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Progress and Challenges in the Prevention, Diagnosis, and Management of Cytomegalovirus Infection in Transplantation

Clin Microbiol Rev

2021 Michael Boeckh

SUMMARYHosts with compromised or naive immune systems, such as individuals living with HIV/AIDS, transplant recipients, and fetuses, are at the highest risk for complications from cytomegalovirus (CMV) infection. Despite substantial progress in prevention, diagnostics, and treatment, CMV continues to negatively impact both solid-organ transplant (SOT) and hematologic cell transplant (HCT) recipients. In this article, we summarize important developments in the field over the past 10 years and highlight new approaches and remaining challenges to the optimal control of CMV infection and disease in transplant settings.

Microdissected "cuboids" for microfluidic drug testing of intact tissues

Lab Chip

2020 Gargi Mishra; Albert Folch; Taranjit Gujral; Robert Pierce

As preclinical animal tests often do not accurately predict drug effects later observed in humans, most drugs under development fail to reach the market. Thus there is a critical need for functional drug testing platforms that use human, intact tissues to complement animal studies. To enable future multiplexed delivery of many drugs to one small biopsy, we have developed a multi-well microfluidic platform that selectively treats cuboidal-shaped microdissected tissues or "cuboids" with well-preserved tissue microenvironments. We create large numbers of uniformly-sized cuboids by semi-automated sectioning of tissue with a commercially available tissue chopper. Here we demonstrate the microdissection method on normal mouse liver, which we characterize with quantitative 3D imaging, and on human glioma xenograft tumors, which we evaluate after time in culture for viability and preservation of the microenvironment. The benefits of size uniformity include lower heterogeneity in future biological assays as well as facilitation of their physical manipulation by automation. Our prototype platform consists of a microfluidic circuit whose hydrodynamic traps immobilize the live cuboids in arrays at the bottom of a multi-well plate. Fluid dynamics simulations enabled the rapid evaluation of design alternatives and operational parameters. We demonstrate the proof-of-concept application of model soluble compounds such as dyes (CellTracker, Hoechst) and the cancer drug cisplatin. Upscaling of the microfluidic platform and microdissection method to larger arrays and numbers of cuboids could lead to direct testing of human tissues at high throughput, and thus could have a significant impact on drug discovery and personalized medicine.

Real-world evidence of tisagenlecleucel for pediatric acute lymphoblastic leukemia and non-Hodgkin lymphoma

Blood Adv

2020 Cameron Turtle

Tisagenlecleucel is a CD19 chimeric antigen receptor (CAR) T-cell therapy approved for treatment of pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia (ALL) and adults with non-Hodgkin lymphoma (NHL). The initial experience with tisagenlecleucel in a real-world setting from a cellular therapy registry is presented here. As of January 2020, 511 patients were enrolled from 73 centers, and 410 patients had follow-up data reported (ALL, n = 255; NHL, n = 155), with a median follow-up of 13.4 and 11.9 months for ALL and NHL, respectively. Among patients with ALL, the initial complete remission (CR) rate was 85.5%. Twelve-month duration of response (DOR), event-free survival, and overall survival (OS) rates were 60.9%, 52.4%, and 77.2%, respectively. Among adults with NHL, the best overall response rate was 61.8%, including an initial CR rate of 39.5%. Six-month DOR, progression-free survival, and OS rates were 55.3%, 38.7%, and 70.7%, respectively. Grade ≥3 cytokine release syndrome and neurotoxicity were reported in 11.6% and 7.5% of all patients, respectively. Similar outcomes were observed in patients with in-specification and out-of-specification products as a result of viability <80% (range, 61% to 79%). This first report of tisagenlecleucel in the real-world setting demonstrates outcomes with similar efficacy and improved safety compared with those seen in the pivotal trials.

Risk Factors for Cytomegalovirus Reactivation and Association with Outcomes in Critically Ill Adults with Sepsis: A Pooled Analysis of Prospective Studies

J Infect Dis

2020 Ying Chen; Michael Boeckh; Hannah Imlay; Sayan Dasgupta

We performed a multivariable analysis of potential risk factors (including CMV reactivation) for clinical outcomes by day 28 (death or continued hospitalization, ventilator-free days [VFD], ICU-free days [ICUFD], hospital free days [HFD]) from pooled cohorts of two previous prospective studies of CMV seropositive adults with sepsis. CMV reactivation at any level, >100, >1,000 IU/mL, peak viral load, and area under the curve were independently associated with the clinical outcomes. We identified the potential effect size of CMV on outcomes that could be used as endpoints for future interventional trials of CMV prevention using antiviral prophylaxis in ICU patients with sepsis.

Gender Differences in Faculty Rank and Subspecialty Choice among Academic Medical Oncologists

Cancer Invest

2020 Laura Graham; Ali Khaki; Qian (Vicky) Wu; Alexandra Sokolova; Nancy Davidson

Gender parity within academic oncology is important. We hypothesized that gender differences exist in subspecialty choice and academic rank among medical oncologists. We performed a cross-sectional study of adult medical oncologists at the top 15 cancer centers. Gender, rank, subspecialty (breast, thoracic, gastrointestinal, and genitourinary) and board certification year were recorded. 570 medical oncologists were identified (60% men; 40% women). More women practice breast oncology (OR 3.1, p <0.001), but less practice genitourinary oncology (OR 0.37, p < 0.001). 22% of women were full professors vs 34% of men (OR 0.55, p = 0.001). Gender differences persist in academic adult medical oncology.

Liquid biopsy for invasive mold infections in hematopoietic cell transplant recipients with pneumonia through next-generation sequencing of microbial cell-free DNA in plasma

Clin Infect Dis

2020 Joshua Hill; Jacob Keane-Candib; Michael Boeckh; Terry Stevens-Ayers; Cynthia Fisher; Joyce Maalouf

BACKGROUND: Non-invasive diagnostic options are limited for invasive mold infections (IMI). We evaluated the performance of a plasma microbial cell-free DNA sequencing (mcfDNA-Seq) test for diagnosing pulmonary IMI after hematopoietic cell transplant (HCT). METHODS: We retrospectively assessed the diagnostic performance of plasma mcfDNA-Seq NGS in 114 HCT recipients with pneumonia after HCT who had stored plasma obtained within 14 days of diagnosis of Proven/Probable Aspergillus IMI (n=51), Proven/Probable non-Aspergillus IMI (n=24), Possible IMI (n=20), and non-IMI controls (n=19). Sequences were aligned to a database including >400 fungi. Organisms above a fixed significance threshold were reported. RESULTS: Among 75 patients with Proven/Probable pulmonary IMI, mcfDNA-Seq detected 1 pathogenic mold in 38 patients (sensitivity, 51%; 95% CI, 39%-62%). When restricted to samples obtained within 3 days of diagnosis, sensitivity increased to 61%. McfDNA-Seq had higher sensitivity for Proven/Probable non-Aspergillus IMI (sensitivity, 79%; 95% CI, 56%-93%) compared to Aspergillus IMI (sensitivity, 31%; 95% CI, 19%-46%). McfDNA-Seq also identified non-Aspergillus molds in an additional 7 patients in the Aspergillus subgroup and Aspergillus in 1 patient with Possible IMI. Among 19 non-IMI pneumonia controls, mcfDNA-Seq was negative in all samples suggesting a high specificity (95% CI, 82%-100%) and up to 100% positive predictive value (PPV) with estimated negative predictive values (NPV) of 81%-99%. The mcfDNA-seq assay was complementary to serum GMI testing; in combination, they were positive in 84% of individuals with Proven/Probable pulmonary IMI. CONCLUSIONS: Non-invasive mcfDNA-Seq had moderate sensitivity and high specificity, NPV, and PPV for pulmonary IMI after HCT, particularly for non-Aspergillus.

FOXM1 drives HPV+ HNSCC sensitivity to WEE1 inhibition

Proc Natl Acad Sci U S A

2020 Keith Loeb; Bruce Clurman; Hakan Gem; Matthew Fitzgibbon; Denise Galloway; Grace Zou; Hee Kim; Eduardo Mendez; Julia Sidorova; William Swanger; Ahmed Diab; Kaleb Smith; Cristina Rodriguez

Head and neck squamous cell carcinoma (HNSCC) associated with high-risk human papilloma virus (HPV) infection is a growing clinical problem. The WEE1 kinase inhibitor AZD1775 (WEE1i) overrides cell cycle checkpoints and is being studied in HNSCC regimens. We show that the HPV16 E6/E7 oncoproteins sensitize HNSCC cells to single-agent WEE1i treatment through activation of a FOXM1-CDK1 circuit that drives mitotic gene expression and DNA damage. An isogenic cell system indicated that E6 largely accounts for these phenotypes in ways that extend beyond p53 inactivation. A targeted genomic analysis implicated FOXM1 signaling downstream of E6/E7 expression and analyses of primary tumors and The Cancer Genome Atlas (TCGA) data revealed an activated FOXM1-directed promitotic transcriptional signature in HPV+ versus HPV- HNSCCs. Finally, we demonstrate the causality of FOXM1 in driving WEE1i sensitivity. These data suggest that elevated basal FOXM1 activity predisposes HPV+ HNSCC to WEE1i-induced toxicity and provide mechanistic insights into WEE1i and HPV+ HNSCC therapies.

Therapy of Myeloid Leukemia using Novel Bispecific Fusion Proteins Targeting CD45 and 90Y-DOTA

Mol Cancer Ther

2020 Oliver Press; Mark Hylarides; Ajay Gopal; Yukang Lin; Shyril O'Steen; Aimee Kenoyer; Brenda Sandmaier; Margaret Nartea; D Wilbur; Johnnie Orozco; Damian Green; Brian Till

Pretargeted radioimmunotherapy (PRIT) has been investigated as a multi-step approach to decrease relapse and toxicity for high-risk acute myeloid leukemia (AML). Relevant factors including endogenous biotin and immunogenicity, however, have limited the use of PRIT with an anti-CD45 antibody (Ab)-streptavidin (SA) conjugate and radiolabeled DOTA-biotin. To overcome these limitations we designed anti-murine and anti-human CD45 bispecific antibody (Ab) constructs using 30F11 and BC8 Ab, respectively, combined with an anti-yttrium (Y)-DOTA single-chain variable fragment (C825) to capture a radiolabeled ligand. The bispecific construct targeting human CD45 (BC8-Fc-C825) had high uptake in leukemia HEL xenografts [7.8 ± 0.02% percent injected dose/gram of tissue (%ID/g)]. Therapy studies showed that 70% of mice with HEL human xenografts treated with BC8-Fc-C825 followed by 44.4 MBq (1200 µCi) of 90Y-DOTA-biotin survived at least 170 days after therapy, while all non-treated controls required euthanasia due to tumor progression by day 32. High uptake at sites of leukemia (spleen and bone marrow) was also seen with 30F11-IgG1-C825 in a syngeneic disseminated SJL murine leukemia model (spleen: 9.0 ± 1.5% ID/g, and bone marrow: 8.1 ± 1.2% ID/g), with minimal uptake in all other normal organs (<0.5% ID/g) at 24 hours after 90Y-DOTA injections. SJL leukemia mice treated with the bispecific 30F11-IgG1-C825 and 29.6 MBq (800 µCi) of 90Y-DOTA-biotin had a survival advantage compared to untreated leukemic mice (median 43 versus 30 days, respectively, p<0.0001). These data suggest bispecific Ab mediated PRIT may be highly effective for leukemia therapy and translation to human studies.

Use of adenovirus type-5 vectored vaccines: a cautionary tale


2020 Larry Corey; Julie McElrath


Cytokine elevation in severe and critical COVID-19: a rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes

Lancet Respir Med

2020 Alexandre Hirayama; Cameron Turtle

The description of a so-called cytokine storm in patients with COVID-19 has prompted consideration of anti-cytokine therapies, particularly interleukin-6 antagonists. However, direct systematic comparisons of COVID-19 with other critical illnesses associated with elevated cytokine concentrations have not been reported. In this Rapid Review, we report the results of a systematic review and meta-analysis of COVID-19 studies published or posted as preprints between Nov 1, 2019, and April 14, 2020, in which interleukin-6 concentrations in patients with severe or critical disease were recorded. 25 COVID-19 studies (n=1245 patients) were ultimately included. Comparator groups included four trials each in sepsis (n=5320), cytokine release syndrome (n=72), and acute respiratory distress syndrome unrelated to COVID-19 (n=2767). In patients with severe or critical COVID-19, the pooled mean serum interleukin-6 concentration was 36·7 pg/mL (95% CI 21·6-62·3 pg/mL; I2=57·7%). Mean interleukin-6 concentrations were nearly 100 times higher in patients with cytokine release syndrome (3110·5 pg/mL, 632·3-15 302·9 pg/mL; p<0·0001), 27 times higher in patients with sepsis (983·6 pg/mL, 550·1-1758·4 pg/mL; p<0·0001), and 12 times higher in patients with acute respiratory distress syndrome unrelated to COVID-19 (460 pg/mL, 216·3-978·7 pg/mL; p<0·0001). Our findings question the role of a cytokine storm in COVID-19-induced organ dysfunction. Many questions remain about the immune features of COVID-19 and the potential role of anti-cytokine and immune-modulating treatments in patients with the disease.