SeroNet Pooling Project of immunocompromised populations

Introduction: COVID-19 vaccination substantially reduces morbidity and mortality associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and severe illness. However, despite effective COVID-19 vaccines many questions remain about the efficacy of vaccines and the durability and robustness of immune responses, especially in immunocompromised persons. The NCI-funded Serological Sciences Network (SeroNet) is a coordinated effort including 11 sites to advance research on the immune response to SARS-CoV-2 infection and COVID-19 vaccination among diverse and vulnerable populations. The goals of the Pooling Project are: (1) to conduct real-world data (RWD) analyses using electronic medical records (EMR) data from four health care systems (Kaiser Permanente Northern California, Northwell Health, Veterans Affairs-Case Western, and Cedars-Sinai) to determine vaccine effectiveness in (a) cancer patients;(b) autoimmune diseases and (c) solid organ transplant recipients (SOTR);(2) to conduct meta-analyses of prospective cohort studies from eight SeroNet institutions (Cedars-Sinai, Johns Hopkins, Northwell Health, Emory University, University of Minnesota, Mount Sinai, Yale University) to determine post-vaccine immune responses in (a) lung cancer patients;(b) hematologic cancers/hematopoietic stem cell transplant (HSCT) recipients;(c) SOTR;(d) lupus. Method(s): For our RWD analyses, data is extracted from EMR using standardized algorithms using ICD-10 codes to identify immunocompromised persons (hematologic and solid organ malignancy;SOTR;autoimmune disease, including inflammatory bowel disease, rheumatoid arthritis, and SLE). We use common case definitions to extract data on demographic, laboratory values, clinical co morbidity, COVID-19 vaccination, SARS-CoV-2 infection and severe COVID-19, and diseasespecific variables. In addition, we pool individual-level data from prospective cohorts enrolling patients with cancer and other immunosuppressed conditions from across network. Surveys and biospecimens from serology and immune profiling are collected at pre-specified timepoints across longitudinal cohorts. Result(s): Currently, we have EMR data extracted from 4 health systems including >715,000 cancer patients, >9,500 SOTR and >180,000 with autoimmune conditions. Prospective cohorts across the network have longitudinal data on >450 patients with lung cancer, >1,200 patients with hematologic malignancies, >400 SOTR and >400 patients with lupus. We will report results examining vaccine effectiveness for prevention of SARS-CoV-2 infection, severe COVID-19 and post-acute sequelae of COVID-19 (PAS-C or long COVID) in cancer patients compared to other immunocompromised conditions. Conclusion(s): Our goal is to inform public health guidelines on COVID-19 vaccine and boosters to reduce SARS-CoV-2 infection and severe illness in immunocompromised populations.

Assessing vulnerability of patients with lung cancer to SARS-CoV-2 infection based on serological antibody analyses

COVID-19 presents a unique threat to patients with lung cancer, with mortality rates as high as ∼32%. Given the convergence of these two deadly diseases, the lung cancer research and advocacy communities rapidly mobilized in early 2020 to create the COVID Lung Cancer Consortium (CLCC), a global assembly of leading experts in thoracic oncology, immunology, virology, vaccines and patient advocacy. With ongoing robust exchange of data and shared learning and rational planning for clinical and laboratory investigations, the CLCC is bringing its collective expertise to bear on beginning to address the question of why patients with lung cancer are at such elevated risk of worse outcomes from COVID-19. These efforts led to a recently funded U54 CA260560 grant as part of the National Cancer Institute's SeroNet initiative to study the magnitude, quality and duration of antibody responses to SARS-CoV-2 infection in patients with lung cancer compared to healthy controls. In the first project, our Mt. Sinai U54 Serological Center of Excellence will follow a prospective lung cancer cohort (750 patients) and a matched non-lung cancer control group (750 individuals) to determine if there are differences in antibody responses related to age, gender, tobacco history, and race/ethnicity. Given that effective SARS-CoV-2 vaccines are now being deployed, the study will also analyze antibody responses to vaccination across these two patient cohorts. The second project will examine biological determinants correlating with susceptibility to infection, including analysis of both ACE2 and TMPRSS2 levels, and antibody-mediated neutralization in pre-clinical models of established lung cancer and normal lung epithelial cell lines. In order to capture a diverse and inclusive patient population, this effort will be supported by GO2 Foundation for Lung Cancer through its national network of Centers of Excellence. This rapid global mobilization of the lung cancer community through the CLCC and the resulting Serological Center of Excellence is positioned to answer fundamental questions regarding the susceptibility of patients with lung cancer to SARS-CoV-2 infection and severe COVID-19 disease and provide information to allow assessment of the value of vaccination and the utility of specifically designed vaccine programs for this high-risk patient population.

Analysis of Lung Cancer Patients Receiving SARS-CoV-2 Vaccines Revealed a Minority Subset With Poor Antibody Responses Relative to Controls

Introduction: Patients with lung cancer (LC) were reported to have a high case fatality rate (30-40%) from SARS-CoV-2 infection, raising the question of whether LC patients mount a weaker antibody response to natural infection and/or vaccination, compared to healthy controls (HCs). We previously analyzed antibody responses to SARS-CoV-2 mRNA vaccination in several hundred healthy individuals, stratified by previous SARS-CoV-2 infection status. Using a validated enzyme-linked immunosorbent assay (ELISA) to the full-length spike protein (PMC8183627, PMC7235504), we found strong responses to infection and a robust neutralizing antibody response to vaccination. We compare these results to data from individuals diagnosed with LC undergoing different types of cancer treatment. Methods: This is an ongoing, prospective, control-matched longitudinal cohort study of 750 LC patients in all stages with or without previous SARS-CoV-2 infection and/or vaccination, comparing SARS-CoV-2 antibody titers at baseline (time of enrollment) and at 3-, 6-, 12- and 24-month intervals. We examine the quality, magnitude, and duration of the SARS-CoV-2 antibody titers against the full-length spike protein compared to the matched (age, tobacco history, sex and ethnicity) HC cohort. Types of Analysis and Data Reporting: ELISAs are performed in a CLIA-certified laboratory using an FDA-approved antibody assay along with other well-established, research-grade assays. We hypothesized that LC patients have a weaker antibody response to SARS-Cov-2 infection and/or vaccination due to cancer or its treatment compared to matched HCs. The non-parametric Kruskal–Wallis test was used to test this hypothesis. If confirmed, a tailored vaccination program would be necessary to ensure immune protection in patient with LC. Results: 111 LC patients have been enrolled to date;with 78 receiving at least one vaccination and 33 unvaccinated. Median age is 69, with 58% female. 39 patients were fully vaccinated (defined as 14+ days after second vaccination). Partially vaccinated (after 1st vaccine dose) LC patients had a lower median antibody level than partially vaccinated HCs (p=0.01). Fully vaccinated LC patients had substantial antibody titers but a lower median antibody level than fully vaccinated HCs (p=0.01) with a subset not raising large antibody titers. Especially important were the 30% of partially vaccinated LC patients who did not develop neutralizing antibodies. To date, there were no significant differences in median antibody levels in LC patients by gender, smoking status, age (< or > 65 years old), or treatment (with or without chemotherapy, immune checkpoint inhibitors, or targeted therapy). Conclusion: While most (∼70%+) of LC patients mounted a good antibody response to vaccination, a subgroup had significantly lower anti-spike antibody/neutralizing levels compared to controls. Further studies are required to evaluate the role of further boost vaccinations in this patient population with a particular focus on patients not producing neutralizing antibodies to further understand the lack of response. We will continue to analyze the effect of systemic anti-cancer therapies as more data becomes available. Keywords: SARS-CoV-2, lung cancer, covid-19

Association of clinical factors and recent anticancer therapy with COVID-19 severity among patients with cancer: a report from the COVID-19 and Cancer Consortium.

BACKGROUND: Patients with cancer may be at high risk of adverse outcomes from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We analyzed a cohort of patients with cancer and coronavirus 2019 (COVID-19) reported to the COVID-19 and Cancer Consortium (CCC19) to identify prognostic clinical factors, including laboratory measurements and anticancer therapies. PATIENTS AND METHODS: Patients with active or historical cancer and a laboratory-confirmed SARS-CoV-2 diagnosis recorded between 17 March and 18 November 2020 were included. The primary outcome was COVID-19 severity measured on an ordinal scale (uncomplicated, hospitalized, admitted to intensive care unit, mechanically ventilated, died within 30 days). Multivariable regression models included demographics, cancer status, anticancer therapy and timing, COVID-19-directed therapies, and laboratory measurements (among hospitalized patients). RESULTS: A total of 4966 patients were included (median age 66 years, 51% female, 50% non-Hispanic white); 2872 (58%) were hospitalized and 695 (14%) died; 61% had cancer that was present, diagnosed, or treated within the year prior to COVID-19 diagnosis. Older age, male sex, obesity, cardiovascular and pulmonary comorbidities, renal disease, diabetes mellitus, non-Hispanic black race, Hispanic ethnicity, worse Eastern Cooperative Oncology Group performance status, recent cytotoxic chemotherapy, and hematologic malignancy were associated with higher COVID-19 severity. Among hospitalized patients, low or high absolute lymphocyte count; high absolute neutrophil count; low platelet count; abnormal creatinine; troponin; lactate dehydrogenase; and C-reactive protein were associated with higher COVID-19 severity. Patients diagnosed early in the COVID-19 pandemic (January-April 2020) had worse outcomes than those diagnosed later. Specific anticancer therapies (e.g. R-CHOP, platinum combined with etoposide, and DNA methyltransferase inhibitors) were associated with high 30-day all-cause mortality. CONCLUSIONS: Clinical factors (e.g. older age, hematological malignancy, recent chemotherapy) and laboratory measurements were associated with poor outcomes among patients with cancer and COVID-19. Although further studies are needed, caution may be required in utilizing particular anticancer therapies. CLINICAL TRIAL IDENTIFIER: NCT04354701.

Thoracic cancers international COVID-19 collaboration (TERAVOLT): Small-cell lung cancer andother rare thoracic malignancies

Background: At the last update of the TERAVOLT registry, patients with thoracic malignancies and COVID-19showed a high mortality rate (35.5% overall and 31% due to COVID-19) compared to the general population and toother solid tumors. Major determinants of mortality were age, Eastern Cooperative Oncology Group PerformanceStatus (ECOG-PS), and previous administration of chemotherapy. No cancer-specific data are available with respectto small-cell lung cancer (SCLC) and other rare thoracic malignancies. Methods: TERAVOLT is an international, multicenter observational registry launched to collect data on patients withthoracic malignancies diagnosed with COVID-19 infection. Risk factors for hospitalization and mortality wereidentified by Wilcoxon rank sum tests (continuous variables) or χ2 tests (categorical variables). Here we present thesubgroup analyses of SCLC and other rare thoracic malignancies, including malignant pleural mesothelioma (MPM), thymic carcinoma/thymoma, and carcinoid/neuroendocrine lung tumors. Results: As of June 4th, 2020, a total of 581 patients with COVID-19 and thoracic cancers have been entered;among them, 66 (11%) were SCLC, 22 (4%) were MPM, 18 (3%) were thymic carcinoma/thymoma, 12 (2%) werecarcinoid/neuroendocrine lung tumors, and 442 (76%) NSCLC;21 were an unknown type. Among SCLC patients,54% were > 65 years old, 56% were males, 98% were current/former smokers, 31% had an ECOG-PS ≥ 2, 67%had stage IV disease, 82% were on current oncologic treatment at the COVID-19 diagnosis, and 58% werereceiving chemotherapy alone or in combination with immune checkpoint inhibitors. Among other non-NSCLCpatients, 56% were > 65 years old, 56% were males, 69% were current/former smokers, 24% had an ECOG-PS ≥ 2,50% had stage IV disease, 52% were on current oncologic treatment at the COVID-19 diagnosis, and 37% werereceiving chemotherapy alone or in combination with immune checkpoint inhibitors. Overall, 79.7% of the patientsrequired hospitalization, 15.4% were admitted to an ICU, and 39.8% died (36.2% due to COVID-19). Among SCLCpatients, 74.2% required hospitalization, 14.3% were admitted to an ICU, and 42.2% died (37.5% due to COVID-19).Among SCLC patients, age > 65 years old (p=0.81), gender (p=0.71), smoking status (p=1.0), ECOG-PS ≥2(p=0.17), disease stage of IV (p=0.37), and having received chemotherapy alone or with checkpoint inhibitors(p=0.84) were not associated with mortality. Conclusions: This analysis confirmed that patients with thoracic malignancies have a high mortality and risk forhospitalization due to COVID-19 overall. SCLC patients showed the highest mortality rate among thoracic cancerpatients.

Clinical impact of COVID-19 on patients with cancer: Data from the COVID-19 and Cancer Consortium (CCC19)

Background: There are limited data on COVID-19 in patients with cancer. We characterize the outcomes of patients with cancer and COVID-19 and identify potential prognostic factors. Methods: The COVID- 19 and Cancer Consortium (CCC19) cohort study includes patients with active or prior hematologic or invasive solid malignancies reported across academic and community sites. Results: We included 1,018 cases accrued March-April 2020. Median age was 66 years (range, 18-90). Breast (20%) and prostate (16%) cancers were most prevalent;43% of patients were on active anti-cancer treatment. At time of data analysis, 106 patients (10.4%) have died and 26% met the composite outcome of death, severe illness requiring hospitalization, and/or mechanical ventilation. In multivariable logistic regression analysis, independent factors associated with increased 30- day mortality were age, male sex, former smoking, ECOG performance status (2 versus 0/1: partially adjusted odds ratio (pAOR) 2.74, 95% CI 1.31-5.7;3/4 versus 0/1: pAOR 5.34, 95% CI 2.44-11.69), active malignancy (stable/responding, pAOR 1.93, 95% CI 1.06-3.5;progressing, pAOR 3.79, 95% CI 1.78-8.08), and receipt of azithromycin and hydroxychloroquine. Tumor type, race/ethnicity, obesity, number of comorbidities, recent surgery, and type of active cancer therapy were not significant factors for mortality. Conclusions: All-cause 30-day mortality and severe illness in this cohort were significantly higher than previously reported for the general population and were associated with general risk factors as well as those unique to patients with cancer. Cancer type and treatment were not independently associated with increased 30-day mortality. Longer follow-up is needed to better understand the impact of COVID-19 on outcomes in patients with cancer, including the ability to continue specific cancer treatments.