Patients with chemo-refractory acute myeloid leukemia (AML) have a dismal prognosis. Chimeric antigen receptor T (CART) cell therapy has produced exciting results in CD19+ malignancies and may ...overcome many of the limitations of conventional leukemia therapies. We developed CART cells to target CD33 (CART33) using the anti-CD33 single chain variable fragment used in gemtuzumab ozogamicin (clone My96) and tested the activity and toxicity of these cells. CART33 exhibited significant effector functions in vitro and resulted in eradication of leukemia and prolonged survival in AML xenografts. CART33 also resulted in human lineage cytopenias and reduction of myeloid progenitors in xenograft models of hematopoietic toxicity, suggesting that permanently expressed CD33-specific CART cells would have unacceptable toxicity. To enhance the viability of CART33 as an option for AML, we designed a transiently expressed mRNA anti-CD33 CAR. Gene transfer was carried out by electroporation into T cells and resulted in high-level expression with potent but self-limited activity against AML. Thus our preclinical studies show potent activity of CART33 and indicate that transient expression of anti-CD33 CAR by RNA modification could be used in patients to avoid long-term myelosuppression. CART33 therapy could be used alone or as part of a preparative regimen prior to allogeneic transplantation in refractory AML.
Therapeutic options for patients with multiple myeloma whose disease has relapsed after a prior auto-SCT include novel biologic therapies, traditional chemotherapy or a second transplant, with no ...clear standard of care. Few published studies address the safety and efficacy of a second auto-SCT for relapsed disease. We reviewed the Abramson Cancer Center experience with salvage auto-SCT for relapsed multiple myeloma. Forty-one patients had received a salvage auto-SCT at our institution; the median time between transplants was 37 months (range 3-91). The overall response rate in assessable patients was 55%, and treatment-related mortality was 7%. With a median follow-up time of 15 months, the median PFS was 8.5 months and the median overall survival (OS) was 20.7 months. In a multivariate analysis of OS, independent prognostic factors were >or=5 prior lines of therapy and time to progression after initial auto-SCT of <or=12 months. We conclude that in well-selected patients, salvage auto-SCT is safe and effective for relapsed myeloma.
Reduction of immunosuppression (RI) is commonly used to treat posttransplant lymphoproliferative disorder (PTLD) in solid organ transplant recipients. We investigated the efficacy, safety and ...predictors of response to RI in adult patients with PTLD. Sixty‐seven patients were managed with RI alone and 30 patients were treated with surgical excision followed by adjuvant RI. The response rate to RI alone was 45% (complete response—37%, partial response—8%). The relapse rate in complete responders was 17%. Adjuvant RI resulted in a 27% relapse rate. The acute rejection rate following RI‐containing strategies was 32% and a second transplant was feasible without relapse of PTLD. The median survival was 44 months in patients treated with RI alone and 9.5 months in patients who remained on full immunosuppression (p = 0.07). Bulky disease, advanced stage and older age predicted lack of response to RI. Survival analysis demonstrated predictors of poor outcome—age, dyspnea, B symptoms, LDH level, hepatitis C, bone marrow and liver involvement. Patients with none or one of these factors had a 3‐year overall survival of 100% and 79%, respectively. These findings support the use of RI alone in low‐risk PTLD and suggest factors that predict response and survival.
The authors describe the response of post‐transplant lymphoproliferative disease to reduction of immunosuppression and analyze predictors of response and survival in a large single‐center cohort.
Abstract
Chimeric antigen receptor (CAR) T cells have transformed the treatment landscape for hematological malignancies. However, CAR T cells are less efficient against solid tumors, largely due to ...poor infiltration resulting from the immunosuppressive nature of the tumor microenvironment (TME). Here, we assessed the efficacy of Lewis Y antigen (Le
Y
)-specific CAR T cells in patient-derived xenograft (PDX) models of prostate cancer. In vitro, Le
Y
CAR T cells directly killed organoids derived from androgen receptor (AR)-positive or AR-null PDXs. In vivo, although Le
Y
CAR T cells alone did not reduce tumor growth, a single prior dose of carboplatin reduced tumor burden. Carboplatin had a pro-inflammatory effect on the TME that facilitated early and durable CAR T cell infiltration, including an altered cancer-associated fibroblast phenotype, enhanced extracellular matrix degradation and re-oriented M1 macrophage differentiation. In a PDX less sensitive to carboplatin, CAR T cell infiltration was dampened; however, a reduction in tumor burden was still observed with increased T cell activation. These findings indicate that carboplatin improves the efficacy of CAR T cell treatment, with the extent of the response dependent on changes induced within the TME.
Background: Among women who practice breast self-examination (BSE), breast cancers may be detected when they are at an earlier stage and are smaller than in women who do not practice BSE. However, ...the efficacy of breast self-examination for decreasing breast cancer mortality is unproven. This study was conducted to determine whether an intensive program of BSE instruction will reduce the number of women dying of breast cancer. Methods: From October 1989 through October 1991, 266 064 women associated with 519 factories in Shanghai were randomly assigned to a BSE instruction group (132 979 women) or a control group (133 085 women). Initial instruction in BSE was followed by reinforcement sessions 1 and 3 years later, by BSE practice under medical supervision at least every 6 months for 5 years, and by ongoing reminders to practice BSE monthly. The women were followed through December 2000 for mortality from breast cancer. Cumulative risk ratios of dying from breast cancer were estimated using Cox proportional hazards models. All statistical tests were two-sided. Results: There were 135 (0.10%) breast cancer deaths in the instruction group and 131 (0.10%) in the control group. The cumulative breast cancer mortality rates through 10 to 11 years of follow-up were similar (cumulative risk ratio for women in the instruction group relative to that in the control group = 1.04, 95% confidence interval = 0.82 to 1.33; P = .72). However, more benign breast lesions were diagnosed in the instruction group than in the control group. Conclusions: Intensive instruction in BSE did not reduce mortality from breast cancer. Programs to encourage BSE in the absence of mammography would be unlikely to reduce mortality from breast cancer. Women who choose to practice BSE should be informed that its efficacy is unproven and that it may increase their chances of having a benign breast biopsy.
In the framework of the Generation IV Sodium Fast Reactor Program, the Advanced Fuel Project has conducted an evaluation of the available fuel systems supporting future sodium cooled fast reactors. ...This paper presents an evaluation of metallic alloy fuels. Early US fast reactor developers originally favored metal alloy fuel due to its high fissile density and compatibility with sodium. The goal of fast reactor fuel development programs is to develop and qualify a nuclear fuel system that performs all of the functions of a conventional fast spectrum nuclear fuel while destroying recycled actinides. This will provide a mechanism for closure of the nuclear fuel cycle. Metal fuels are candidates for this application, based on documented performance of metallic fast reactor fuels and the early results of tests currently being conducted in US and international transmutation fuel development programs.
Anti-CD19 chimeric antigen receptor T-cell immunotherapy (CAR-T) is now a standard treatment of relapsed or refractory B-cell non-Hodgkin lymphomas; however, a significant portion of patients do not ...respond to CAR-T and/or experience toxicities. Lymphodepleting chemotherapy is a critical component of CAR-T that enhances CAR-T-cell engraftment, expansion, cytotoxicity, and persistence. We hypothesized that the lymphodepletion regimen might affect the safety and efficacy of CAR-T.
We compared the safety and efficacy of lymphodepletion using either fludarabine/cyclophosphamide (n = 42) or bendamustine (n = 90) before tisagenlecleucel in two cohorts of patients with relapsed or refractory large B-cell lymphomas treated consecutively at three academic institutions in the United States (University of Pennsylvania, n = 90; Oregon Health & Science University, n = 35) and Europe (University of Vienna, n = 7). Response was assessed using the Lugano 2014 criteria and toxicities were assessed by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and, when possible, the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading.
Fludarabine/cyclophosphamide led to more profound lymphocytopenia after tisagenlecleucel infusion compared with bendamustine, although the efficacy of tisagenlecleucel was similar between the two groups. We observed significant differences, however, in the frequency and severity of adverse events. In particular, patients treated with bendamustine had lower rates of cytokine release syndrome and neurotoxicity. In addition, higher rates of hematological toxicities were observed in patients receiving fludarabine/cyclophosphamide. Bendamustine-treated patients had higher nadir neutrophil counts, hemoglobin levels, and platelet counts, as well as a shorter time to blood count recovery, and received fewer platelet and red cell transfusions. Fewer episodes of infection, neutropenic fever, and post-infusion hospitalization were observed in the bendamustine cohort compared with patients receiving fludarabine/cyclophosphamide.
Bendamustine for lymphodepletion before tisagenlecleucel has efficacy similar to fludarabine/cyclophosphamide with reduced toxicities, including cytokine release syndrome, neurotoxicity, infectious and hematological toxicities, as well as reduced hospital utilization.
We examined the associations of Epstein–Barr virus (EBV) status with characteristics and outcomes of posttransplantation lymphoproliferative disorder (PTLD) by studying 176 adult solid organ ...transplant recipients diagnosed with PTLD between 1990 and 2013 (58 33% EBV‐negative; 118 67% EBV‐positive). The proportion of EBV‐negative cases increased over time from 10% (1990–1995) to 48% (2008–2013) (p < 0.001). EBV‐negative PTLD had distinct characteristics (monomorphic histology, longer latency) though high‐risk features (advanced stage, older age, high lactate dehydrogenase, central nervous system involvement) were not more common compared to EBV‐positive PTLD. In multivariable analysis, EBV negativity was not significantly associated with worse response to initial therapy (adjusted odds ratio, 0.84; p = 0.75). The likelihood of achieving a complete remission (CR) was not significantly different for EBV‐negative versus EBV‐positive PTLD including when therapy was reduction of immunosuppression alone (35% vs. 43%, respectively, p = 0.60) or rituximab (43% vs. 47%, p = 1.0). EBV negativity was also not associated with worse overall survival (adjusted hazard ratio, 0.91; p = 0.71). Our findings indicate that EBV status is not prognostic or predictive of treatment response in adults with PTLD. The high proportion of EBV‐negative disease diagnosed in recent years highlights the need for new strategies for prevention and management of EBV‐negative PTLD.
In a study of 176 solid organ transplant recipients with posttransplantation lymphoproliferative disorder, the authors show that the proportion of Epstein–Barr virus–negative cases has increased over time, but Epstein–Barr virus negativity is not associated with high‐risk features, worse response to initial therapy, or worse overall survival.
•One-stop resource for available clearing and staining methods in CNS research•Tissue clearing methods provide new insights into many facets of the nervous system•Trends are emerging in the types of ...neuroscience questions being addressed•Advancements and limitations of current protocols for human & large animal studies
Modern clearing techniques enable high resolution visualization and 3D reconstruction of cell populations and their structural details throughout large biological samples, including intact organs and even entire organisms. In the past decade, these methods have become more tractable and are now being utilized to provide unforeseen insights into the complexities of the nervous system. While several iterations of optical clearing techniques have been developed, some are more suitable for specific applications than others depending on the type of specimen under study. Here we review findings from select studies utilizing clearing methods to visualize the developing, injured, and diseased nervous system within numerous model systems and species. We note trends and imbalances in the types of research questions being addressed with clearing methods across these fields in neuroscience. In addition, we discuss restrictions in applying optical clearing methods for postmortem tissue from humans and large animals and emphasize the lack in continuity between studies of these species. We aim for this review to serve as a key outline of available tissue clearing methods used successfully to address issues across neuronal development, injury/repair, and aging/disease.
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