Sarah Ophelia Colley Cannon (October 25, 1912 – March 4, 1996), known professionally as her stage character Minnie Pearl, was an American comedienne who appeared at the Grand Ole Opry for more than 50 years (1940–1991) and on the television show Hee Haw from 1969 to 1991.
10543 Background: Radiographic findings concerning for malignancy frequently prompt extensive diagnostic evaluations that fail to yield a definitive diagnosis, resulting in delayed treatment, persistent uncertainty, and unnecessary interventions. Multi-cancer early detection (MCED) tests based on circulating cell-free DNA (cfDNA) methylation have demonstrated high specificity in asymptomatic screening populations; however, performance in individuals with clinical suspicion of malignancy remains unclear. We compared the performance of a cfDNA methylation–based MCED test in asymptomatic participants and in participants with imaging-based suspicion of malignancy. Methods: Adults aged 45–79 years enrolled in CORE-HH (NCT05435066) were evaluated in (1) a case–control cohort (n = 4,137) comprising asymptomatic participants who reported no history of cancer (n = 2,523) and newly diagnosed cancer participants (n = 1,614); and (2) a prospective cohort (n = 209) of individuals with imaging-based suspicion of malignancy undergoing clinical evaluation (cancer confirmed, n = 155; no cancer, n = 54). Cancer types included lung, breast, colorectal, prostate, pancreatic/hepatobiliary, head and neck, gynecologic, and hematologic malignancies. Samples were analyzed using a cfDNA methylation–based MCED test incorporating an AI/ML model, at a pre-specified specificity of 98.5%. Test performance was compared between cohorts among non-cancer participants and among early-stage (stage I–II) and late-stage (stage III–IV) cancer cases using Fisher’s exact test (two-sided). Results: Among non-cancer participants (n = 2,577), empirical specificity was 98.1% (53/54) in the clinical suspicion cohort and 98.5% (2,485/2,523) in the asymptomatic case–control cohort (OR, 1.23; 95% CI, 0.03–7.6; p = 0.56). Overall sensitivity was 54.8% (85/155) in the clinical suspicion cohort and 53.9% (870/1,614) in newly diagnosed cancer cases from the case–control cohort (OR, 1.04; 95% CI, 0.74–1.47; p = 0.87). Stage I–II sensitivity was 27.7% (18/65) vs 28.7% (204/711) (p = 1.00), and stage III–IV sensitivity was 82.9% (58/70) vs 81.5% (573/703) (p = 0.87), for the clinical suspicion and case–control cohorts, respectively. Overall cancer stage distribution was similar between cohorts (p = 0.89). Conclusions: At the prespecified 98.5% specificity threshold, the cfDNA methylation–based MCED test demonstrated comparable specificity and sensitivity in prospectively enrolled participants undergoing evaluation for imaging-based suspicion of malignancy and in a case–control cohort of newly diagnosed cancer cases versus asymptomatic controls. Recognizing the tendency of case–control designs to overestimate test performance, these results describe MCED test performance in a cohort with clinical suspicion of malignancy, extending characterization beyond asymptomatic screening populations. Clinical trial information: NCT05435066 .
Abstract Introduction Tregs play a key role in establishing and maintaining immune tolerance and homeostasis but despite progress, current Treg therapies face challenges of unstable phenotypes, lack of IL-2 support, and tissue specificity. Methods We present a strategy to address these challenges by harnessing a gene editing platform with dual AAV to engineer human regulatory T cells (EngTreg) from bulk CD4+ T cells resulting in the stable expression of FOXP3 and a chemically inducible cytokine signaling complex providing IL-2 signaling support. Additionally, a novel hypoimmune approach improves allogeneic cell persistence by preventing T, B, and NK cell mediated rejection, making possible an off-the-shelf approach. This modular engineering allows for indication specific, interchangeable tissue specific targeting including TCRs, CARs, or inflammation tuned alarmin receptors. Results We present transcriptomic and flow cytometry analyses showing EngTregs express higher levels of core Treg and FOXP3 synergy genes, stability markers and tolerogenic proteins compared to cultured Tregs. EngTregs have been tailored for multiple indications: GNTI-122 targets IGRP for T1D, showing strong bystander suppression and disease prevention in mouse models. CAR19 EngTregs target B-cell driven autoimmune diseases with better safety compared to CAR-T cells. Gut epithelium targeting EngTregs ameliorate disease in murine IBD models. Tissue EngTregs target alarmin mediated inflammation and show efficacy in models of lung injury, AKI, and stroke. Conclusion Together, these data support EngTregs as a potent, stable, and versatile cell therapy platform for autoimmune, inflammatory, and ischemic diseases. Funding Source NIH-SBIR, venture capital, foundation funding Topic Categories Translational and Interventional Immunology (TI)
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