Citations

e14516 Background: IEC are arguably the most promising therapy in oncology, and FDA approvals for CAR T cells are a testament to their real potential. This has led to a great growth of clinical trials (CT), making the evaluation of their associated data increasingly challenging. To facilitate this process, we performed a systematic review of ClinicalTrials.gov focused on IEC therapies in oncology. We performed an analysis of the CT data and forecast trends for 2025. Methods: CT registries were retrieved from ClinicalTrials.gov with a systematic search query. We included CT registered between 1993-2020, which used IEC-based therapies in oncology. Statistical analysis using descriptive and inferential methods allowed us to identify trends and establish forecasts. Results: We identified 938 registrations of IEC-CTs in oncology, and 51% of those were active. The most common IEC type was CAR T (51%), followed by NK (15%), TCR T (8%), TIL (8%), and CIK (3%). 69% of IEC-CTs were aimed at a specific target vs. 31% that lack that specificity. The number of annual CAR T-CTs continue to increase, and we forecast 320 registrations during 2025. Since 2018, the number of CTs using unmodified T cells and TIL has increased (largely due to metastatic melanoma studies). NK cells CTs represent 8% of all registrations, and by 2025 we anticipate that >150 NK-based CTs will be registered per year, a number similar to CAR T-CTs registered during 2020. IEC-CTs based on allogeneic sources represent 18% of all registrations and are expected to grow 2.5 fold in the next 5 years. In solid tumors, the most common IEC-CTs are based on Non-CAR studies, while in hem-malignancies 76% of CTs are CAR T. Only one solid tumor, CAR T-CT, has reached phase 2/3, while 7 CIK-CTs were used to target various organ tumors. Conclusions: IEC-CTs continue to grow exponentially and represent an active field of clinical research in oncology. Allogeneic and NK-CTs increase rapidly and are among the most promising IEC-CTs. A rising proportion of CTs in solid tumors are using CIK and TIL rather than CAR T-cells, which are more popular for treating hem-malignancies. This is a direct reflection of the challenges associated with CAR T infiltration and persistence in solid tumors. Our analyses indicate that annual IEC-CTs registrations will double by 2025. We anticipate the increase in cellular therapy options will demand an organized response, including adequate logistical planning and policy implementation in response to the landscape changes in clinical oncology during the upcoming years.[Table: see text]

AbstractCSNK2B has recently been implicated as a disease gene for neurodevelopmental disability (NDD) and epilepsy. Information about developmental outcomes has been limited by the young age and short follow‐up for many of the previously reported cases, and further delineation of the spectrum of associated phenotypes is needed. We present 25 new patients with variants in CSNK2B and refine the associated NDD and epilepsy phenotypes. CSNK2B variants were identified by research or clinical exome sequencing, and investigators from different centers were connected via GeneMatcher. Most individuals had developmental delay and generalized epilepsy with onset in the first 2 years. However, we found a broad spectrum of phenotypic severity, ranging from early normal development with pharmacoresponsive seizures to profound intellectual disability with intractable epilepsy and recurrent refractory status epilepticus. These findings suggest that CSNK2B should be considered in the diagnostic evaluation of patients with a broad range of NDD with treatable or intractable seizures.

Abstract Background: Corticosteroid treatment is an effective and common therapeutic strategy for various inflammatory lung pathologies and may be an effective treatment for coronavirus disease 2019 (COVID-19). The purpose of this systematic review and meta-analysis of current literature was to investigate the clinical outcomes associated with corticosteroid treatment of COVID-19. Methods: We systematically searched PubMed, medRxiv, Web of Science, and Scopus databases through March 10, 2021 to identify randomized controlled trials (RCTs) that evaluated the effects of corticosteroid therapies for COVID-19 treatment. Outcomes of interest were mortality, need for mechanical ventilation, serious adverse events (SAEs), and superinfection. Results: A total of 7737 patients from 8 RCTs were included in the quantitative meta-analysis, of which 2795 (36.1%) patients received corticosteroids plus standard of care (SOC) while 4942 (63.9%) patients received placebo and/or SOC alone. The odds of mortality were significantly lower in patients that received corticosteroids as compared to SOC (odds ratio [OR] = 0.85 [95% CI: 0.76; 0.95], P = .003). Corticosteroid treatment reduced the odds of a need for mechanical ventilation as compared to SOC (OR = 0.76 [95% CI: 0.59; 0.97], P = .030). There was no significant difference between the corticosteroid and SOC groups with regards to SAEs and superinfections. Conclusion: Corticosteroid treatment can reduce the odds for mortality and the need for mechanical ventilation in severe COVID-19 patients.

Abstract Introduction There is increasing interest in plasma amyloid beta (Aβ) as an endophenotype of Alzheimer's disease (AD). Identifying the genetic determinants of plasma Aβ levels may elucidate important biological processes that determine plasma Aβ measures. Methods We included 12,369 non‐demented participants from eight population‐based studies. Imputed genetic data and measured plasma Aβ1‐40, Aβ1‐42 levels and Aβ1‐42/Aβ1‐40 ratio were used to perform genome‐wide association studies, and gene‐based and pathway analyses. Significant variants and genes were followed up for their association with brain positron emission tomography Aβ deposition and AD risk. Results Single‐variant analysis identified associations with apolipoprotein E ( APOE ) for Aβ1‐42 and Aβ1‐42/Aβ1‐40 ratio, and BACE1 for Aβ1‐40. Gene‐based analysis of Aβ1‐40 additionally identified associations for APP , PSEN2 , CCK , and ZNF397 . There was suggestive evidence for interaction between a BACE1 variant and APOE ε4 on brain Aβ deposition. Discussion Identification of variants near/in known major Aβ‐processing genes strengthens the relevance of plasma‐Aβ levels as an endophenotype of AD.

Adipose inflammation is proposed to be at the nexus of the systemic inflammation and metabolic derangements associated with obesity. The present study provides evidence to support adipose inflammation as a central feature of the pathophysiology of obesity. Adipose inflammation is associated with systemic and peripheral metabolic derangements, including increased systemic inflammation, reduced insulin sensitivity and reduced skeletal muscle mitochondrial respiration.

There is a need for multimodal strategies to keep research participants informed about study results. Our aim was to characterize preferences of genomic research participants from two institutions along four dimensions of general research result updates: content, timing, mechanism, and frequency. Methods: We conducted a web-based cross-sectional survey that was administered from 25 June 2018 to 5 December 2018. Results: 397 participants completed the survey, most of whom (96%) expressed a desire to receive research updates. Preferences with high endorsement included: update content (brief descriptions of major findings, descriptions of purpose and goals, and educational material); update timing (when the research is completed, when findings are reviewed, when findings are published, and when the study status changes); update mechanism (email with updates, and email newsletter); and update frequency (every three months). Hierarchical cluster analyses based on the four update preferences identified four profiles of participants with similar preference patterns. Very few participants in the largest profile were comfortable with budgeting less money for research activities so that researchers have money to set up services to send research result updates to study participants. Conclusion: Future studies may benefit from exploring preferences for research result updates, as we have in our study. In addition, this work provides evidence of a need for funders to incentivize researchers to communicate results to participants.

AbstractIntroductionWhile most patients with mantle cell lymphoma (MCL) receive therapy shortly after diagnosis, a subset of patients with indolent‐behaving disease can safely defer treatment. In this subgroup, we evaluated the importance of treatment intensity in patients with MCL who defer initial therapy.MethodsOut of 1134 patients with MCL from 12 academic centers, we analyzed 219 patients who initiated therapy at least 90 days after diagnosis. Patients who received induction with high‐dose cytarabine and/or autologous stem cell transplantation (ASCT) in first remission were considered to have received intensive therapy (n = 88) while all other approaches were non‐intensive (n = 131).ResultsThere was no difference in progression‐free (PFS; P = .224) or overall survival (OS; P = .167) in deferred patients who received non‐intensive vs. intensive therapy. Additionally, univariate and multivariate Cox proportional hazards models were performed for PFS and OS. Treatment at an academic center (HR 0.43, P = .015) was associated with improved OS in both univariate and multivariate models, while intensity of treatment was not associated with improved OS in either model.ConclusionsThese results indicate that intensified initial treatment is not associated with improved survival after deferring initial therapy, although prospective studies are needed to determine which of these patients with MCL may benefit from intensive therapy.

Abstract BCMA/CD3-targeting bispecific antibodies (BsAb) are a recently developed immunotherapy class that shows potent tumor killing activity in multiple myeloma. Here, we investigated a murine BCMA/CD3-targeting BsAb in the immunocompetent Vk*MYC model and its immunomodulatory imide drug (IMiD)–sensitive derivative Vk*MYChCRBN model of multiple myeloma. The BCMA/CD3 BsAb was safe and efficacious in a subset of mice but failed in those with high tumor burden, consistent with clinical reports of BsAb in leukemia. The combination of BCMA/CD3 BsAb with pomalidomide expanded lytic T cells and improved activity even in IMiD-resistant high–tumor burden cases. Yet, survival was only marginally extended due to acute toxicity and T-cell exhaustion, which impaired T-cell persistence. In contrast, the combination with cyclophosphamide was safe and allowed for a tempered proinflammatory response associated with long-lasting complete remission. Concurrent cytotoxic therapy with BsAb actually improved T-cell persistence and function, offering a promising approach to patients with a large tumor burden. Significance: BCMA-targeted therapy induces deep but transient clinical responses. We developed an immunocompetent, IMiD-sensitive genetically engineered mouse model and show that IMiDs potentiate T-cell activation, increasing short-term efficacy of anti-BCMA/CD3 BsAb, but exacerbate T-cell exhaustion. Surprisingly, by reducing tumor burden and depleting regulatory T cells, cyclophosphamide prevents BsAb-induced T-cell exhaustion and promotes long-term multiple myeloma control. See related commentary by Louvet et al., p. 297.

Objective To assess photophobia and allodynia in subjects with post-traumatic headache and examine how these sensory hypersensitivities associate with clinical measures of disease burden. Background Post-traumatic headache is the most frequent and disabling long-term consequence of mild traumatic brain injury. There is evidence of sensory dysfunction in acute post-traumatic headache, and it is known from other headache conditions that sensory amplifications correlate with more severe disease. However, systematic studies in post-traumatic headache are surprisingly scarce. Methods We tested light and tactile sensitivity, along with measures of disease burden, in 30 persistent post-traumatic headache subjects and 35 controls. Results In all, 79% of post-traumatic headache subjects exhibited sensory hypersensitivity based on psychophysical assessment. Of those exhibiting hypersensitivity, 54% exhibited both light and tactile sensitivity. Finally, sensory thresholds were correlated across modalities, as well as with headache attack frequency. Conclusions In this study, post-traumatic headache subjects with both light and tactile sensitivity had significantly higher headache frequencies and lower sensitivity thresholds to both modalities, compared to those with single or no sensory hypersensitivity. This pattern suggests that hypersensitivity across multiple modalities may be functionally synergistic, reflect a higher disease burden, and may serve as candidate markers of disease.