PURPOSE Variation in risk of adverse clinical outcomes in patients with cancer and COVID-19 has been reported from relatively small cohorts. The NCATS’ National COVID Cohort Collaborative (N3C) is a centralized data resource representing the largest multicenter cohort of COVID-19 cases and controls nationwide. We aimed to construct and characterize the cancer cohort within N3C and identify risk factors for all-cause mortality from COVID-19. METHODS We used 4,382,085 patients from 50 US medical centers to construct a cohort of patients with cancer. We restricted analyses to adults ≥ 18 years old with a COVID-19–positive or COVID-19–negative diagnosis between January 1, 2020, and March 25, 2021. We followed N3C selection of an index encounter per patient for analyses. All analyses were performed in the N3C Data Enclave Palantir platform. RESULTS A total of 398,579 adult patients with cancer were identified from the N3C cohort; 63,413 (15.9%) were COVID-19–positive. Most common represented cancers were skin (13.8%), breast (13.7%), prostate (10.6%), hematologic (10.5%), and GI cancers (10%). COVID-19 positivity was significantly associated with increased risk of all-cause mortality (hazard ratio, 1.20; 95% CI, 1.15 to 1.24). Among COVID-19–positive patients, age ≥ 65 years, male gender, Southern or Western US residence, an adjusted Charlson Comorbidity Index score ≥ 4, hematologic malignancy, multitumor sites, and recent cytotoxic therapy were associated with increased risk of all-cause mortality. Patients who received recent immunotherapies or targeted therapies did not have higher risk of overall mortality. CONCLUSION Using N3C, we assembled the largest nationally representative cohort of patients with cancer and COVID-19 to date. We identified demographic and clinical factors associated with increased all-cause mortality in patients with cancer. Full characterization of the cohort will provide further insights into the effects of COVID-19 on cancer outcomes and the ability to continue specific cancer treatments.

Costimulatory receptors such as glucocorticoid-induced tumor necrosis factor receptor–related protein (GITR) play key roles in regulating the effector functions of T cells. In human clinical trials, however, GITR agonist antibodies have shown limited therapeutic effect, which may be due to suboptimal receptor clustering-mediated signaling. To overcome this potential limitation, a rational protein engineering approach is needed to optimize GITR agonist-based immunotherapies. Here we show a bispecific molecule consisting of an anti-PD-1 antibody fused with a multimeric GITR ligand (GITR-L) that induces PD-1-dependent and FcγR-independent GITR clustering, resulting in enhanced activation, proliferation and memory differentiation of primed antigen-specific GITR+PD-1+ T cells. The anti-PD-1–GITR-L bispecific is a PD-1-directed GITR-L construct that demonstrated dose-dependent, immunologically driven tumor growth inhibition in syngeneic, genetically engineered and xenograft humanized mouse tumor models, with a dose-dependent correlation between target saturation and Ki67 and TIGIT upregulation on memory T cells. Anti-PD-1–GITR-L thus represents a bispecific approach to directing GITR agonism for cancer immunotherapy.

1500 Background: The impact of COVID-19 has disproportionately affected every aspect of cancer care and research—from introducing new risks for patients to disrupting the delivery of treatment and continuity of research. Variation in risk of adverse clinical outcomes in COVID-19 patients by cancer type has been reported from relatively small cohorts. Gaps in understanding effects of COVID-19 on cancer patients can be addressed through the study of a well-constructed representative cohort. The NCATS’ National COVID Cohort Collaborative (N3C) is a centralized data resource representing the largest multi-center cohort of COVID-19 cases and controls nationwide. We aimed to construct and characterize the cohort of cancer patients within N3C and identify risk factors for all-cause mortality from COVID-19. Methods: From the harmonized N3C clinical dataset, we used 3,295,963 patients from 39 medical US centers to construct a cancer patient cohort. We restricted analyses to adults ≥18 yo with a COVID-19 positive PCR or antigen test or ICD-10-CM diagnostic code for COVID-19 between 1/1/2020 and 2/14/2021. We followed N3C definitions where each lab-confirmed positive patient has one single index encounter. A modified WHO Clinical Progression Scale was used to determine clinical severity. All analyses were performed in the N3C Data Enclave on the Palantir platform. Results: A total of 372,883 adult patients with cancer were identified from the N3C cohort; 54,642 (14.7%) were COVID-19 positive. Most common represented cancers were skin (11.5%), breast (10.2%), prostate (8%), and lung cancer (5.6%). Mean age of COVID-19 positive patients was 61.6 years (SD 16.7), 47.3% over 65yo, 53.7% females, 67.2% non-Hispanic White, 21.0% Black, and 7.7% Hispanic or Latino. A total of 14.6% were current or former smokers, 22.3% had a Charlson Comorbidity Index (CCI) score of 0, 4.6% score of 1 and 28.1% score of 2. Among hospitalized COVID-19 positive patients, average length of stay in the hospital was 6 days (SD 23.1 days), 7.0% patients had died while in their initial COVID-19 hospitalization, 4.5% required invasive ventilation, and 0.1% extracorporeal membrane oxygenation. Survival probability was 86.4% at 10 days and 63.6% at 30 days. Older age over 65yo (Hazard ratio (HR) = 6.1, 95%CI: 4.3, 8.7), male gender (HR = 1.2, 95%CI: 1.1, 1.2), a CCI score of 2 or more (HR = 1.15, 95%CI: 1.1, 1.2), and acute kidney injury during hospitalization (HR = 1.3, 95%CI: 1.2, 1.4) were associated with increased risk of all-cause mortality. Conclusions: Using the N3C cohort we assembled the largest nationally representative cohort on patients with cancer and COVID-19 to date. We identified demographic and clinical factors associated with increased all-cause mortality in cancer patients. Full characterization of the cohort will provide further insights on the effects of COVID-19 on cancer outcomes and the ability to continue specific cancer treatments.

Steroids induce resistance to neuromuscular blocking drugs. Betamethasone-induced resistance to vecuronium has been demonstrated in vitro, and a presynaptic site of interaction has been suggested. This study investigated whether atracurium is similarly affected. Rat phrenic nerve-hemidiaphragm preparations were bathed in a physiologic solution, and one-half were exposed to betamethasone (1 mumol/L). Dose responses were recorded for atracurium (8-13 mumol/L) and vecuronium (2-12 mumol/L) for control and betamethasone-treated preparations. In comparison to control, the betamethasone groups had significantly less depression of muscle contraction force at all concentrations of atracurium (P = 0.0004) and vecuronium (P = 0.002). The calculated ED50 (50% depression of muscle contraction force, expressed as mean +/- SEM) for atracurium was 8.83 +/- 0.62 mumol/L for controls and 11.19 +/- 0.54 mumol/L for betamethasone-treated preparations. The calculated ED50 for vecuronium was 4.72 +/- 0.41 mumol/L for controls and 6.84 +/- 0.66 mumol/L for betamethasone-treated preparations. Betamethasone therefore increased the ED50 for atracurium by 27% and vecuronium by 45%; however, the magnitudes of these differences were not significant (P = 0.74) between the neuromuscular blocking agents. These results indicate that betamethasone-induced resistance to nondepolarizing neuromuscular blockade affects both atracurium and vecuronium to similar degrees in vitro.

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