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Safety and efficacy of a novel anti-CD19 chimeric antigen receptor T cell product targeting a membrane-proximal domain of CD19 with fast on- and off-rates against non-Hodgkin lymphoma: a first-in-human study
Background
Commercial anti-CD19 chimeric antigen receptor T-cell therapies (CART19) are efficacious against advanced B-cell non-Hodgkin lymphoma (NHL); however, most patients ultimately relapse. Several mechanisms contribute to this failure, including CD19-negative escape and CAR T dysfunction. All four commercial CART19 products utilize the FMC63 single-chain variable fragment (scFv) specific to a CD19 membrane-distal epitope and characterized by slow association (on) and dissociation (off) rates. We hypothesized that a novel anti-CD19 scFv that engages an alternative CD19 membrane-proximal epitope independent of FMC63 and that is characterized by faster on- and off-rates could mitigate CART19 failure and improve clinical efficacy.
Methods
We developed an autologous CART19 product with 4-1BB co-stimulation using a novel humanized chicken antibody (h1218). This antibody is specific to a membrane-proximal CD19 epitope and harbors faster on/off rates compared to FMC63. We tested h1218-CART19 in vitro and in vivo using FMC63-CART19-resistant models. We conducted a first-in-human multi-center phase I clinical trial to test AT101 (clinical-grade h1218-CART19) in patients with relapsed or refractory (r/r) NHL.
Results
Preclinically, h1218- but not FMC63-CART19 were able to effectively eradicate lymphomas expressing CD19 point mutations (L174V and R163L) or co-expressing FMC63-CAR19 as found in patients relapsing after FMC63-CART19. Furthermore, h1218-CART19 exhibited enhanced killing of B-cell malignancies in vitro and in vivo compared with FMC63-CART19. Mechanistically, we found that h1218-CART19 had reduced activation-induced cell death (AICD) and enhanced expansion compared to FMC63-CART19 owing to faster on- and off-rates. Based on these preclinical results, we performed a phase I dose-escalation trial, testing three dose levels (DL) of AT101 (the GMP version of h1218) using a 3 + 3 design. In 12 treated patients (7 DLBCL, 3 FL, 1 MCL, and 1 MZL), AT101 showed a promising safety profile with 8.3% grade 3 CRS (
n
= 1) and 8.3% grade 4 ICANS (
n
= 1). In the whole cohort, the overall response rate was 91.7%, with a complete response rate of 75.0%, which improved to 100% in DL-2 and -3. AT101 expansion correlates with CR and B-cell aplasia.
Conclusions
We developed a novel, safe, and potent CART19 product that recognizes a membrane-proximal domain of CD19 with fast on- and off-rates and showed significant efficacy and promising safety in patients with relapsed B-cell NHL.
Trial registration
NCT05338931; Date: 2022–04-01.
Journal Article
Adhesive Properties of Eco‐Friendly Hot Melt Adhesive Based on Poly(butylene adipate‐co‐terephthalate) and Rosin Maleic Resin
As environmental problems increase, disposable products are being replaced and recommended with materials with a low environmental load when it discarded. So the demand for bioplastics for building a sustainable society is increasing. This study focuses mainly on the applicability of biodegradable plastics and rosin maleic resin (RMR, DX‐250) blends with potential use in eco‐friendly hot‐melt adhesives (HMA). Poly (butylene adipate‐co‐terephthalate) (PBAT), which has high dimensional stability owing to low crystallinity, is used as the main polymer of the HMA. And rosin maleic resin, which is effective for increasing adhesive properties and compatibility as a tackifier. The HMA based on PBAT and RMR blends are prepared via melt‐blend extrusion. Compatibility and wettability are increased under the influence of RMR, and adhesion properties are improved, compared to that of PBAT. In addition, as confirmed polarizing microscope (POM), the addition of RMR leads to a decrease in crystallinity, which can be expected to be effective for biodegradation. This result PBAT/RMR 7/3 blend significantly enhances the adhesion strength of PBAT from 1.8 to 7.3 MPa. Therefore, PBAT with the blends containing 30 wt.% of RMR has considerable potential application in the HMA field.
Journal Article
Leadership toolkit for Asians : the definitive resource guide for breaking the bamboo ceiling
\"Breakthrough strategies to help Asian Americans in the workplace build their personal leadership acumen and map a career advancement path that is achievable, authentic, and culturally relevant. 17 years after Jane Hyun wrote her groundbreaking book, Breaking the Bamboo Ceiling, Asians remain grossly underrepresented in the upper ranks of American organizations. Asians are 12% of the workforce, but just 1.5% of Fortune 500 corporate officers. Hyun says for Asians to lead authentically, they need to move away from \"code switching\" and \"getting along by going along.\" This workbook is built around her three-part framework for developing an intentional, courageous, culturally grounded approach to working and leading: ASSESS: Identify your personal and professional values, assets, and style. EQUIP: Learn to navigate the organizational environment-push back against stereotypes, find mentors and advisors, develop your professional networks, and more. TRANSFORM: Pull it all together to create your own leadership blueprint. The Toolkit is full of activities to help readers put ideas into action. It also includes inspiring real-life lessons from Asian executives and leaders. The Asian Leadership Toolkit acknowledges the wide range of cultures, identities, and experiences that exist within Asian America, and sees the particulars of identity not as impediments but as integral to crafting a bespoke leadership journey\"-- Provided by publisher.
BOOK
Subclinical alterations in left ventricular structure and function according to obesity and metabolic health status
Obesity and metabolic syndrome (MetS) are associated with high risk of cardiac dysfunction and heart failure. We assessed the effect of obesity and metabolic health status on left ventricular (LV) structure and function in subjects without overt heart disease.
In 789 subjects (58.8±13.0 years, 50.7% males) without overt heart disease, LV morphology and function were compared among 6 groups stratified by body mass index (BMI) (normal weight, overweight and obese) and metabolic health status (meeting ≤1 criterion of MetS excluding waist circumference defined as metabolically healthy; otherwise, metabolically unhealthy).
LV ejection fraction (LVEF) was not different among the 6 groups (P>0.05). However, high BMI and poor metabolic health were associated with poorer global longitudinal strain (GLS), higher LV mass index (LVMI) and higher E/e' (P<0.001). Poor metabolic health status was associated with greater adverse changes in LV structure and function than obesity, and among MetS components, high systolic blood pressure (SBP) showed the greatest impact. Higher SBP, BMI and triglycerides were independently associated with worse GLS, and higher SBP was also associated with worse LVMI and E/e´. GLS, LVMI and E/e´ worsened in proportion to the number of MetS criteria or continuous MetS scores. Adverse myocardial changes associated with obesity were significant in the metabolically healthy group, but not in the metabolically unhealthy group.
Obesity and poor metabolic health status were associated with subclinical decrement in LV systolic and diastolic function, and higher LV mass, but not with LVEF, in subjects without overt heart disease.
Journal Article
Sovereignty and status in East Asian international relations
\"This book provides a theoretical and empirical analysis of a key concept in East Asian security debates, sovereign autonomy, and how it reproduces hierarchy in the regional order. Park argues that contemporary strategic debates in East Asia are based on shared contextual knowledge - that of international hierarchy - reconstructed in the late nineteenth century. The mechanism that reproduces this lens of hierarchy is domestic legitimacy politics in which embattled political leaders contest the meaning of sovereign autonomy. Park argues that the idea of status-seeking has remained embedded in the concept of sovereign autonomy and endures through distinct and alternative security frames that continue to inform contemporary strategic debates in East Asia. This book makes a significant contribution to debates in IR theory and security studies about autonomy and status, as well as to the now extensive literature on the nature of East Asian regional order\"-- Provided by publisher.
Book
Prediction-based highly sensitive CRISPR off-target validation using target-specific DNA enrichment
CRISPR effectors, which comprise a CRISPR-Cas protein and a guide (g)RNA derived from the bacterial immune system, are widely used for target-specific genome editing. When the gRNA recognizes genomic loci with sequences that are similar to the target, deleterious mutations can occur. Off-target mutations with a frequency below 0.5% remain mostly undetected by current genome-wide off-target detection techniques. Here we report a method to effectively detect extremely small amounts of mutated DNA based on predicted off-target-specific amplification. In this study, we used various genome editors to induce intracellular genome mutations, and the CRISPR amplification method detected off-target mutations at a significantly higher rate (1.6~984 fold increase) than an existing targeted amplicon sequencing method. In the near future, CRISPR amplification in combination with genome-wide off-target detection methods will allow detection of genome editor-induced off-target mutations with high sensitivity and in a non-biased manner.
Off-target mutations that occur at a frequency below 0.5% can be difficult to detect. Here the authors use predicted off-target amplification to increase detection sensitivity.
Journal Article
Psychological and Biochemical Effects of an Online Pilates Intervention in Pregnant Women during COVID-19: A Randomized Pilot Study
The purpose of this study was to analyze the effect of real-time online Pilates exercise during COVID-19 on women’s body composition, blood lipids, and psychological health after childbirth. The participants were 16 pregnant women (24–28 weeks pregnant) enrolled at the C Women’s Culture Center in Seoul, South Korea, classified into online Pilates groups and non-exercise groups (PE, n = 8; CON, n = 8). The online Pilates program was conducted for 8 weeks, twice a week, and 50 min a day using a real-time video chat app. Participants visited the hospital twice for body composition and blood tests. Questionnaires on postpartum depression, sleep disorder, and stress were conducted at 6 weeks and 12 weeks after childbirth. We found a significant difference between groups in body composition. The weight, percentage of body fat, body fat mass, and BMI of the PE group decreased. Blood lipids showed significant differences between the groups in TC, TG, LDL and CRP, while insulin and HDL showed no difference. All blood lipids, insulin, and CRP in the PE group were reduced. There were significant differences between the groups in postpartum depression, sleep disorders, and perceived stress indices performed in the post-test, and the serotonin concentration in the PE group increased. Serotonin levels were significantly correlated with postpartum depression, body fat mass, and body fat rate. Pregnant women’s online Pilates in this study was effective at reducing weight and depression in women after childbirth and should be used to promote women’s mental health during COVID-19.
Journal Article