Background and Aims: Chimeric antigen receptor engineered T cells (CARTs) for HCC and other solid tumors are not as effective as they are for blood cancers. CARTs may lose function inside tumors due to persistent antigen engagement. The aims of this study are to develop low-affinity monoclonal antibodies (mAbs) and low-avidity CARTs for HCC and to test the hypothesis that low-avidity CARTs can resist exhaustion and maintain functions in solid tumors, generating durable antitumor effects. Methods and Results: New human glypican-3 (hGPC3) mAbs were developed from immunized mice. We obtained three hGPC3-specific mAbs that stained HCC tumors, but not the adjacent normal liver tissues. One of them, 8F8, bound an epitope close to that of GC33, the frequently used high-affinity mAb, but with approximately 17-fold lower affinity. We then compared the 8F8 CARTs to GC33 CARTs for their in vitro function and in vivo antitumor effects.In vitro, low-avidity 8F8 CARTs killed both hGPC3 high and hGPC3 low HCC tumor cells to the same extent as high-avidity GC33 CARTs. 8F8 CARTs expanded and persisted to a greater extent than GC33 CARTs, resulting in durable responses against HCC xenografts. Importantly, compared with GC33 CARTs, there were 5-fold more of 8F8-BBz CARTs in the tumor mass for a longer period of time. Remarkably, the tumor-infiltrating 8F8 CARTs were less exhausted and apoptotic, and more functional than GC33 CARTs.
Sports-related concussions occur with high incidence in the United States. Google Trends™ (GT) analyses indicate changes of public interest in a topic over time, and can be correlated with incidence of health events such as concussion. Internet searches represent a primary means of patient education for many health topics, including concussion; however, the quality of medical information yielded by internet searches is variable and frequently of an inappropriate reading level. This study therefore aims to describe GT over time and evaluate the quality and readability of information produced by Google™ searches of the term “concussion.” We identified a strong negative correlation from 2009 to 2016 between GT scores and total number of American high school football participants ( R 2 = 0.8553) and participants per school ( R 2 = 0.9533). Between 2004 and 2020, the monthly GT popularity score were variable ( p = 3.193E-08), with September having the greatest scores, correlating with the height of American tackle football season. Applying five validated quality assessment scoring systems at two time points, it was confirmed that different sources yielded varying quality of information. Academic and non-profit healthcare sources demonstrated the highest quality metrics across two time points. There was significant variability of scores among the different scoring systems, however. The majority of searches at both time points yielded information that was rated as “fair” to “poor” in quality. Applying six readability tests, we revealed that only a single commercial website offered information written at or below the American Medical Association– recommended 6th-grade level for healthcare information. In summary, GT data analyses suggest that searches correlate with the American tackle football season and increased between 2009 and 2016, given that public interest in concussion increased and annual participation in football decreased. The quality of information yielded by Google™ searches and readability are inadequate, indicating the need for significant improvement.
ObjectiveThis investigation employs 2004–2020 Google Trends data to correlate concussion search popularity and high school sports participation while assessing search seasonality and factors associated with search escalation.BackgroundEvents linked to concussions, from news to entertainment, altered public perception of concussions and discouraged high-risk activities. Such sentiment likely promoted high school football's 2004–2018 8% decrease in participation, despite simultaneous 8% increase for sports overall. Google Trends (GT) analysis calculates distinct subjects' popularity scores (0–100) by normalizing Google search frequency with other subjects in the same topic. With 35% of patients researching their conditions using Google, tracking concussion popularity scores allows robust analysis of event-driven fluctuation, seasonal variation, and sports impact.Design/MethodsWorldwide GT analysis was conducted for the disease topic “Concussion” with the categorical filter “Health” from 2004 to 2020. This period's monthly popularity scores with annual averages and annual high school sports participation data were subsequently obtained from Google Trends and the National Federation of State High School Associations, respectively.ResultsConcurrence of significant score changes with CTE studies' publication, release of 2015 film Concussion, and the COVID-19 pandemic validates GT's measurement of public interest. From 2006 to 2016, Pearson's correlation coefficients demonstrated strong negative correlation between GT popularity scores for “Concussion” with total number of high school football participants overall (R2 = 0.8553) and participants per school (R2 = 0.9533). Confirming football-related seasonality, one-way ANOVA regression analysis concluded 2004–2020's mean change in month-specific popularity score is not the same (p = 3.193E-08), and months during football season had statistically significant variability (September: p = 4.389E-05) with elevated average z-scores.ConclusionsCoupled with ANOVA regression and normalized analyses, strong negative correlations between concussion popularity score and high school football participation produce quantitative measures of a long-suspected relationship. Tracking concussion popularity and seasonality with Google Trends provides insight into how, when, and why patients are educating themselves online.
Background & Aims Chimeric antigen receptor engineered T cells (CARTs) for hepatocellular carcinoma (HCC) and other solid tumors are not as effective as they are for blood cancers. CARTs may lose function inside tumors due to persistent antigen engagement. The aims of this study are to develop low-affinity monoclonal antibodies (mAb) and low-avidity CARTs for HCC and to test the hypothesis that low-avidity CARTs can resist exhaustion and maintain functions in solid tumors, generating durable antitumor effects. Methods and results New human glypican-3 (hGPC3) mAbs were developed from immunized mice. We obtained 3 hGPC3-specific mAbs that stained HCC tumors, but not the adjacent normal liver tissues. One of them, 8F8, bound an epitope close to that of GC33, the frequently used high-affinity mAb, but with ~17 fold lower affinity. We then compared the 8F8 CARTs to GC33 CARTs for their in vitro function and in vivo antitumor effects. In vitro, low-avidity 8F8 CARTs killed both hGPC3high and hGPC3low HCC tumor cells to the same extent as high-avidity GC33 CARTs. 8F8 CARTs expanded and persisted to a greater extent than GC33 CARTs, resulting in durable responses against HCC xenografts. Importantly, compared to GC33 CARTs, there were 5 folds more of 8F8-BBz CARTs in the tumor mass for a longer period of time. Remarkably, the tumor infiltrating 8F8 CARTs were less exhausted and apoptotic, and more functional than GC33 CARTs. Conclusion The novel low-avidity 8F8-BBz CART resists exhaustion and apoptosis inside tumor lesions, demonstrating a greater therapeutic potential than high-avidity CARTs.
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