Functional antibody and T-cell immunity following SARS-CoV-2 infection, including by variants of concern, in patients with cancer: the CAPTURE study

Patients with cancer have higher COVID-19 morbidity and mortality. Here we present the prospective CAPTURE study (NCT03226886) integrating longitudinal immune profiling with clinical annotation. Of 357 patients with cancer, 118 were SARS-CoV-2-positive, 94 were symptomatic and 2 patients died of COVID-19. In this cohort, 83% patients had S1-reactive antibodies, 82% had neutralizing antibodies against WT, whereas neutralizing antibody titers (NAbT) against the Alpha, Beta, and Delta variants were substantially reduced. Whereas S1-reactive antibody levels decreased in 13% of patients, NAbT remained stable up to 329 days. Patients also had detectable SARS-CoV-2-specific T cells and CD4+ responses correlating with S1-reactive antibody levels, although patients with hematological malignancies had impaired immune responses that were disease and treatment-specific, but presented compensatory cellular responses, further supported by clinical. Overall, these findings advance the understanding of the nature and duration of immune response to SARS-CoV-2 in patients with cancer.


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Patients with cancer have an increased risk of severe outcomes from coronavirus disease 2019 123 , 1,2 with risk factors including general (e.g. increased age, male sex, obesity, co-124 morbidities) as well as cancer-specific features (e.g. haematological and thoracic malignancies, 125 active cancer, poor performance status). [3][4][5][6][7][8] The precise effects of anti-cancer treatments on the 126 course and outcome of SARS-CoV-2 infection are yet to be fully understood, with different reports 127 yielding conflicting results. 5,7,9,10 Understanding of the immune response to SARS-CoV-2 in this 128 heterogeneous population, spanning multiple malignancy types and numerous treatment regimens, 129 is crucial for optimal clinical management of those patients during the ongoing pandemic. 149 were male, 89% had solid malignancy, and the majority (64%) had advanced disease ( Table 1).

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A sensitive flow cytometric assay conducted on sera from a subset of patients with S1- Finally, we evaluated matched pre-pandemic sera from 47 patients, 10 with and 37 without 229 S1-reactive antibodies in their sample collected during the pandemic. We found no evidence of S1-230 reactive antibodies in the pre-pandemic sera in any patient (Extended Data Figure 2g), but S-231 reactive IgG or IgM were detected in 18 patients without S1-reactive antibodies indicating cross-232 reactivity to seasonal human coronaviruses.   (Figure 2d). In a binary logistic regression model including all cancer 242 patients (n=118), presence of haematological malignancy, but not comorbidities, age, sex, or COVID-243 19 severity was associated with lack of NAb (Figure 2e). In patients with solid tumours (n=97), there 244 was no association with cancer type, stage, progressive disease or cancer therapy (Figure 2f,g)

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There was a significant correlation between S1-reactive and NAbT for all variants (P < 0.01) 255 (Extended Data Figure 2h); but we note that presence of S1-reactive antibodies was not always 256 predictive of neutralising response, especially to VOCs. 257 258 SARS-CoV-2 antibody response lasts up to 11 months 259 Next, we assessed antibody kinetics in 81/97 patients with S1-reactive antibodies and known 260 timing of POD (n=70 solid tumours, n=11 haematological malignancy). We analysed a median of two 261 timepoints per patient (range: 1-10) at a median follow-up of 56 days after POD (range: 1-344).

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SsT-cell compensation in patients without humoral response 296 Patients with haematological malignancies had a wide range of antibodies (Figure 4a,b) and SsT-cell 297 responses. In patients with leukaemia, NAb were detected in 6/11 and SsT-cells in 5/10 evaluable 298 patients (two had both CD4+ and CD8+, two had CD4+ only, and one had CD8+ only). In patients 299 with myeloma, 2/4 had NAb, and 3/4 had detectable SsT-cells (two both CD4+ and CD8+, one CD4+ 300 only). None of the six lymphoma patients, including five who were treated with anti-CD20, had 301 detectable NAbs, while SsT-cells were detected in 5/6 (three had both CD4+ and CD8+, one had 302 CD4+ only, and one had CD8+ only). One further patient with AML treated with anti-CD20 had 303 neither NAb nor SsT-cell responses. In total, we observed a discordance between antibody and T-cell 304 responses amongst patients with haematological malignancy, whereby 7/9 patients with NAbT to 305 WT SARS-CoV-2 lacked SsT-cell response (CD4+ and/or CD8+), and in 12 patients without NAb 306 activity 7 had SsT-cell response. (Figure 4c

Plasma and PBMC isolation
Whole blood was collected in EDTA tubes (VWR) and stored at 4ºC until processing. All samples were 557 processed within 24 hours. Time of blood draw, processing, and freezing was recorded for each 558 sample. Prior to processing tubes were brought to room temperature (RT). PBMC and plasma were 559 isolated by density-gradient centrifugation using pre-filled centrifugation tubes (pluriSelect). Up to 560 30 ml of undiluted blood was added on top of the sponge and centrifuged for 30 minutes at 1000g at 561 RT. Plasma was carefully removed then centrifuged for 10 minutes at 4000g to remove debris,

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