Background

Pandemic COVID-19 by SARS-CoV-2 infection is facilitated by the ACE2 receptor and protease TMPRSS2. Patients with cancer may be at particularly high risk for SARS-CoV-2 infection and deleterious outcomes to the disease. A better understanding of potential host risk factors, notably ACE2 and TMPRSS2, in malignant tissues may inform considerations surrounding SARS-CoV-2 and COVID-19 in patients with cancer and more broadly in the general population.

Methods

We performed a large-scale integrated study of ACE2 and TMPRSS2 gene expression in 10,038 patients with cancer across and within organ systems, by normal versus tumor. We investigated its correlative pattern with clinical factors (age, gender, race, BMI and smoking history, etc.), HLA, immune signatures, and commensal microbiome.

Results

Matched normal tissues generally display higher ACE2 and TMPRSS2 expression compared with tumor, with digestive organs expressing the highest levels. No consistent association was observed between clinical groups or HLA genotypes and ACE2/TMPRSS2 levels, after adjusting for tissue-specific expression. ACE2 expression showed a significant correlation with clinically relevant immune signatures including interferon-stimulated genes and the T cell-inflamed phenotype, and with macrophage cell subsets. Single-cell RNAseq analysis demonstrated little to no ACE2 or TMPRSS2 expression in lymphocytes or macrophages. ACE2 and TMPRSS2 showed a distinctive correlative pattern with 75 bacterial taxa in normal tissues particularly from colorectal cancers (gram-negative to positive ratio = 2.6:1). LASSO regression models integrating multi-dimensional correlates revealed immune and microbiota are among the top-ranked features predicting ACE2 expression, while epithelial cell abundance is the dominant predictor for TMPRSS2.

Conclusions

We investigated ACE2 and TMPRSS2 expression across clinical, genetic, immune, and microbiome domains. We identify novel associations with the microbiota and confirm host immunity associations with gene expression. We hope these data may better inform clinical considerations surrounding risk stratification and prevention approaches.

Legal entity responsible for the study

The authors.

Funding

Search Results Web results U.S. Department of Defense.

Disclosure

All authors have declared no conflicts of interest.

Background

Clinical data suggest an aggravated COVID-19 disease course in cancer patients treated with immune checkpoint inhibitors (ICI). European guidelines advise to defer ICI therapy until complete resolution of COVID-19. However, mechanistic insight into how ICI impacts COVID-19 immunopathology is absent.

Methods

We performed single-cell RNA- and T-Cell Receptor-sequencing (TCR-seq) on bronchoalveolar lavage fluid of COVID-19 pneumonia (n=19) and non-COVID pneumonia (n=10), and co-analyzed CD8+ T-cells with publicly available tumor-infiltrating T-cell data of treatment-naïve and ICI-treated patients (Sade-Feldman, Cell, 2018; Lambrechts, Nat Med, 2018). Cell lineages were determined by trajectory inference (Slingshot, Monocle v2) and stratified per condition. Pathogen- or tumor-directed T-cells were defined based on clonal selection (Zhang, Nature, 2018). To identify ICI responsive cells, we calculated a score derived from a validated gene set denoting ICI reactivity (Okamura, J. Autoimmun, 2019).

Results

We identified 3 CD8+ T-cell lineages, with ‘Naïve’ T-cells transitioning into ‘Effector Memory’ cells and then branching into either ‘Recently Activated Effector Memory (T_EMRA)’, ‘Exhausted (T_EX)’ or ‘Resident Memory (T_RM)’ T-cells. In COVID-19, clonal expansion indicating a SARS-CoV-2 antigen-specific T-cell response, was mainly observed in the highly cytotoxic ‘T_EMRA’ lineage. In contrast, tumor-specific T-cells were found in the ‘T_EX’ lineage. Of importance, the ICI responsiveness score was significantly higher in the non-pathogen-directed ‘T_RM’ and ‘T_EX’ cells in COVID-19. In cancer, ‘T_EX’ cells were shown to be ICI responsive as expected. Table: LBA81

Demographics and characteristics of study cohort

Conclusions

We are the first to provide a mechanistic rationale for an aggravated COVID-19 disease course in ICI-treated patients. Whereas ICI reactivates tumor-directed ‘exhausted’ T-cells in cancer, it preferentially potentiates non-pathogen-directed T-cells in COVID-19, thereby contributing to lung damage without boosting the antiviral immune response.

Clinical trial identification

In-depth Immunological Investigation of COVID-19 (COntAGIouS). - Clinical Trial identifier: NCT04327570. - Ethical approval obtained by the Ethics Committee of University Hospitals - KU Leuven. File number S63881.

Legal entity responsible for the study

University Hospitals - KU Leuven.

Funding

Kom op tegen Kanker (Stand up to Cancer).

Disclosure

All authors have declared no conflicts of interest.

Background

The susceptibility of advanced cancer patients treated with immune checkpoint inhibitors (ICI) for viral infections has not been investigated. Currently, there are no robust data supporting the efficacy, safety and recommendation for influenza vaccination in cancer patients receiving ICI.

Methods

The prospective, multicenter, observational INVIDIa-2 study investigated the clinical efficacy of influenza vaccination in advanced cancer patients with solid tumors receiving ICI between October 2019 and January 2020. The incidence of influenza-like illness (ILI, primary endpoint) was observed until April 30, 2020. Secondary endpoints included a non-prespecified analysis for COVID-19.

Results

The study enrolled 1279 patients; 1188 were evaluable. Of them, 11 patients developed ILI symptoms with confirmed diagnosis of COVID-19 (incidence of 0.9% and lethality of 72%, irrespective of the flu vaccination). Of the remaining 1177 patients, 574 received flu vaccination (48.8%). The ILI incidence was 7.7% (91 patients of 1177). Patients receiving the flu vaccine were significantly more frequently elderly (p<0.0001), former or active smokers (p<0.0001), affected by lung cancer (p=0.017) and by non-cancer comorbidities (p<0.0001) when compared to unvaccinated patients. The flu vaccine did not prevent ILI in the study population, irrespective of the vaccine type (quadrivalent vs trivalent, adjuvated vs non): the incidence of ILI was 8.2% in vaccinated vs 7.3% in unvaccinated patients (p=0.57). ILI complications were significantly less frequent for patients receiving flu vaccine (12.8% vs 40.9%, p=0.002). Hospital admission due to ILI occurred for 10 patients (11% of ILI cases; 7 were unvaccinated). The ILI lethality was 2.2% (2 of 91 patients, both unvaccinated). Among vaccinated patients, those receiving adjuvated vaccines had lower incidence of ILI (4.8% vs 9.9%, p=0.046).

Conclusions

Flu vaccination was not effective for ILI prevention, nor for COVID-19. Nevertheless, it reduced ILI complications, with no ILI-related deaths in vaccinated patients. We recommend the vaccine in ICI-treated cancer patients.

Clinical trial identification

Eudract number of the trial: 2020-002603-18.

Legal entity responsible for the study

FICOG Federation of Italian Cooperative Oncology Groups.

Funding

FICOG (Federation of Italian Cooperative Oncology Groups, promoter and main sponsor), in turn funded by Seqirus UK and Roche S.p.A. for the present study.

Disclosure

M. Bersanelli: Research grant/Funding (self), Research grant/Funding (institution), for the present study: Seqirus and Roche; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses, for other activities outside the present study: Pfizer, BMS, Novartis. S. Buti: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Bristol-Myers Squibb (BMS), Pfizer; MSD, Ipsen, Roche, Eli-Lilly, AstraZeneca and Novartis. U. De Giorgi: Research grant/Funding (institution): AstraZeneca, Roche, Sanofi; Honoraria (self): Astellas, Bayer, BMS, Ipsen, Janssen, Merck, Pfizer, Sanofi. P. Bonomo: Honoraria (self): Merck Serono, Angelini Pharma,. All other authors have declared no conflicts of interest.

Background

The coronavirus disease (COVID-19) pandemic has caused 180,000 confirmed cases in France with more than 28, 000 deaths as of May 19. A large part of COVID-19 patients seem asymptomatic and cancer patients may be more vulnerable. We evaluated a screening strategy combining chest computed tomography (CT) and PCR for patients treated with radiotherapy (RT).

Methods

A screening strategy was organized from March 18, in our RT department. An inspiratory breath hold chest acquisition was proposed during the CT simulation for RT. Images was reviewed by a radiologist according to the CO-RADS classification. A nasal swab with a polymerase chain reaction (PCR) assay was proposed by the radiation oncologist in case of evocative imaging or clinical context. For patients who were already undergoing RT at this time, a PCR was proposed in case of evocative symptoms and before concomitant chemotherapy.

Results

From March 18 to May 1, 2020, 507 CT simulation were performed for 449 patients, including 445 chest acquisition. 237 of the chest CT (53%) showed lung abnormalities, of which 34 (8%) were COVID-19 compatible (CO-RADS ≥ 3). 102 patients were tested by PCR after the chest CT. 24 of the 449 (5.3%) patients were considered as COVID-19 patients: 19 had positive PCR, and five were considered positive on the basis of imaging despite PCR-negative PCR. Four of the patients (17%) were diagnosed during RT: 3 on routine screening before chemoradiotherapy, and one on symptoms. Four patients needed several PCR for the diagnosis of COVID-19 with six confirmed false negative PCR (Sensitivity (Se)= 76 % (19/25)). Three PCR positive patients had no evocative lung images (Se = 84%). During this period, an additional 169 patients whose CT simulation was prior to March 18, were also undergoing RT. Among them, six patients (3.6%) were diagnosed with COVID-19 by PCR during RT, performed for symptoms in 4 cases and on screening for the other 2. Of the 30 COVID-19 patients, only 8 (27%) had symptoms at the time of diagnosis. Twelve patients (40%) reported no symptoms and benefited from screening.

Conclusions

This study confirms the high proportion of asymptomatic patients with COVID-19 and suggests the value of screening by CT and PCR during COVID-19 pandemics.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

R. Sun: Travel/Accommodation/Expenses: AstraZeneca. E. Deutsch: Advisory/Consultancy: Roche, BMS, Boehringer, Astrazeneca, Lilly Amgen and Merck-Serono. All other authors have declared no conflicts of interest.

Background

The European SARS-CoV-2 pandemic had its first epicentre in Italy, particularly in the area of Bergamo. In spite of a significant mortality rate, in the majority of cases the spectrum of COVID-19 ranges from asymptomatic to mildly symptomatic infection. No information is available on the prevalence and clinical impact of asymptomatic or mildly symptomatic SARS-CoV-2 infection among actively treated cancer patients during pandemic.

Methods

From April 1^st, 2020 to the end of the month, 560 consecutive and unselected patients, scheduled for anticancer treatment at our facility and without clinical suspicious of COVID-19, were evaluated and tested for SARS-CoV-2. We implemented a two-step diagnostics, including a rapid serological immunoassay for anti-SARS-CoV-2 IgG/IgM and a pharyngeal swab RT-PCR assay in case of IgM seropositivity.

Results

In 560 patients, 172 (31%) resulted positive for SARS-CoV-2 IgM/IgG antibodies, regardless of type of cancer, stage and treatment. All IgM-seropositives were then tested with RT-PCR pharyngeal swabs and 55/146 (38%) proved to be SARS-CoV-2 carriers, with slightly difference b/w mildly symptomatic vs. asymptomatic patients (38 vs. 17). Therefore, the two-step procedure allowed the identification of 55 (10%) silent carriers in the whole study population and magnified the number needed to test (NNT) with the pharyngeal swab RT-PCR assay to detect a silent virus carrier (NNT: 2.6 vs. 10, with or without serological selection). At a very early follow up (8 wks), in 114 SARS-CoV-2-seropostive/RT-PCR-negative patients, who continued their anticancer therapies, none but one developed a symptomatic COVID-19 illness.

Conclusions

Among cancer patients, the two-step diagnostics strategy with serology followed by pharyngeal swab for asymptomatic or mildly symptomatic SARS-CoV-2 infection is feasible and effective and can help selecting cancer patients on treatment who might be silent carriers of the virus. The early safety outcome of patients previously exposed to SARS-CoV-2 supports the recommendation to continue active treatment, at least in the case of negative RT-PCR test.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

The high prevalence and associated healthcare, social and economic challenges of the 2019 novel coronavirus disease (COVID-19) suggests this pandemic is likely to have a major impact on cancer management, and has been shown to potentially have worse outcomes in this cohort of vulnerable patients. This study aims to compare the outcomes of RT-PCR confirmed COVID-19 positive disease in patients with or without a history of cancer.

Methods

We retrospectively collected clinical, pathological and radiological characteristics and outcomes of COVID-19 RT-PCR positive cancer patients treated consecutively in 5 different North London hospitals (cohort A) and compared their outcomes to consecutively admitted COVID-19 positive patients without a history of cancer (cohort B). Patients were matched for age, gender and comorbidty and treated during the same time period (1st March- 30th April 2020).

Results

The median age in both cohorts was 74 years, with 67% male, and comprised of 30 patients with cancer, and 90 without (1:3 ratio). For cohort B, 579 patients without a history of cancer and consecutively admitted were screened from the primary London hospital, 105 were COVID-19 positive and 90 were matched and included. Excluding cancer, both cohorts had a median of 2 comorbidities. The odds ratio (OR) for mortality, comparing patients with cancer to those without, was 1.05 (95% CI 0.4-2.5), and severe outcome (OR 0.89, 95% CI 0.4-2.0) suggesting no increased risk of death or a severe outcome in patients with cancer. Cancer patients who received systemic treatment within 28 days had an OR for mortality of 4.05 (95% CI 0.68-23.95), p=0.12. On presentation anaemia, hypokalaemia, hypoalbuminaemia and hypoproteinaemia were identified predominantly in cohort A. Median duration of admission was 8 days for cancer patients and 7 days for non-cancer.

Conclusions

Old age, late stage of cancer diagnosis and multiple co-morbidities adversely influence the outcome of patients with COVID-19 positive patients. These data do not demonstrate a higher risk to cancer patients compared to their non-cancer counterparts. If a second peak of pandemic strikes, a coordinated response of all overlapping specialities in the fight against cancer is required.

Legal entity responsible for the study

Research and Ethics Committee North Middlesex University Hospital.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Individuals with cancer, particularly those who are receiving systemic anti-cancer treatments, have been postulated to be at increased risk of mortality from SARS-CoV-2 related coronavirus disease (COVID-19). This conjecture has considerable impact on the treatment of cancer patients and large, multi-centre data to support this assumption is lacking due to the contingencies of the pandemic.

Methods

The cancer community of the United Kingdom (UK) has launched the UK Coronavirus Cancer Monitoring Project (UKCCMP). The UKCCMP is the first COVID-19 clinical registry that enables near real-time reports to frontline doctors about the effect of COVID-19 on cancer patients.

Results

An analysis of the first 800 cancer patients with symptomatic COVID-19 disease entered into the UKCCMP registry has been performed. Approximately half of these patients have a mild COVID-19 disease course (52%). Mortality was observed in 226 patients (28%) and risk of death was significantly associated with advancing patient age, sex (M>F) and the presence of other co-morbidities. Approximately one third had received cytotoxic chemotherapy within 4 weeks prior to testing positive for COVID-19. After adjusting for age, sex and comorbidities, recent receipt of chemotherapy had no significant effect on mortality from COVID-19 disease, when compared to cancer patients who had not received recent chemotherapy. No significant effect on mortality was also observed for patients with recent immunotherapy, hormonal therapy, targeted therapy or radiotherapy use.

Conclusions

Mortality from COVID-19 in cancer patients appears to be principally driven by age, sex and co-morbidities. We are not able to identify evidence that cancer patients on cytotoxic chemotherapy or other anti-cancer treatment are at significantly increased risk of mortality from COVID-19 disease compared to those not on active treatment.

Legal entity responsible for the study

Gary Middleton.

Funding

University of Birmingham.

Disclosure

All authors have declared no conflicts of interest.