BRIEF RESEARCH REPORT published: 05 July 2022 doi: 10.3389/fimmu.2022.908108 Brief Research Report: Anti-SARS- CoV-2 Immunity in Long Lasting Responders to Cancer Immunotherapy Through mRNA- Based COVID-19 Vaccination Edited by: Samir Kumar-Singh, Marta Sisteré-Oró 1, Diana D. J. Wortmann 1, Naı́na Andrade 1, Andres Aguilar 2, University of Antwerp, Belgium Clara Mayo de las Casas 2,3, Florencia Garcia Casabal 2, Susana Torres 2, Eduardo Bona Salinas 2, Laura Raventos Soler 2, Andrea Arcas 2, Carlos Esparre 2, Reviewed by: Beatriz Garcia 2,3, Joselyn Valarezo 2,3, Rafael Rosell 2,3,4, Roberto Güerri-Fernandez 5, Avik Mandal, All India Institute of Medical Sciences Maria Gonzalez-Cao 2* and Andreas Meyerhans 1,6* Raipur, India 1Infection Biology Laboratory, Department of Medicine and Life Sciences, Universitat Pompeu Fabra (UPF), Barcelona, Sentiljana Gumeni, Spain, 2 Instituto Oncologico Dr Rosell, Hospital Quiron-Dexeus Barcelona, Barcelona, Spain, 3 Laboratorio Oncología, National and Kapodistrian University of Hospital Universitario Dexeus, Pangaea Oncology Lab, Barcelona, Spain, 4 Laboratorio Oncología, Germans Trias i Pujol Athens, Greece Health Science Insitute and Hospital (IGTP), Badalona, Spain, 5 Infectious Diseases Unit, Hospital del Mar, Universitat *Correspondence: Autònoma de Barcelona, Barcelona, Spain, 6 Catalan Institution for Research and Advanced Studies (ICREA) Pg. Lluiı´s Maria Gonzalez-Cao Companys 23, Barcelona, Spain mgonzalezcao@oncorosell.com Andreas Meyerhans andreas.meyerhans@upf.edu Cancer patients (CPs) have been identified as particularly vulnerable to SARS-CoV-2 infection, and therefore are a priority group for receiving COVID-19 vaccination. From the Specialty section: patients with advanced solid tumors, about 20% respond very efficiently to This article was submitted to Vaccines and Molecular Therapeutics, immunotherapy with anti-PD1/PD-L1 antibodies and achieve long lasting cancer a section of the journal responses. It is unclear whether an efficient cancer-specific immune response may also Frontiers in Immunology correlate with an efficient response upon COVID-19 vaccination. Here, we explored the Received: 30 March 2022 Accepted: 01 June 2022 antiviral immune response to the mRNA-based COVID-19 vaccine BNT162b2 in a group Published: 05 July 2022 of 11 long-lasting cancer immunotherapy responders. We analysed the development of Citation: SARS-CoV-2-specific IgG serum antibodies, virus neutralizing capacities and T cell Sisteré-Oró M, Wortmann DDJ, responses. Control groups included patients treated with adjuvant cancer Andrade N, Aguilar A, Mayo de las Casas C, Casabal FG, Torres S, Bona immunotherapy (IMT, cohort B), CPs not treated with immunotherapy (no-IMT, cohort Salinas E, Raventos Soler L, Arcas A, C) and healthy controls (cohort A). The median ELISA IgG titers significantly increased after Esparre C, Garcia B, Valarezo J, Rosell R, Güerri-Fernandez R, the prime-boost COVID vaccine regimen in all cohorts (Cohort A: pre-vaccine = 900 (100- Gonzalez-Cao M and Meyerhans A 2700), 3 weeks (w) post-boost = 24300 (2700-72900); Cohort B: pre-vaccine = 300 (100- (2022) Brief Research Report: Anti- 2700), 3 w post-boost = 8100 (300-72900); Cohort C: pre-vaccine = 500 (100-2700), 3 w SARS-CoV-2 Immunity in Long Lasting Responders to Cancer post-boost = 24300 (300-72900)). However, at the 3 w post-prime time-point, only the Immunotherapy Through mRNA- healthy control group showed a statistically significant increase in antibody levels (Cohort Based COVID-19 Vaccination. Front. Immunol. 13:908108. A = 8100 (900-8100); Cohort B = 900 (300-8100); Cohort C = 900 (300-8100)) (P < 0.05). doi: 10.3389/fimmu.2022.908108 Strikingly, while all healthy controls generated high-level antibody responses after the Frontiers in Immunology | www.frontiersin.org 1 July 2022 | Volume 13 | Article 908108 Sisteré-Oró et al. COVID-19 Vaccination in Cancer Patients complete prime-boost regimen (Cohort A = 15/15 (100%), not all CPs behaved alike [Cohort B= 12/14 (84'6%); Cohort C= 5/6 (83%)]. Their responses, including those of the long-lasting immunotherapy responders, were more variable (Cohort A: 3 w post-boost (median nAb titers = 95.32 (84.09-96.93), median Spike-specific IFN-g response = 64 (24- 150); Cohort B: 3 w post-boost (median nAb titers = 85.62 (8.22-97.19), median Spike- specific IFN-g response (28 (1-372); Cohort C: 3 w post-boost (median nAb titers = 95.87 (11.8-97.3), median Spike-specific IFN-g response = 67 (20-84)). Two long-lasting cancer responders did not respond properly to the prime-boost vaccination and did not generate S-specific IgGs, neutralizing antibodies or virus-specific T cells, although their cancer immune control persisted for years. Thus, although mRNA-based vaccines can induce both antibody and T cell responses in CPs, the immune response to COVID vaccination is independent of the capacity to develop an efficient anti-cancer immune response to anti PD-1/PD-L1 antibodies. Keywords: COVID-19 vaccination, mRNA-based vaccines, cancer, SARS-CoV-2, long lasting responders, immunotherapy, immune checkpoint inhibitors (ICIs) INTRODUCTION MATERIALS AND METHODS The pandemic caused by the new severe acute respiratory Sample Collection syndrome coronavirus 2 (SARS-CoV-2) has a strong pathogenic This is a post-authorization observational study that impact on different subgroups of the general population (1). This prospectively collected data and blood samples from CPs generates the need to test efficacies of the rapidly developed treated with anti PD-1/PD-L1 antibodies that were vaccinated COVID-19 vaccines in particularly vulnerable groups which with mRNA-based COVID-19 vaccines (cohort B, subgroups B.1 have been excluded from the initial vaccine efficacy studies. and B.2). Subgroup B.1 consists of long-lasting responders, Amongst these groups are immunocompromised individuals which are CPs with advanced tumors that survive longer than that are with active cancers, that receive immunosuppressive the expected median survival achieved with non-immunological drugs i.e. after organ transplantation or that are infected with therapies. Subgroup B.2 consists of CPs under adjuvant therapy human immunodeficiency viruses (2–5). Due to their after receiving an initial primary therapy, either radiation or immunocompromised state, these individuals have a surgery. Adjuvant therapy is given to help prevent cancer relapse. significantly higher mortality upon SARS-CoV-2 infection than The study included other cohorts as controls: one of CPs not non-compromised individuals and thus should be taken care of treated with anti-PD-1 antibodies (cohort C) and a second with high priority (6, 7). However, there are now CPs that generate cohort of healthy individuals vaccinated against COVID-19 exceptional cancer responses after immunotherapy with anti-PD- (cohort A). From 14 patients treated with immunotherapy 1/PD-L1 antibodies and that achieve a long survival time (8, 9). (cohort B), 11 were on active treatment (cohort B.1) and had Such patients may possibly respond better to COVID-19 received their last dose of anti PD-1/PD-L1 antibody within a vaccination or may experience vaccine toxicity via an median of 31 days (range 42 days to 21 days) before COVID-19 exaggerated immune response. vaccination. Three patients (cohort B.2) had discontinued anti The mRNA-based COVID-19 vaccines from BioNTech/Pfizer PD-1/PD-L1 treatment 8 months, 10 months and 14 months and Moderna have been developed in record-speed and were given before COVID-19 vaccination due to immune-related adverse emergency approval in December 2020 after demonstrating to be events that were finally resolved. These three patients maintained safe and highly efficient (10, 11). They are inducing virus-specific their cancer response in spite of not being under active antibody and cellular immunity, and about a 95% protection from anticancer treatment. From 6 CPs not treated with SARS-CoV-2-induced disease (12, 13). However, vaccine immunotherapy (cohort C), 4 were on active anticancer immunogenicity in immunocompromised individuals is treatment: three of them with daily oral therapy (one with expected to be diminished to various degrees depending on the BRAF plus MEK (tyrosin-kinase inhibitors (TKIs)) and two particular condition and state of immunosuppression (2, 14–17). with hormonal therapy), and 2 patients were on treatment Here we report vaccination outcomes in a small cohort of solid with chemotherapy that received their last dose 14 days and 20 CPs including a cohort of long survivors under immunotherapy days before COVID-19 vaccination, respectively. (cohort B, subgroup B.1) with checkpoint inhibitors (mainly anti Participants received anti-COVID vaccinations following the PD-1/PD-L1 antibodies) and relate them to COVID-19 vaccine standard schedule. The primary endpoint was to describe the studies of cancer patients that have been published until January specific IgG serum antibody response, the virus neutralizing 2022 (3, 14, 16, 18–28). capacity of these antibodies, and the T cell response. The study Frontiers in Immunology | www.frontiersin.org 2 July 2022 | Volume 13 | Article 908108 Sisteré-Oró et al. COVID-19 Vaccination in Cancer Patients analyzed blood samples pre-vaccination, post-prime, and 3 positive if the results were ≥14 IFN-g-secreting cells per weeks (w) and 9 w after the boost. The protocol of the study 106 PBMCs. was approved by the institutional review board of “Grupo Hospitalario Quiró n Salud-Catalunya”. Written informed Statistics consent was obtained from each patient. The sample size for the study was not based on statistical hypothesis testing. The primary objective was to evaluate by descriptive summary statistics the immunogenicity at different Quantification of SARS-CoV-2 Spike- times points in three cohorts of patients, including one cohort of Specific IgG Antibody Responses and RBD long survivors treated with anti PD-1/PD-L1 antibodies. Neutralization Capacity of Patient Sera Statistical analyses and graphical representations of all data SARS-CoV-2-specific IgG antibodies towards the full-length were performed using GraphPad PRISM7. For comparison of SARS-CoV-2 S protein were assessed by an enzyme-linked means and P-value determinations, the Mann-Whitney-U and immunosorbent assay (ELISA). Costar 96-well flat-bottom, the Kruskal Wallis test were conducted. P-values < 0.05 were high-binding plates (2240096, Bio-Rad) were coated with 2 mg/ considered significant. mL full-length SARS-CoV-2 S protein (40592-V08B1, Sino Biologicals) and blocked with 3% BSA (A4503, Sigma-Aldrich) in 1x PBS. Three-fold serial dilutions of serum samples were added in duplicates to the corresponding wells. Next, a detection RESULTS step using an IgG HRP antibody (A18811, Life technologies) was Thirty-five persons participated in the study, including 20 CPs. performed and 3,3’,5,5’-Tetramethylbenzidine (TMB) substrate Fourteen patients were on treatment with anti PD-1/PD-L1- (T0440-100mL, Sigma-Aldrich) was dispensed and stopped with based immunotherapy: three of them in the adjuvant setting 1N H2SO4. Finally, absorbance was measured at 450 nm using a (cohort B, subgroup B.2) and eleven patients were long lasting microplate reader (iMark™ Microplate Absorbance Reader responders to immune-based therapies in advanced stage of #1681130, Bio-Rad). For each sample dilution duplicate, the cancer disease (cohort B, subgroup B.1). The study included mean absorbance was calculated. Endpoint-titres of S-specific two control cohorts: 6 CPs not treated with anti-PD-1/PD-1-L binding antibodies were defined as the reciprocal of the last antibodies (cohort C) and 15 healthy persons (cohort A). All serum dilution that provided 3 times the mean optical density of persons received after inclusion two doses of the BNT162b2 the negative control (wells without sera). Endpoint-titres above a vaccine (prime at day 0 and boost after 21 days), except two dilution of 1:2100 were scored positive. persons from the healthy cohort that received ChAdOx1-S Neutralising antibodies against the receptor binding domain (boost after 90 days) and Ad26.COV2.S (one single dose), (RBD) of the S protein were evaluated from patient sera using a respectively. No previous infection by SARS-CoV-2 was commercial NeutraLISA assay (EI 2606-9601-4, Euroimmune). recorded at inclusion in the study. Sera were always analysed in duplicates and processed according Noteworthy, all patients included in the immunotherapy to the manufacturer’s instructions (EI 2606-9601-4, cohort, were patients with a good control of the cancer disease, Euroimmune). A microplate reader (iMark Microplate Reader, including 11 patients with long lasting responses to Bio-Rad) was used to measure the optical densities of the plates. immunotherapy (six in complete response and five in partial Percentages of inhibition (% IH) against SARS-COV-2 were response; median time on treatment was 36 months -range 12 calculated as detailed by the assay’s manual: % IH = 100% - months to 72 months-) (cohort B, subgroup B.1) and three [(extinction sample x 100%)/average extinction blank]. patients with no active cancer disease and treated with Percentages of IH were interpreted as positive if ≥35%, as immunotherapy in the adjuvant setting with anti-PD-1 doubtful if ≥20 and <35, and as negative if <20. antibodies (two as single agent and one patient in combination with bempegaldesleukin) (cohort B, subgroup B.2). From the Quantification of Spike-Specific T Cells cohort of CPs with non-immunologic treatments (cohort C), From PBMCs only one patient was in cancer progression at the time of being SARS-CoV-2-specific T cells were determined using an IFN-g included into the current study. In cohort B, cancer treatment enzyme-linked immunospot (ELISpot) assay (3420-2H, consisted of single anti-PD-1 or anti-PD-L1 antibodies in seven Mabtech) according to the manufacturer’s instructions. Briefly, (63%) and three (27%) cases, respectively, and one (9%) patient 250,000 PBMCs per well were incubated with SARS-CoV-2 spike received chemotherapy in combination with an anti-PD-1 peptides at a final concentration of 2 mg/ml for 16 - 24h (JPT- antibody. From cohort C, two (33%) patients were under PM-WCPV-S, Sino Biologicals). A CEF peptide pool (JPT-PM- treatment with chemotherapy, one (17%) patient with targeted CEF-S1, Sino Biologicals, 2 ug/mL) and PMA (P8139, Sigma, drugs against BRAF mutations and two (33%) patients were on 15ng/mL) plus ionomycin (I0634, Sigma, 250ng/mL) were used treatment with hormonotherapy. Additional patient as positive controls. To quantify antigen-specific responses, characteristics are included in Table 1. There was no apparent mean spots of the RPMI control wells were subtracted from increase in adverse events due to the BNT162b2 vaccine, as well the positive wells, and the results were expressed as spot-forming as no increase in immune related adverse events due to units (SFU) per 106 PBMCs. T cell responses were considered cancer immunotherapy. Frontiers in Immunology | www.frontiersin.org 3 July 2022 | Volume 13 | Article 908108 Sisteré-Oró et al. COVID-19 Vaccination in Cancer Patients TABLE 1 | Patient characteristics. Cohort AHealthy persons Cohort BCancer patients IMT treatment Cohort CCancer patients no-IMT treatment (n=15) (n=14) (n=6) Characteristics Age – y, Median (range) 53 (26-72) 67 (38-84) 59 (47-61) Sex – n (%) Female 8 (53) 7 (50) 4 (67) ECOG PS – n (%) 0 15 (100) 7 (50) 4 (67) 1 0 7 (50) 2 (33) Cancer type– n (%) Non-squamous NSCLC NA 7 (50) 2 (33) Squamous NSCLC NA 3 (21) 0 Melanoma NA 3 (21) 2 (33) Colon cancer NA 1 (6) 0 Breast cancer NA 2 (33) Tumor stage – n (%) II NA 1 (7) 1 (17) III NA 3 (21) 0 IV NA 10 (71) 5 (83) Cancer control – n (%) No active disease NA 3 (21) 1 (17) Complete response NA 6 (43) 2 (33) Partial response NA 5 (36) 2 (33) Progression disease NA 0 1 (17) Anticancer drug– n (%) Nivolumab 0 2 (14) 0 Pembrolizumab 0 6 (43) 0 Durvalumab 0 1 (7) 0 Atezolizumab 0 3 (21) 0 Pembrolizumab-ChT 0 1 (7) 0 Nivolumab- 0 1 (7) 0 bempegaldesleukin Cht 0 0 2 (33) BRAFi-MEKi 0 0 1 (17) Hormonotherapy 0 0 2 (33) No anticancer treatment 0 0 1 (17) NA, Not applicable. To assess SARS-CoV-2-specific humoral immune responses To further access vaccine-induced neutralising antibodies and induced by the mRNA-based COVID-19 vaccine from Pfizer/ virus-specific cellular immune responses, NeutraLISA and IFN-g BioNTech, ELISAs against the Spike protein (S) of the SARS- ELISpot assays were performed. The results were comparable to CoV-2 Wuhan isolate were carried out at 4 defined time-points, those of the ELISA assays. All cohorts experienced a significant pre-vaccine, 3 w post prime, 3 w post boost and 9 w post boost. increase in neutralising antibodies (Figure 1C) and cellular Th1 The median ELISA IgG titres significantly increased after the responses (Figure 1E) demonstrating the capacity of the mRNA- prime-boost vaccine regimen in all cohorts (Figure 1A) based vaccines to induce both antibody and T cell responses. demonstrating that CPs were responsive to the vaccine and Again, the response was more variable in cohorts B (B.1 and B.2) generated virus-specific antibodies. However, at the 3 w post- and C than in the healthy controls from cohort A, and not all prime time-point, only cohort A (healthy control group) showed cancer CPs responded to the vaccines (non-responders for the a statistically significant increase in antibody levels (P < 0.05). nAb: cohort B=28.6%, cohort C=17%; non-responders for the The respective increase in cohorts B and C was more variable and ELISPOT: cohort B=21.5%, cohort C=0%). A simple overview of did not reach significance. Importantly, not all of the CPs all responses of the different groups is given in Figure S1. To generated high level antibody responses after the complete better visualize differences within the subgroups of cohort B, we prime-boost regimen (Cohort B, 12/14=85,7%; Cohort C, 5/6 = plotted the responses of B.1 and B.2 in Figure S2. 83%), while all individuals of the cohort A of healthy controls did Noteworthy, there was one individual from cohort C with (15/15=100%). Together this supports the strong advanced breast cancer in complete response to hormonotherapy immunogenicity of mRNA-based COVID-19 vaccines and (CP19; red dots in Figures 1A, C, E) that showed virus-specific reveals the immunocompromised state of some CPs, including IgG and Th1 responses, and a high neutralising antibody also 2 cases from the cohort B of long lasting cancer response before starting the vaccination scheme. This patient immune responders. had been probably infected by SARS-CoV-2 previously. Frontiers in Immunology | www.frontiersin.org 4 July 2022 | Volume 13 | Article 908108 Sisteré-Oró et al. COVID-19 Vaccination in Cancer Patients A B C D E F FIGURE 1 | SARS-CoV-2-specific immune responses after COVID-19 vaccination. Spike-specific IgG titers (A, B), nAb titers (C, D) and spike-specific T cell responses (E, F) in healthy donors (Cohort A), CP under immunotherapy (anti-PD1/PD-L1) (IMT; Cohort B, subgroups B.1 and B.2) and CP not treated with immunotherapy (no-IMT; Cohort C) after two doses of mRNA-based COVID-19 vaccines. Individuals from subgroups B.1 are represented by circles and individuals from subgroup B.2 are represented by blue squares. Dotted lines indicate positive thresholds for Spike-specific IgG and T cells. In case of nAbs (C, D), the dotted line determines the thresholds for negative, intermediate, and positive results according to manufacturer’s instructions. Patients with a supposedly previous asymptomatic SARS-CoV-2 infection are differently coloured (red circled symbols for CP19; blue circled symbols for CP7 and green circled symbols for CP16) and excluded from statistical analyses. Bars represent medians. Differences between the groups were calculated using Mann– Whitney test or Kruskal-Wallis test for comparison of two or three groups. Non-significant differences were indicated as “ns”. P-values below 0.05 were considered significant and wereindicated by asterisks: *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001. Frontiers in Immunology | www.frontiersin.org 5 July 2022 | Volume 13 | Article 908108 Sisteré-Oró et al. COVID-19 Vaccination in Cancer Patients TABLE 2 | Summary of COVID-19 vaccination trials in cancer patients under diverse therapies. Author/ Total patients Type of cancer Median age (range) Patient received vaccine [n] Patients Cancer treatment Country/ [n] [years] on active Reference treatment CP Control Patients Patients with CP Control BNT162b2 mRNA- Ad26.COV2.S [n] never CHT CHT IMT TT group with solid hematological group 1273 treated and tumor [n] cancer [n] IMT (3) 44 0 0 44 (CCL) 71 (37–89) n.a. 25 19 0 18 26 n.a. n.a. 14 n.a. (14) 816 274 816 0 62 (21-97) 47 (21- CP: 786; 0 0 738 n.r. 55 240 228 215 69) Control: 251 (16) 151 54 95 56 73.0 40·5 SC: 25; HC: 0 0 13 SC: 9/ SC:1/ SC: SC:3/ n.a. (64.5–79.5) (31·3– 6; Control: 25; HC: 25 4/25 25 50·0) 16 4/6 (18) 232 261 232 0 68 (25-88) 64 (25- CP: 218 0 0 232 0 n.a. 134 83 n.a. 81) (9) 167 52 0 167 (CLL) 71 (63-76) 68 (64- 219 0 0 75 58 n.a. n.a. n.a. n.a. 74) (20) 36 72 26 10 82 (80-89) n.r. 108 0 0 31 n.r. 11 10 2 n.a. (21) 102 78 102 0 66 (56-72) 62 (49- 180 0 0 102 0 14 30 22 n.a. 70) (22) 92 36 0 MM: 42; MPM: 50 MM:73 81 (79– 128 0 0 92 0 n.a. n.a. n.a. n.a. (47–78); 87) MPM:70 (28–80) (23) 200 26 134 66 67 (27–90) 64 (37- 115 62 20 135 11 n.a. 112 54 n.a. 82) (24) 163 0 163 0 66 (27-89) n.r. 163 0 0 163 0 0 122 15 26 (25) 171 2406 171 0 68 (58-73) 48 (36- 150 21 0 171 0 4 110* 23* 78* 56) (26) 176 25 49 91 SC: 66 68 (28- 106 95 0 140 n.r. n.r. n.r. n.r. n.r. (31-81); 90) HC: 71 (47-97) (27) 60 0 60 0 66 (60-71) n.r. 60 0 0 60 0 10 0 50 0 (28) 75 0 75 0 68 (61.5- n.r. 75 0 0 75 0 20 0 66 4 73) Abbreviations: EC50, 50% effective concentration; CLL, chronic lymphocytic leukemia; CI,confidence interval; CP, Cancer patients; n, numbers; nAbs, neutralizing antibodies; MM, multiple myeloma; MPM, myeloproliferative malignancy; n.r., not reported; n.a., not applicable; Th1, T helper 1 cells; SC, solid cancer; HC, hematologic cancer; IQR,interquartile range; GMC, geometric mean concentration; CHT, chemotherapy; IMT, immunotherapy; TT, targeted therapy; anti-S, anti-spike protein; IFNg,interferon-g *Total column values may not sum up to total as categories are not mutually exclusive (e.g. participants may have received CHT and TT) Nevertheless, before inclusion in the study, CP19 did neither anti-PD-1 plus bempegaldesleukin, cohort B, subgroup B.2) and have symptoms of a SARS-COV-2 infection nor was previously CP14 (metastatic non-small cell lung cancer in partial response diagnosed of being infected. Interestingly, while vaccination to chemotherapy plus anti-EGFR antibody, cohort C), responded increased the specific antibody response, the respective Th1 weakly with borderline responses in all three assays. The response was diminished. Patients CP7 (blue dots in remaining 15 CPs showed a vaccine response that was Figures 1A, C, E) (metastatic non-small cell lung cancer in comparable to the healthy control group. Together this complete response to anti-PD-L1 antibody; cohort B, subgroup demonstrates an important immune response heterogeneity in B.1) and CP16 (green dots in Figures 1A, C, E) (metastatic solid CPs and argues for the need of a careful diagnostic melanoma in progression after several lines of treatment, cohort follow-up. C) were potentially SARS-CoV-2-infected before vaccination as Comparison of the 3 w and 9 w post-boost responses they had clear positive S-specific IgG titres and borderline Th1 revealed a rather stable immunity with no significant responses. Upon their first vaccination, both developed strong differences within the cohorts (Figures 1B, D, F). Only CP2 neutralising antibody responses and showed an increase in their (metastatic non-small cell lung cancer in complete response to specific T cells. However, as CP7 obtained anti-PDL1 antibodies anti-PD-L1 antibody; cohort B, subgroup B.1) had a drop in just 1 week before the first vaccine dose, an immunotherapy- the S-specific IgG titre by two serum dilutions. As this was not mediated enhancement of the response cannot be excluded. To accompanied by a loss of neutralising antibodies or Th1 avoid ambiguities, all 3 patients were not considered for the responses, it was not considered clinically relevant. Patients statistical evaluation. CP3 (metastatic colorectal cancer in complete response to Amongst the 20 CPs, there were three patients that did not anti-PD-1 antibody; cohort B, subgroup B.1) and CP11 respond properly to the prime-boost vaccination. These were (metastatic non-small cell lung cancer in complete response CP1 and CP8 from the cohort B; subgroup B.1 and CP18 from to anti-PD-L1 antibody, cohort B, subgroup B.1) showed a cohort C. All these patients did not generate S-specific IgGs, reduction of their neutralising antibodies which was for CP11 neutralising antibodies or virus-specific T cells. An additional accompanied by an over 2-fold reduction in the Th1 response. two patients, CP6 (stage III melanoma treated with adjuvant However, most notably was the strong increase of all three Frontiers in Immunology | www.frontiersin.org 6 July 2022 | Volume 13 | Article 908108 Frontiers in Immunology | www.frontiersin.org Sisteré-Oró et al. TABLE 3 | Summary of immune responses of COVID-19 vaccination trials in cancer patients under diverse therapies. Author/ Positive Cutoff/ Unit Number of individuals with vaccine-specific immune response Patients’ Median Controls’ Country/ Serum IgG Level Median Serum Reference anti-S IgG nAbs Th1 (IFNg-ELISpot) (Post-Vaccina- IgG Level tions) (Post-Vaccina- anti-S nAbs Th1 never CHT CHT, IMT, [n]/ TT, CP, [n]/ Control, CP, [n]/ Control, all CP, [n]/ total Control, tions) IgG cells treated, and [n]/ total [n] [n]/ total [n] [n]/ total total [n] [n]/ total [n] (%) [n]/ total [n]/ IMT, [n]/ total [n] (%) total (%) [n] (%) (%) [n] (%) [n] (%) total [n] total [n] (%) [n] (%) (%) (3) IgG n.a. n.a. 17/18 n.a. n.a. 2/14 n.a. 23/44 n.a. n.a. n.a. n.a. n.a. n.r. n.r. ≥15 (94%) (14%) (52%) AU/ml (14) IgG Co/S n.a. n.r. n.r. 230/261 126/129 195/ 181/ 194 204/204 240/301 131/175 n.a. n.a. 236.37 (13.77- 262.98 (101.42- ≥15 > 10 (88.1%) (97.7%) 201 (93.3%) (100%) (79.7%) (74.9%) 4055.91) 681.96) AU/ml (97%) (16) ≥ 70 n.r. ≥7 n.a. n.a. n.a. n.a. n.a. SC: 18/19 12/12 n.a. n.a. SC: 14/16 (87.5%) 3/3 n.r. n.r. EC50 cytokine (95%); (100%) ; HC: 3/4 (75%) (100%) dilution secreting HC: 3/5 units cells/106 (60%) (18) IgG n.a. n.a. n.a. n.a. 102/ 125 71/79 n.a. 187/218 n.r. n.a. n.a. n.a. n.a. n.r. n.r. ≥15 (82%) (89%) (86%) AU/ml (19) IgG n.a. n.a. 32/58 n.a. n.a. n.a. n.a. 66/167 52/52 n.a. n.a. n.a. n.a. 155 (IQR, 7.6-490.3) 1084 (IQR, ≥0.8 U/ (55%) (39.5%) (100%) U/mL 128.9–1879) U/ ml ml 7 (20) IgG n.a. n.a. n.a. n.r. n.r. n.r. n.a. SC: 25/26 12/12 n.a. n.a. n.a. n.a. 2396.10 (range 0– 8737.49 (range ≥50 (96%); (100%) 32,763) AU/ml 398.90– AU/ml HC: 4/10 976,280) AU/ml (40%) (21) IgG n.a. n.a. n.a. n.r.; n.r.; n.r.; n.a. 92/102 78/78 n.a. n.a. n.a. n.a. 1931 (IQR, 509– 7160 (IQR, ≥50 Median Median Median (90%) (100%) 4386) AU/ml 3129–11,241) AU/ml IgG titer: IgG titer: IgG titer: AU/ml 310 AU/ 1363 3020 AU/ ml AU/ml ml (22) IgG n.a. n.a. n.a. n.a. n.a. n.a. n.a. MM:33/42 36/36 n.a. n.a. n.a. n.a. GMC (CI): MM 106.7 GMC (CI): 353.3 ≥15 (79%); (100%) (62.3–179.7) AU/ml; (255.6–470.0) AU/ml MPM:44/ MPM 172.9 (106.5– AU/ml 50 (88%) 257.0) AU/ml COVID-19 Vaccination in Cancer Patients July 2022 | Volume 13 | Article 908108 (23) IgG n.a. n.a. n.a. n.a. 103/112 46/54 n.a. SC: 131/ 26/26 n.a. n.a. n.a. n.a. SC: 7858 AU/ml; Higher than ≥50 (92%) (85%) 134 (100%) HC:2528 AU/ml 15,000 AU/ml AU/ml (98%); HC: 56/ 66 (85%) (24) IgG n.a. n.a. n.a. n.a. 66/106 12/14 14/22 92/142 n.a. n.a. n.a. n.a. n.a. 1996.3 (IQR 498.2- n.a. ≥1000 (62 %)* (86%)* (64%)* (65%)* 5575.3) AU/ml AU/ml (25) IgG nAb n.a. n.a. n.r. 102/110 22/23 73/78 161/171 2402/ 122/161 n.a. n.a. n.a. n.a. n.a. ≥33.8 ≥20 (92.7%) (95.7%) (93.6%) (94.2%) 2406 (76,2%) AU/mL % (99.8%) (Continued) Frontiers in Immunology | www.frontiersin.org Sisteré-Oró et al. TABLE 3 | Continued Author/ Positive Cutoff/ Unit Number of individuals with vaccine-specific immune response Patients’ Median Controls’ Country/ Serum IgG Level Median Serum Reference anti-S IgG nAbs Th1 (IFNg-ELISpot) (Post-Vaccina- IgG Level tions) (Post-Vaccina- anti-S nAbs Th1 never CHT CHT, IMT, [n]/ TT, CP, [n]/ Control, CP, [n]/ Control, all CP, [n]/ total Control, tions) IgG cells treated, and [n]/ total [n] [n]/ total [n] [n]/ total total [n] [n]/ total [n] (%) [n]/ total [n]/ IMT, [n]/ total [n] (%) total (%) [n] (%) (%) [n] (%) [n] (%) total [n] total [n] (%) [n] (%) (%) (26) IgG n.a. n.a. n.a. n.a. n.a. n.a. n.a. SC: 27/49 59/61 n.a. n.a. n.a. n.a. n.a. n.a. ≥500 (55.1%); (96.7%) U/mL HC: 7/91 (7.7%) (27) IgG ≥ nAb ≥ 10 net n.a. n.a. n.a. 72/75 n.a. 72/75 n.a. n.r.; 1:80 n.a. n.r; Median: 125 n.a. n.a. n.a. 15 AU/ ≥ spot/ (95%) (95%) (IQR (IQR 52.5-345) mL 1:10 million 1:20- IFN-g SFU/million PBMCs 1:160) PBMCs (28) IgG ≥ nAb ≥ 10 net n.a. n.r.; n.a. n.r.; n.a. n.r.; n.a. n.r.; n.a. n.r.; Median 50 n.a. n.a. n.a. 33.8 ≥ spot/ Median Median Median: Median: (IQR 20-118.8) BAU/ 1:10 million IgG titer: IgG titer: 205.2 1:20 IFN-g-producing mL PBMCs 80.6 196.3 (IQR 73.2- (IQR cells/million BAU/ml BAU/ml 654.6) 1:10- PBMCs 1:40) Abbreviations: EC50, 50% effective concentration; CLL, chronic lymphocytic leukemia; CI,confidence interval; CP, Cancer patients; n, numbers; nAbs, neutralizing antibodies; MM, multiple myeloma; MPM, myeloproliferative malignancy; n.r., 8 not reported; n.a., not applicable; Th1, T helper 1 cells; SC, solid cancer; HC, hematologic cancer; IQR,interquartile range; GMC, geometric mean concentration; CHT, chemotherapy; IMT, immunotherapy; TT, targeted therapy; anti-S, anti- spike protein; IFNg,interferon-g * Values obtained one month after the 3rd vaccination were: for patients under CHT 73% (22/30), for patients with TT 83% (5/6) and for IMT no patients were analyzed. 75% (27/36) of the CP seroconverted. COVID-19 Vaccination in Cancer Patients July 2022 | Volume 13 | Article 908108 Sisteré-Oró et al. COVID-19 Vaccination in Cancer Patients immune response measures for CP6 (stage III melanoma The three vaccine non-responders and the two low- treated with adjuvant anti-PD-1 plus bempegaldesleukin, responders represent together 25% of our patient group. They cohort B, subgroup B.2). This patient was a weak responder were low in both humoral and cellular immune responses. to the vaccine itself but then had a huge increase in virus- Importantly, one of them received bempegdesleukin that specific IgG titre, neutralising antibodies and Th1 response significantly boosted both types of responses suggesting that (Figures 1B, D, F; highlighted in red). Thus, the combination this low-responsive subgroup of patients has no inherent defect of a checkpoint inhibitor with long lasting interleukin 2 may to respond and thus may benefit from booster vaccinations or trigger superior vaccine-induced immunity in an otherwise combinations with other immune modulating drugs (29). This low responder. should particularly be true for vaccines, like the ones used here, that induce antibodies and cellular immunity because both antiviral effector mechanisms seem to cooperate in antiviral defence in a multiplicative, synergistic way (30). DISCUSSION Immunotherapy with checkpoint inhibitors is a common Our study demonstrates a significant albeit variable treatment option for patients with solid tumours. Respective immunogenicity of mRNA-based COVID-19 vaccines for therapeutic antibodies disrupt inhibitory signaling pathways in patients with solid tumours under anti-PD1/PDL1 inhibitor lymphocytes and thereby augment cellular immune responses. immunotherapy or chemotherapy. Long lasting responders to In the context of antiviral vaccines, this might have the cancer immunotherapy did not have higher responses to immunological benefit of generating increased immune COVID vaccines, although there was a relevant case with an responses and thus better host protection against subsequent exaggerated response during cancer treatment with the virus infections. However, our study revealed no significant combination of anti-PD-1 antibody plus bempegdesleukin. differences in the vaccine responses between the immune There was no relevant toxicity due to vaccination nor cancer cancer responders (cohort B) and the CPs not-treated with treatment. These data are in line with previous findings immunotherapy (cohort C), and both cohorts contained (summarised in Tables 2, 3) and enable altogether the following individuals that lacked an efficient response. Furthermore, general and clinically relevant conclusions. (1) mRNA-based there were no additional side effects compared to the healthy COVID-19 vaccines are highly immunogenic and safe even in control group suggesting that the mRNA-based vaccine immunocompromised solid tumour patients under various regimen is safe and well tolerated in solid CPs independent therapy regimens. (2) Roughly up to 30% of solid tumour on the type of therapy, including those patients with excellent patients may not generate a proper vaccine response and thus response to cancer immunotherapy. These findings are in line require additional boosters. (3) The biology of the cancer type (i.e. with those of others (2, 14, 23, 27, 29, 31) and support the haematological tumour vs solid tumour) dictates vaccine efficacy. current recommendations to vaccinate CPs against COVID-19 (4) The therapy regimen may affect immune response induction independent of their therapy regimens (14). and duration of immune memory. In conclusion, our results here and the very recent findings of Our study included only 20 solid CPs under diverse others consistently support COVID-19 vaccination of tumour therapies and thus is limited in its informative value. We patients to reduce their enhanced mortality risks upon SARS- therefore reviewed previously published work and included CoV-2 infection. The existence of a significant portion of low- their results, as summarised in Tables 2, 3, to obtain the vaccine responders argues for diagnostic follow-up and booster mentioned conclusions. In particular, the work of Thakkar vaccinations or novel combinations. Further studies that evaluate et al., 2021 demonstrates the significant differences of the and optimise the timing between cancer therapies and cancer type and therapy regimen on vaccination efficacy. vaccination schedules are warranted. Given that vaccines rely on the coordinated functioning of antigen-presenting cells and B and T lymphocytes, it is not surprising that haematological tumours and their DATA AVAILABILITY STATEMENT therapies which affect these cell types, impede vaccine responses the most (23). Furthermore, since the induction of The raw data supporting the conclusions of this article will be a vaccine response requires lymphocyte proliferation and made available by the authors, without undue reservation. differentiation, chemotherapies that target dividing cells are expected to influence this process negatively and thus reduce vaccine efficacies. Indeed, this is observed albeit the differences, ETHICS STATEMENT for example, in SARS-CoV-2-S-specific antibody titres for CPs with or without chemotherapy were not statistically significant The studies involving human participants were reviewed and (23). However, the response level between the patients was very approved by “Grupo Hospitalario Quiró nsalud-Catalunya”. The divergent and it may well be that the timing between cytotoxic patients/participants provided their written informed consent to drug intake and the vaccine schedule might have an important participate in this study. Written informed consent was obtained influence (29). Detailed studies on this are still lacking and from the individual(s) for the publication of any potentially clearly require further attention. identifiable images or data included in this article. Frontiers in Immunology | www.frontiersin.org 9 July 2022 | Volume 13 | Article 908108 Sisteré-Oró et al. COVID-19 Vaccination in Cancer Patients AUTHOR CONTRIBUTIONS SUPPLEMENTARY MATERIAL Concept and funding acquisition: MG-C and AM. Experimental The Supplementary Material for this article can be found online design: MS-O, MG-C and AM. Experiment performance: MS-O, at: https://www.frontiersin.org/articles/10.3389/fimmu.2022. DDJW and NA. Patient recruitment and handling: MG-C, RR, 908108/full#supplementary-material AAg and RG-F. Sample collection: AAg, CM, FGC, ST, EBS, LRS, Supplementary Figure 1 | Percentages of responders from cohorts A, B.1, B.2 AAr, CE, BG, JV, RR and RG-F. Figures and tables: MG-C, MS- and C upon COVID-19 vaccination. The percentage of responders from Cohorts A O, DDJW and NA. Manuscript drafting: MS-O, DDJW and NA (healthy donors), B.1 (CP under IMT, long lasting responders), B.2 (CP under IMT, with corrections from AM, RR and MG-C. All authors adjuvant therapy) and C (CP not treated with IMT, no-IMT) in ELISA (A), NeutraLISA contributed to the article and approved the submitted version. (B) and ELISPOTs (C) after two doses of mRNA-based COVID-19 vaccines (3 w post boost time-point). Cohort A is represented by black bars, cohort B.1 by light blue bars, cohort B.2 by dark blue bars and cohort C by red bars. The ratio of responders to group size is given above each individual bar. FUNDING Supplementary Figure 2 | SARS-CoV-2-specific immune responses from cohort B subgroups B.1 and B.2 after COVID-19 vaccination. Spike-specific IgG The authors are supported by Spanish Melanoma Group Grant titers (A), nAb titers (B) and Spike-specific T cell responses (C) in CPs under (III Beca GEM para Grupos Emergentes), the Spanish Ministry immunotherapy (anti-PD1/PD-L1) from subgroup B.1 (long lasting responders) and of Science and Innovation grant no. PID2019-106323RB-I00 subgroup B.2 (adjuvant therapy) after two doses of mRNA-based COVID-19 vaccines. Dotted lines indicate positive thresholds for Spike-specific IgG and T cells. AEI//10.13039/501100011033, the “Unidad de Excelencia In case of nAbs (C, D), the dotted line determines the thresholds for negative, Marı́a de Maeztu”, funded by the MCIN and the AEI (DOI: intermediate, and positive results according to manufacturer’s instructions. Bars 10.13039/501100011033); Ref: CEX2018-000792-M. represent medians. 13. Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, et al. Efficacy REFERENCES and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med (2021) 384 1. Al-Quteimat OM, Amer AM. The Impact of the COVID-19 Pandemic on (5):403–16. doi: 10.1056/NEJMoa2035389 Cancer Patients. Am J Clin Oncol Cancer Clin Trials (2020) 43(6):452–5. doi: 14. 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A this article, or claim that may be made by its manufacturer, is not guaranteed or Snapshot of the Immunogenicity, Efficacy and Safety of a Full Course of endorsed by the publisher. BNT162b2 Anti-SARS-CoV-2 Vaccine in Cancer Patients Treated With PD- 1/PD-L1 Inhibitors: A Longitudinal Cohort Study. ESMO Open (2021) 6 Copyright © 2022 Sistere-́ Oro,́ Wortmann, Andrade, Aguilar, Mayo de las Casas, (5):100272. doi: 10.1016/j.esmoop.2021.100272 Casabal, Torres, Bona Salinas, Raventos Soler, Arcas, Esparre, Garcia, Valarezo, 28. Lasagna A, Lilleri D, Agustoni F, Percivalle E, Borgetto S, Alessio N, et al. Rosell, Güerri-Fernandez, Gonzalez-Cao and Meyerhans. This is an open-access Analysis of the Humoral and Cellular Immune Response After a Full Course article distributed under the terms of the Creative Commons Attribution License of BNT162b2 Anti-SARS-CoV-2 Vaccine in Cancer Patients Treated With (CC BY). The use, distribution or reproduction in other forums is permitted, provided PD-1/PD-L1 Inhibitors With or Without Chemotherapy: An Update After 6 the original author(s) and the copyright owner(s) are credited and that the original Months of Follow-Up. ESMO Open (2022) 7(1):100359. doi: 10.1016/ publication in this journal is cited, in accordance with accepted academic practice. No j.esmoop.2021.100359 use, distribution or reproduction is permitted which does not comply with these terms. Frontiers in Immunology | www.frontiersin.org 11 July 2022 | Volume 13 | Article 908108