Chimeric antigen receptor (CAR) T-cells targeting CD19 demonstrate remarkable efficacy in treating B-lineage acute lymphoblastic leukemia (BL-ALL), yet up to 39% of treated patients relapse with CD19(−) disease. We report that CD19(−) escape is associated with downregulation, but preservation, of targetable expression of CD20 and CD22. Accordingly, we reasoned that broadening the spectrum of CD19CAR T-cells to include both CD20 and CD22 would enable them to target CD19(−) escape BL-ALL while preserving their upfront efficacy. We created a CD19/20/22-targeting CAR T-cell by coexpressing individual CAR molecules on a single T-cell using one tricistronic transgene. CD19/20/22CAR T-cells killed CD19(−) blasts from patients who relapsed after CD19CAR T-cell therapy and CRISPR/Cas9 CD19 knockout primary BL-ALL both in vitro and in an animal model, while CD19CAR T-cells were ineffective. At the subcellular level, CD19/20/22CAR T-cells formed dense immune synapses with target cells that mediated effective cytolytic complex formation, were efficient serial killers in single-cell tracking studies, and were as efficacious as CD19CAR T-cells against primary CD19(+) disease. In conclusion, independent of CD19 expression, CD19/20/22CAR T-cells could be used as salvage or front-line CAR therapy for patients with recalcitrant disease.

Radiopharmaceuticals are rapidly developing as a field, with the successful use of targeted beta emitters in neuroendocrine tumors and prostate cancer serving as catalysts. Targeted alpha emitters are in current development for several potential oncologic indications. Herein, we review the three most prevalently studied conjugated/chelated alpha emitters (²²⁵actinium, ²¹²lead, and ²¹¹astatine) and focus on contemporary clinical trials in an effort to more fully appreciate the breadth of the current evaluation. Phase I trials targeting multiple diseases are now underway, and at least one phase III trial (in selected neuroendocrine cancers) is currently in the initial stages of recruitment. Combination trials are now also emerging as alpha emitters are integrated with other therapies in an effort to create solutions for those with advanced cancers. Despite the promise of targeted alpha therapies, many challenges remain. These challenges include the development of reliable supply chains, the need for a better understanding of the relationships between administered dose and absorbed dose in both tissue and tumor and how that predicts outcomes, and the incomplete understanding of potential long-term deleterious effects of the alpha emitters. Progress on multiple fronts is necessary to bring the potential of targeted alpha therapies into the clinic.

Metastatic prostate cancer continues to be an incurable disease. Despite all the novel therapies approved in the past two decades, overall patient outcomes remain relatively poor, and these patients die on a regular basis. Clearly, improvements in current therapies are needed. Prostate-specific membrane antigen (PSMA) is a target for prostate cancer given its increased expression on the surface of the prostate cancer cells. PSMA small molecule binders include PSMA-617 and PSMA-I&T and monoclonal antibodies such as J591. These agents have been linked to different radionuclides including beta-emitters such as lutetium-177 and alpha-emitters such as actinium-225. The only regulatory-approved PSMA-targeted radioligand therapy (PSMA-RLT) to date is lutetium-177–PSMA-617 in the setting of PSMA-positive metastatic castration-resistant prostate cancer that has failed androgen receptor pathway inhibitors and taxane chemotherapy. This approval was based on the phase III VISION trial. Many other clinical trials are evaluating PSMA-RLT in various settings. Both monotherapy and combination studies are underway. This article summarizes pertinent data from recent studies and provides an overview of human clinical trials in progress. The field of PSMA-RLT is rapidly evolving, and this therapeutic approach will likely play an increasingly important role in the years to come.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) mortality is high in patients with hypertension, obesity, and diabetes. We examined the association between hypertension, obesity, and diabetes, individually and clustered as metabolic syndrome (MetS), and COVID-19 outcomes in patients hospitalized in New Orleans during the peak of the outbreak. RESEARCH DESIGN AND METHODS: Data were collected from 287 consecutive patients with COVID-19 hospitalized at two hospitals in New Orleans, LA, from 30 March to 5 April 2020. MetS was identified per World Health Organization criteria. RESULTS: Among 287 patients (mean age 61.5 years; female, 56.8%; non-Hispanic Black, 85.4%), MetS was present in 188 (66%). MetS was significantly associated with mortality (adjusted odds ratio [aOR] 3.42 [95% CI 1.52–7.69]), intensive care unit requirement (ICU) (aOR 4.59 [CI 2.53–8.32]), invasive mechanical ventilation (IMV) (aOR 4.71 [95% CI 2.50–8.87]), and acute respiratory distress syndrome (ARDS) (aOR 4.70 [95% CI 2.25–9.82]) compared with non-MetS. Multivariable analyses of hypertension, obesity, and diabetes individually showed no association with mortality. Obesity was associated with ICU (aOR 2.18 [95% CI 1.25–3.81]), ARDS (aOR 2.44 [95% CI 1.28–4.65]), and IMV (aOR 2.36 [95% CI 1.33–4.21]). Diabetes was associated with ICU (aOR 2.22 [95% CI 1.24–3.98]) and IMV (aOR 2.12 [95% CI 1.16–3.89]). Hypertension was not significantly associated with any outcome. Inflammatory biomarkers associated with MetS, CRP and lactate dehydrogenase (LDH), were associated with mortality (CRP [aOR 3.66] [95% CI 1.22–10.97] and LDH [aOR 3.49] [95% CI 1.78–6.83]). CONCLUSIONS: In predominantly Black patients hospitalized for COVID-19, the clustering of hypertension, obesity, and diabetes as MetS increased the odds of mortality compared with these comorbidities individually.

One carbon (1C) metabolism nutrients influence epigenetic regulation and they are supplied by diet and synthesized by gut microbiota. We examined the association between dietary consumption of methyl donors (methionine, betaine and choline) and B vitamins (folate, B2, B6, and B12) and the community composition and structure of the colonic mucosa-associated gut microbiota determined by 16S rRNA gene sequencing in 97 colonic biopsies of 35 men. We used the food frequency questionnaire to assess daily consumption of nutrients, and the UPARSE and SILVA databases for operational taxonomic unit classification. The difference in bacterial diversity and taxonomic relative abundance were compared between low versus high consumption of these nutrients. False discover rate (FDR) adjusted p value < 0.05 indicated statistical significance. The bacterial richness and composition differed significantly by the consumption of folate and B vitamins (p < 0.001). Compared with higher consumption, a lower consumption of these nutrients was associated with a lower abundance of Akkermansia (folate), Roseburia (vitamin B2), and Faecalibacterium (vitamins B2, B6, and B12) but a higher abundance of Erysipelatoclostridium (vitamin B2) (FDR p values < 0.05). The community composition and structure of the colonic bacteria differed significantly by dietary consumption of folate and B vitamins.

Autophagy is required for the long-term maintenance of Ag-specific memory B cells. However, whether autophagy is also important for the initial formation of memory B cells remains unclear. In this study, we show that newly generated memory B cells do not display active autophagy but are capable of forming Ab-secreting cells after rechallenge with Ags. Increases in autophagy took place over time after the initial formation of memory B cells. The expression of transcription factors involved in autophagy, but not changes in epigenetic regulation by DNA methylation, was required for autophagy gene expression and the development of active autophagy in memory B cells. This indicates that autophagy is not critical for the initial generation of memory B cells but is required for their long-term persistence. Our results suggest that promoting autophagy to improve Ab-dependent immunological memory is more effective during memory B cell maintenance stage.