Humoral and cellular immune responses against SARS-CoV-2 after third dose BNT162b2 following double-dose vaccination with BNT162b2 versus ChAdOx1 in cancer patients.

PURPOSE: Cancer patients display reduced humoral responses after double-dose COVID-19 vaccination while their cellular response is more comparable to that in healthy individuals. Recent studies demonstrated that a third vaccination dose boosts these immune responses, both in healthy people and cancer patients. Due to the availability of many different COVID-19 vaccines, many people have been boosted with a different vaccine from the one used for double-dose vaccination. Data on such alternative vaccination schedules are scarce. This prospective study compares a third dose of BNT162b2 after double-dose BNT162b2 (homologous) versus ChAdOx1 (heterologous) vaccination in cancer patients. EXPERIMENTAL DESIGN: 442 subjects (315 patients and 127 healthy) received a third dose of BNT162b2 (230 homologous vs 212 heterologous). Vaccine-induced adverse events (AE) were captured up to 7 days after vaccination. Humoral immunity was assessed by SARS-CoV-2 anti-S1 IgG antibody levels and SARSCoV-2 50% neutralization titers (NT50) against Wuhan and BA.1 Omicron strains. Cellular immunity was examined by analyzing CD4+ and CD8+ T cell responses against SARS-CoV-2 specific S1 and S2 peptides. RESULTS: Local AEs were more common after heterologous boosting. SARS-CoV-2 anti-S1 IgG antibody levels did not differ significantly between homologous and heterologous boosted subjects (GMT 1755.90 BAU/mL [95% CI 1276.95-2414.48] vs 1495.82 BAU/mL (95% CI 1131.48-1977.46)). However, homologous boosted subjects show significantly higher NT50 values against BA.1 Omicron. Subjects receiving heterologous boosting demonstrated increased spike-specific CD8+ T cells, including higher IFNγ and TNFα levels. CONCLUSIONS: In cancer patients who received double-dose ChAdOx1, a third heterologous dose of BNT162b2 was able to close the gap in antibody response.

Predictive model for BNT162b2 vaccine response in cancer patients based on blood cytokines and growth factors.

Background: Patients with cancer, especially hematological cancer, are at increased risk for breakthrough COVID-19 infection. So far, a predictive biomarker that can assess compromised vaccine-induced anti-SARS-CoV-2 immunity in cancer patients has not been proposed. Methods: We employed machine learning approaches to identify a biomarker signature based on blood cytokines, chemokines, and immune- and non-immune-related growth factors linked to vaccine immunogenicity in 199 cancer patients receiving the BNT162b2 vaccine. Results: C-reactive protein (general marker of inflammation), interleukin (IL)-15 (a pro-inflammatory cytokine), IL-18 (interferon-gamma inducing factor), and placental growth factor (an angiogenic cytokine) correctly classified patients with a diminished vaccine response assessed at day 49 with >80% accuracy. Amongst these, CRP showed the highest predictive value for poor response to vaccine administration. Importantly, this unique signature of vaccine response was present at different studied timepoints both before and after vaccination and was not majorly affected by different anti-cancer treatments. Conclusion: We propose a blood-based signature of cytokines and growth factors that can be employed in identifying cancer patients at persistent high risk of COVID-19 despite vaccination with BNT162b2. Our data also suggest that such a signature may reflect the inherent immunological constitution of some cancer patients who are refractive to immunotherapy.

Expression of SARS-CoV-2-Related Surface Proteins in Non-Small-Cell Lung Cancer Patients and the Influence of Standard of Care Therapy.

In this study, we aimed to study the expression of SARS-CoV-2-related surface proteins in non-small-cell lung cancer (NSCLC) cells and identify clinicopathological characteristics that are related to increased membranous (m)ACE2 protein expression and soluble (s)ACE2 levels, with a particular focus on standard of care (SOC) therapies. ACE2 (n = 107), TMPRSS2, and FURIN (n = 38) protein expression was determined by immunohistochemical (IHC) analysis in NSCLC patients. sACE2 levels (n = 64) were determined in the serum of lung cancer patients collected before, during, or after treatment with SOC therapies. Finally, the TCGA lung adenocarcinoma (LUAD) database was consulted to study the expression of ACE2 in EGFR- and KRAS-mutant samples and ACE2 expression was correlated with EGFR/HER, RAS, BRAF, ROS1, ALK, and MET mRNA expression. Membranous (m)ACE2 was found to be co-expressed with mFURIN and/or mTMPRSS2 in 16% of the NSCLC samples and limited to the adenocarcinoma subtype. TMPRSS2 showed predominantly atypical cytoplasmic expression. mACE2 and sACE2 were more frequently expressed in mutant EGFR patients, but not mutant-KRAS patients. A significant difference was observed in sACE2 for patients treated with targeted therapies, but not for chemo- and immunotherapy. In the TCGA LUAD cohort, ACE2 expression was significantly higher in EGFR-mutant patients and significantly lower in KRAS-mutant patients. Finally, ACE2 expression was positively correlated with ERBB2-4 and ROS1 expression and inversely correlated with KRAS, NRAS, HRAS, and MET mRNA expression. We identified a role for EGFR pathway activation in the expression of mACE2 in NSCLC cells, associated with increased sACE2 levels in patients. Therefore, it is of great interest to study SARS-CoV-2-infected EGFR-mutated NSCLC patients in greater depth in order to obtain a better understanding of how mACE2, sACE2, and SOC TKIs can affect the course of COVID-19.

Blood Cytokine Analysis Suggests That SARS-CoV-2 Infection Results in a Sustained Tumour Promoting Environment in Cancer Patients.

Cytokines, chemokines, and (angiogenic) growth factors (CCGs) have been shown to play an intricate role in the progression of both solid and haematological malignancies. Recent studies have shown that SARS-CoV-2 infection leads to a worse outcome in cancer patients, especially in haematological malignancy patients. Here, we investigated how SARS-CoV-2 infection impacts the already altered CCG levels in solid or haematological malignancies, specifically, whether there is a protective effect or rather a potentially higher risk for major COVID-19 complications in cancer patients due to elevated CCGs linked to cancer progression. Serially analysing immune responses with 55 CCGs in cancer patients under active treatment with or without SARS-CoV-2 infection, we first showed that cancer patients without SARS-CoV-2 infection (n = 54) demonstrate elevated levels of 35 CCGs compared to the non-cancer, non-infected control group of health care workers (n = 42). Of the 35 CCGs, 19 were common to both the solid and haematological malignancy groups and comprised previously described cytokines such as IL-6, TNF-α, IL-1Ra, IL-17A, and VEGF, but also several less well described cytokines/chemokines such as Fractalkine, Tie-2, and T cell chemokine CTACK. Importantly, we show here that 7 CCGs are significantly altered in SARS-CoV-2 exposed cancer patients (n = 52). Of these, TNF-α, IFN-ß, TSLP, and sVCAM-1, identified to be elevated in haematological cancers, are also known tumour-promoting factors. Longitudinal analysis conducted over 3 months showed persistence of several tumour-promoting CCGs in SARS-CoV-2 exposed cancer patients. These data demonstrate a need for increased vigilance for haematological malignancy patients as a part of long COVID follow-up.

Meeting the Challenges in Cancer Care Management During the SARS-Cov-2 Pandemic: A Retrospective Analysis.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has overwhelmed the capacity of healthcare systems worldwide. Cancer patients, in particular, are vulnerable and oncology departments drastically needed to modify their care systems and established new priorities. We evaluated the impact of SARS-CoV-2 on the activity of a single cancer center. METHODS: We performed a retrospective analysis of (i) volumes of oncological activities (2020 vs 2019), (ii) patients' perception rate of the preventive measures, (iii) patients' SARS-CoV-2 infections, clinical signs thereof, and (iv) new diagnoses made during the SARS-CoV-2 pandemic. RESULTS: As compared with a similar time frame in 2019, the overall activity in total numbers of outpatient chemotherapy administrations and specialist visits was not statistically different (P = .961 and P = .252), while inpatient admissions decreased for both medical oncology and thoracic oncology (18% (P = .0018) and 44% (P < .0001), respectively). Cancer diagnosis plummeted (-34%), but no stage shift could be demonstrated.Acceptance and adoption of hygienic measures was high, as measured by a targeted questionnaire (>85%). However, only 46.2% of responding patients regarded telemedicine, although widely deployed, as an efficient surrogate to a consultation.Thirty-three patients developed SARS-CoV-2, 27 were hospitalized, and 11 died within this time frame. These infected patients were younger, current smokers, and suffered more comorbidities. CONCLUSIONS: This retrospective cohort analysis adds to the evidence that continuation of active cancer therapy and specialist visits is feasible and safe with the implementation of telemedicine. These data further confirm the impact of SARS-CoV-2 on cancer care management, cancer diagnosis, and impact of infection on cancer patients.

Immunoglobin G/total antibody testing for SARS-CoV-2: A prospective cohort study of ambulatory patients and health care workers in two Belgian oncology units comparing three commercial tests.

BACKGROUND: Coronavirus disease (COVID-19) is interfering heavily with the screening, diagnosis and treatment of cancer patients. Better knowledge of the seroprevalence and immune response after Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection in this population is important to manage them safely during the pandemic. METHODS: 922 cancer patients, 100 non-cancer patients and 94 health care workers (HCW) attending the Multidisciplinary Oncology Unit of Antwerp University Hospital from 24th of March 2020 till 31st of May 2020, and the Oncology Unit of AZ Maria Middelares Hospital, Ghent, from 13th of April 2020 till 31st of May 2020 participated in the study. The Alinity® (A; Abbott) and Liaison® (D; DiaSorin) commercially available assays were used to measure SARS-CoV-2 IgG, while total SARS-CoV-2 Ig was measured by Elecsys® (R; Roche). RESULTS: In the overall study population IgG/total SARS-CoV-2 antibodies were found in respectively 32/998 (3.2%), 68/1020 (6.7%), 37/1010 (3.7%) and of individuals using the A, D or R test. Forty-six out of 618 (7.4%) persons had a positive SARS-CoV-2 polymerase chain reaction (RT-PCR) test. Seroprevalence in cancer patients (A:2.2%, D:6.2%, R:3.0%), did not significantly differ from that in non-cancer patients (A:1.1%, D:5.6%, R:0.0%), but was lower than the HCW (A:13%, D:12%, R:12%; respectively Fisher's exact test p = 0.00001, p = 0.046, p = 0.0004). A positive SARS-CoV-2 RT-PCR was found in 6.8% of the cancer patients, 2.3% of the non-cancer patients and 28.1% of the HCW (Fisher's exact test p = 0.0004). Correlation between absolute values of the different Ig tests was poor in the cancer population. Dichotomising a positive versus negative test result, the A and R test correlated well (kappa 0.82 p McNemar test = 0.344), while A and D and R and D did not (respectively kappa 0.49 and 0.57; result significantly different p McNemar test = <0.0001 for both). The rate of seroconversion (>75%) and median absolute antibody levels (A: 7.0 versus 4.7; D 74.0 versus 26.6, R: 16.34 versus 7.32; all >P Mann Whitney U test = 0.28) in cancer patients and HCW with a positive RT-PCR at least 7 days earlier did not show any differences. However, none (N = 0/4) of the patients with hematological tumours had seroconversion and absolute antibody levels remained much lower compared to patients with solid tumours (R: 0.1 versus 37.6, p 0.003; D 4.1 versus 158, p 0.008) or HCW (all p < 0.0001). CONCLUSION: HCW were at high risk of being infected by SARS-CoV-2 during the first wave of the pandemic. Seroprevalence in cancer patients was low in the study period. Although Ig immune response in cancer patients with solid tumours does not differ from healthy volunteers, patients with hematological tumours have a very poor humoral immune response. This has to be taken into account in future vaccination programmes in this population. SARS-CoV-2 antibody tests have divergent results and seem to have little added value in the management of cancer patients.

The tele-transition of toxicity management in routine oncology care during the severe acute respiratory syndrome (SARS-CoV-2) pandemic.

BACKGROUND: Telehealth modalities were introduced during the SARS-CoV-2 pandemic to assure continuation of cancer care and maintain social distance. METHODS: This is a retrospective cohort analysis of our telehealth expansion programme. We adapted two existing patient-reported outcome (PRO) telemonitoring tools that register and (self-)manage toxicities to therapy, while screening for SARS-CoV-2-related symptoms. Outpatients from a tertiary cancer centre were enrolled. The adapted PRO interface allowed for uniform registration of SARS-CoV-2-related symptoms and effective triage of patients at home where we also implemented systematic throat washings, when available. RESULTS: Three hundred and sixty patients registered to the telemonitoring systems from March 13 to May 15, 2020. Four prespecified SARS-CoV-2 alarms resulted in three patients with positive PCR testing. Other Covid-19 symptoms (fever 5× and cough 2×) led to pretreatment triage resulting in 1 seroconversion after initial negative testing. One of the 477 throat washings proved positive. CONCLUSIONS: The rapid adoption of an amended PRO (self-)registrations and toxicity management system was feasible and coordinated screening for Covid-19. Continued clinical cancer care was maintained, with significant decreased waiting time. The systemic screening with throat washings offered no real improvement.

Expected Medium- and Long-Term Impact of the COVID-19 Outbreak in Oncology.

PURPOSE: The COVID-19 pandemic has affected healthcare systems globally, leading to reorganization of medical activities. We performed an international survey aimed to investigate the medium- and long-term impact on oncology units. MATERIALS AND METHODS: An 82-item survey was distributed from June 17 to July 14, 2020 among medical oncologists worldwide. RESULTS: One hundred nine medical oncologists from 18 countries in Europe (n = 93), United States (n = 5), and Latin America (n = 11) answered the survey. A systematic tracing of COVID-19-positive patients was continued in the postacute phase by 77.1% of the centers; 64.2% of the respondents participated in a local registry and 56% in international or national registries of infected patients. Treatment adaptations were introduced, and surgery was the most affected modality being delayed or canceled in more than 10% of patients in 34% of the centers, whereas early cessation of palliative treatment was reported in 32.1% of the centers; 64.2% of respondents reported paying attention to avoid undertreatments. The use of telemedicine has been largely increased. Similarly, virtual tools are increasingly used particularly for medical education and international or national or multidisciplinary meetings. 60.6% of the participants reduced clinical activity, and 28.4% compensated by increasing their research activity. Significant reduction of clinical trial activities is expected in 37% of centers this year. The well-being of healthcare staff would not recover by the end of the year according to 18% of the participants. CONCLUSION: The COVID-19 outbreak has had a major impact on oncologic activity, which will persist in the future, irrespective of geographical areas.

Oncological care organisation during COVID-19 outbreak.

BACKGROUND: COVID-19 appeared in late 2019, causing a pandemic spread. This led to a reorganisation of oncology care in order to reduce the risk of spreading infection between patients and healthcare staff. Here we analysed measures taken in major oncological units in Europe and the USA. METHODS: A 46-item survey was sent by email to representatives of 30 oncological centres in 12 of the most affected countries. The survey inquired about preventive measures established to reduce virus spread, patient education and processes employed for risk reduction in each oncological unit. RESULTS: Investigators from 21 centres in 10 countries answered the survey between 10 April and 6 May 2020. A triage for patients with cancer before hospital or clinic visits was conducted by 90.5% of centres before consultations, 95.2% before day care admissions and in 100% of the cases before overnight hospitalisation by means of phone calls, interactive online platforms, swab test and/or chest CT scan. Permission for caregivers to attend clinic visits was limited in many centres, with some exceptions (ie, for non-autonomous patients, in the case of a new diagnosis, when bad news was expected and for terminally ill patients). With a variable delay period, the use of personal protective equipment was unanimously mandatory, and in many centres, only targeted clinical and instrumental examinations were performed. Telemedicine was implemented in 76.2% of the centres. Separated pathways for COVID-19-positive and COVID-19-negative patients were organised, with separate inpatient units and day care areas. Self-isolation was required for COVID-19-positive or symptomatic staff, while return to work policies required a negative swab test in 76.2% of the centres. CONCLUSION: Many pragmatic measures have been quickly implemented to deal with the health emergency linked to COVID-19, although the relative efficacy of each intervention should be further analysed in large observational studies.

SARS-CoV-2 and cancer: Are they really partners in crime?

The outbreak of the SARS-CoV-2 pandemic has overwhelmed health care systems in many countries. The clinical presentation of the SARS-CoV-2 varies between a subclinical or flu-like syndrome to that of severe pneumonia with multi-organ failure and death. Initial reports have suggested that cancer patients may have a higher susceptibility to get infected by the SARS-CoV-2 virus but current evidence remains poor as it is biased by important confounders. Patients with ongoing or recent cancer treatment for advanced active disease, metastatic solid tumors and hematological malignancies are at higher risk of developing severe COVID-19 respiratory disease that requires hospitalization and have a poorer disease outcome compared to individuals without cancer. However it is not clear whether these are independent risk factors, or mainly driven by male gender, age, obesity, performance status, uncontrolled diabetes, cardiovascular disease and various other medical conditions. These often have a greater influence on the probability to die due to SARS-CoV-2 then cancer. Delayed diagnosis and suboptimal cancer management due to the pandemic results in disease upstaging and has considerable impact cancer on specific death rates. Surgery during the peak of the pandemic seems to increase mortality, but there is no convincing evidence that adjuvant systemic cancer therapy and radiotherapy are contraindicated, implicating that cancer treatment can be provided safely after individual risk/benefit assessment and some adaptive measures. Underlying immunosuppression, elevated cytokine levels, altered expression of the angiotensin converting enzyme (ACE-2) and TMPRSS2, and a prothrombotic status may fuel the effects of a SARS-CoV-2 in some cancer patients, but have the potential to be used as biomarkers for severe disease and therapeutic targets. The rapidly expanding literature on COVID-19 should be interpreted with care as it is often hampered by methodological and statistical flaws.