysphasia with profound word-finding difficulties; the latter were all associated with generalised rhythmic delta activity or generalised periodic discharges on EEG. CONCLUSIONS: Language dysfunction after CAR-T cell therapy is associated with generalised EEG abnormalities.

Similar outcomes of alemtuzumab-based hematopoietic cell transplantation for SAA patients older or younger than 50 years.

Survival after allogeneic hematopoietic cell transplantation (HSCT) for severe aplastic anemia (SAA) among older patients remains poor and associated with increased risk for graft-versus-host disease (GVHD). In this retrospective study of 65 consecutive patients with acquired SAA who were transplanted using fludarabine, low-dose cyclophosphamide, and alemtuzumab (FCC), outcomes of 27 patients aged at least 50 years were compared with those of 38 patients younger than 50 years. The median age of the older cohort was 61 years (range, 51-71 years); 21 (78%) patients were transplanted from unrelated donors (3 of 21 from HLA 9/10 mismatch donors) and 6 from matched sibling donors. One-year GVHD-free, relapse-free survival (GRFS) was comparable to that of patients younger than 50 years (84% vs 94%, respectively; P = .23). Both groups showed low rates of acute (5% vs 4%) and chronic (18% vs 14%) GVHD, with no cases of severe GVHD among matched donor transplants, and similar 1-year transplant-related mortality (14% vs 5.4%, older vs younger; P = .23). HSCT comorbidity index (HTC-CI) scores were similar between the groups, but overall survival with an HCT-CI of at least 3 was lower compared with a score less than 3 (76% vs 98%; P = .005). Median donor T-cell chimerism among older patients was 64% and 60% at 1 and 3 years, respectively, and was similar to that of younger patients. Increased B regulatory cells potentially contributed to low alloreactivity and mutual donor-recipient tolerance in older patients. Effect of comorbidities rather than age alone may be a more important determinant of suitability for FCC HSCT in older patients.

Secondary Diffuse Choroid Plexus B-Cell Lymphoma: Case Report and Review of Literature.

BACKGROUND: Central nervous system (CNS) relapse is an uncommon complication of diffuse large B cell lymphoma and is associated with significant mortality and morbidity. It is becoming a more prevalent pathologic entity in the rituximab era. Our case provides insight into the pathophysiology, diagnosis, prevention, and management of secondary intraventricular CNS lymphomas. CASE DESCRIPTION: We report an unusual case of a 64-year-old man who presented with an isolated secondary CNS lymphoma involving the choroid plexus in a diffuse pattern. He initially presented with obstructive hydrocephalus from diffuse choroid plexus lesions and was commenced on systemic therapy after confirmation of diagnosis via samples obtained from an open biopsy. CONCLUSIONS: This case highlights the lack of high-quality evidence behind the use of high-dose intravenous methotrexate as CNS prophylaxis. The case provides additional insight into the pathophysiology of intraventricular CNS lymphomas and the importance of establishing a histopathologic diagnosis via an open biopsy before the administration of high-dose steroids.

Radiation exposure during cardiac catheterisation is similar for both femoral and radial approaches.

OBJECTIVES: Radial approach invasive coronary angiography has been shown to be superior to the femoral approach in terms of reducing vascular access complications and improving patient comfort. However, one major limitation has been the perception of higher patient radiation exposure, with guidelines recommending 7mSv as an appropriate average effective dose (E) for routine coronary angiography. Therefore, we sought here to assess differences in radiation exposure between the femoral and radial access routes in patients undergoing diagnostic coronary angiography with or without angioplasty (CA +/- PCI), as performed by two operators, experienced in both techniques. METHODS: Consecutive patients (n=870) from July 2011-December 2012, undergoing routine CA +/- PCI at Royal Prince Alfred Hospital, Sydney by two experienced interventional cardiologists were identified. Radiation doses were automatically recorded as dose area products (DAPs) at procedure time and converted into E using a conversion factor of 0.18 mSv/(Gycm2), as validated by the National Radiological Protection Board (NRPB). RESULTS: Of the 870 patients, 598 underwent diagnostic CA (347 femoral, 251 radial); and 272 underwent CA+ PCI (179 femoral, 93 radial). The mean age of the patients was 65±12 years and the majority (n=617, 71%) were male. Both groups were well matched with respect to baseline demographics, clinical presentation and angiographic characteristics, though there was an excess of patients with a history of coronary grafts in the femoral group, due to operator preference. In the patients who underwent diagnostic CA, there was no significant difference in the average effective radiation dose for femoral versus radial arterial access (E=7.9±8.2 vs. 8.3±10.6mSv; p=0.66). Similarly, there was also no difference in average effective radiation dose for femoral versus radial arterial access in patients undergoing CA+PCI (E=13.2±8.1 vs E=14.4±8.3 mSv; p=0.26). CONCLUSION: In our high volume cardiac catheterisation laboratory, radiation doses for routine angiography were near UNSC targets. Patient radiation exposure was comparable between femoral and radial approaches, for both CA and CA +/- PCI. Thus, our results allay concerns that radial cardiac catheterisation might be associated with greater radiation exposure.

The 10-metre gait speed as a functional biomarker in amyotrophic lateral sclerosis.

There remains a critical need to develop biomarkers of disease progression in amyotrophic lateral sclerosis (ALS). Mobility is a key determinant of disease status and quality of life. The present study assessed the utility of 10-metre gait speed as a functional biomarker of disability in ALS. The gait speed, ALSFRS-R score, body mass index (BMI) and forced vital capacity (FVC), measured in 50 consecutive ALS patients at the time of diagnosis were assessed. ALS patients were managed in the multidisciplinary clinic for up to three years. 10-metre gait speed was significantly reduced in ALS patients with lower limb-onset disease (0.9 ± 0.1 m/s) compared to those with upper limb (1.3 ± 0.1 m/s, p <0.01) and bulbar onset (1.2 ± 0.1 m/s, p <0.01) disease. The 10-metre gait speed correlated with the total ALSFRS-R score (R = 0.6) and the gross motor subscore (R = 0.8, p <0.001). As such, the 10-metre gait speed may serve as a robust marker of disability and disease progression in ALS.