Search

Introduction: Patients with hematologic malignancies are at an increased risk of morbidity and mortality from COVID-19 disease (Vijenthira, Blood 2020). This is likely a result of combination of immunodeficiency conferred by the disease and the therapeutics. The immunogenicity of the COVID-19 vaccines in patients with exposure to CD19 directed Chimeric Antigen Receptor (CAR)-T cell therapy is not established. CD19 CAR-T cell therapies cause B-cell aplasia, which in turn can affect humoral immune response against novel antigens. Herein, we present results from our prospectively conducted clinical study to evaluate immune responses against mRNA based COVID-19 vaccines in patients with lymphoma who have received CD19 directed CAR-T cell therapy. Methods: All patients and healthy controls were enrolled in a prospective clinical study evaluating immune responses against commercial COVID-19 RNA vaccines in patients with hematologic malignancies. Plasma samples were generated from heparinized peripheral blood of 4 heathy controls (HCs) receiving the same vaccines and 19 B cell lymphoma patients treated with CD19 CAR- T cells. Samples from ~4 weeks post second dose of the vaccine (d56) were available for 14 CAR-T patients, for 5 CAR-T patients samples were available from ~4 weeks after the first dose (d28). Plasma samples were analyzed in an enzyme-linked immunosorbent assay (ELISA) using different full-length recombinant SARS-CoV-2 proteins and control proteins. Neutralizing activity was measured using the cPass Neutralization Antibody Detection Kit (GenScript Biotech). Results: Results from 4 healthy controls and 19 patients (12 males and 7 females) with lymphoma are reported. Median age for the lymphoma patients is 65 years. Eleven patients had large B cell lymphoma, 5 had follicular lymphoma and 3 had mantle cell lymphoma as primary diagnoses. Seventeen patients had advance stage disease (III/IV stage) and had received a median of 3 prior lines of therapy. All patients received CD19 directed CAR-T cell therapy. Ten patients received Moderna vaccine and 9 received Pfizer vaccine. Median time between CAR-T infusion and first COVID-19 vaccine was 258 days. While the peripheral blood plasma from 3/4 HCs already showed substantial SARS-CoV-2 neutralizing activity at ~4 weeks after the first dose of COVID-19 mRNA vaccine, none of the 5 CD19 CAR-T patients analyzed evidenced any antibody-mediated neutralizing activity in their blood at the same point in time (Figure 1A). Around 4 weeks after receiving the second dose of the vaccine, all 4 HCs tested evidenced complete or almost complete neutralizing activity (Figure 1B). In marked contrast, only 1 out of 14 CAR-T patients analyzed evidenced any relevant antibody-mediated SARS-CoV-2 neutralizing activity in their blood (Figure 1B). Interestingly, when we asked whether a globally insufficient antibody-mediated immunity was the underlying cause of the lack of a response to the COVID-19 vaccine in our CAR-T patients, we found that that was clearly not the case since anti-Flu, -TT, and -EBV responses were equivalent to the ones observed in HCs (Figure 2A). However, while at ~4 weeks post second dose of the vaccine the HCs showed marked antibody titers against all the viral spike proteins including their "delta" variants (Figure 2B), that was not the case for our CAR-T patients. The vast majority of our CAR-T patients did not evidence IgG antibody responses against any of the SARS-CoV-2 proteins analyzed such as S1, S1 delta, RBD, RBD delta, or S2 (Figure 2B). Conclusion: In this prospectively conducted clinical study, 18 of 19 patients with lymphoma who have received CD19 CAR-T therapy had poor immunogenicity against mRNA based COVID-19 vaccines as measured by neutralization assays and antibody titers. The antibody titers against B.1.617.2 (delta variant, S1 and RBD protein) were also demonstrably poor. The antibody response to common pathogens (flu, EBV, TT) were preserved, suggesting impaired immune response against novel antigens. Long-term follow-up of this study is ongoing. APR and DJ contributed equally Figure 1 Figure 1. Disclosures Dahiya: Kite, a Gilead Company: Consultancy; Atara Biotherapeutics: Consultancy; BMS: Consultancy; Jazz Pharmaceuticals: Research Funding; Miltenyi Biotech: Research Funding. Hardy: American Gene Technologies, International: Membership on an entity's Board of Directors or advisory committees; InCyte: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees.

Background The ongoing Coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is having an enormous impact on society worldwide and is especially posing a threat to health in vulnerable patients, such as patients with immune deficiencies. It is expected that patients who received Chimeric Antigen Receptor T-cell (CAR T-cell) therapy for hematologic malignancies are at risk for poor outcomes after COVID-19 due to their severely immunocompromised state caused by prior cumulative immunochemotherapy, on-target/off-tumor B-cell depletion, hypogammaglobulinemia and ongoing cytopenias. Current data are limited to small case series and case reports. This study describes the clinical characteristics and outcomes of CAR T-cell therapy recipients after developing COVID-19 in the largest cohort to date. Methods In response to the COVID-19 pandemic, the European Society for Blood and Marrow Transplantation (EBMT) developed a special COVID-19 report form to capture data from all patients with COVID-19 after treatment with CAR T-cell therapy for hematologic malignancies. Only PCR positive SARS-CoV-2 diagnosed patients before June 1 st, 2021 were included. The aim of this study was to describe the clinical course after COVID-19 diagnosis and evaluate overall survival. Overall survival probabilities were calculated using the Kaplan Meier method. Factors associated with mortality after COVID-19 diagnosis were examined using a Cox proportional hazard model. Results A total of 57 patients from 11 countries were reported to the EBMT. One patient with incomplete data at diagnosis and without any follow up information had to be excluded from the analysis. The median age of these 56 patients was 57.7 years (min-max 5.2 - 72.8) including 55 adults and one child. Of these patients, 32 were male. CAR T-cell therapy was given to 46 patients with B-cell-non-Hodgkin lymphoma, 7 patients with B-cell acute lymphoblastic leukemia, and 3 patients with multiple myeloma. The median time from CAR T-cell infusion to COVID-19 diagnosis was 7.4 months (min-max 0.03 - 25.3). At the time of COVID-19 diagnosis, 62.5% of patients were in complete remission, 12.5% of patients had a partial response and 25% of patients had relapsed/refractory disease. Forty-five patients (80%) were admitted to hospital (median 26,5 days, min-max 3-171) due to COVID-19. Of the admitted patients, 24 (53%) needed oxygen support. Twenty-two (49%) patients were admitted to the intensive care unit (median 14 days, min - max 2-65) and 16 (73%) of these patients received invasive ventilation. At the time of analysis, 25 of the 56 patients had died (44.6%), most (23/25) due to COVID-19, resulting in a COVID-19 attributable mortality rate of 41%. The Kaplan-Meier estimate of overall survival is shown in Figure 1. The median follow-up from COVID-19 diagnosis was 20.9 weeks. In 1 of the 32 alive patients there was no resolution of COVID-19 at the time of analysis. In multivariate analysis, older age (hazard ratio (HR) 1.50, 95% CI 1.11-2.03, p=0.009) and comorbidities (HR 2.56, 95% CI 1.05-6.23, p=0.001) had a negative impact on overall survival. Better performance status at time of admission (HR 0.72, 95% CI 0.59-0.88, p=0.038) had a positive impact on overall survival. Sex, time from CAR T-cell therapy to COVID-19 diagnosis, disease remission status and the occurrence of neurotoxicity or cytokine release syndrome after CAR T-cell infusion did not have a significant effect on overall survival in the multivariate analysis. Conclusion Patients with COVID-19 after B-cell-targeted CAR T-cell therapy have a very poor outcome. As it remains uncertain whether currently applied vaccination strategies against SARS-CoV-2 are effective after CAR T-cell therapy, vaccination of health-care personnel and family members in combination with protective measures against viral exposure are likely to play the most important role in protecting this vulnerable group of patients. Better treatment strategies are urgently needed. Figure 1 Figure 1. Disclosures Ljungman: OctaPharma: Other: DSMB; Enanta: Other: DSMB; Janssen: Other: Investigator; Takeda: Consultancy, Other: Endpoint committee, speaker; AiCuris: Consultancy; Merck: Other: Investigator, speaker. De La Camara: IQONE: Consultancy; Roche: Consultancy. Ortiz-Maldonado: Kite, Novartis, BMS, Janssen: Honoraria. Barba: Novartis: Honoraria; Gilead: Honoraria; BMS: Honoraria; Amgen: Honoraria; Pfizer: Honoraria. Kwon: Novartis, Celgene, Gilead, Pfizer: Consultancy, Honoraria. Sesques: Novartis: Honoraria; Chugai: Honoraria; Kite, a Gilead Company: Honoraria. Bachy: Kite, a Gilead Company: Honoraria; Novartis: Honoraria; Daiishi: Research Funding; Roche: Consultancy; Takeda: Consultancy; Incyte: Consultancy. Di Blasi: Kite, a Gilead Company: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Thieblemont: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses , Research Funding; Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Hospira: Research Funding; Bayer: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses . Mutsaers: BMS: Consultancy; AstraZeneca: Research Funding. Nicholson: Kite, a Gilead Company: Other: Conference fees, Speakers Bureau; Novartis: Consultancy, Other: Conference fees; BMS/Celgene: Consultancy; Pfizer: Consultancy. Martínez-López: Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfizer: Consultancy; Roche, Novartis, Incyte, Astellas, BMS: Research Funding. Ribera: NOVARTIS: Consultancy, Speakers Bureau; TAKEDA: Consultancy, Research Funding, Speakers Bureau; ARIAD: Consultancy, Research Funding, Speakers Bureau; SHIRE: Consultancy, Speakers Bureau; AMGEN: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau. Sanderson: Kite, a Gilead Company: Honoraria; Novartis: Honoraria. Bloor: Kite, a Gilead Company: Honoraria; Novartis: Honoraria. Ciceri: IRCCS Ospedale San Raffaele: Current Employment. Ayuk: Novartis: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Mallinckrodt/Therakos: Honoraria, Research Funding; Gilead: Honoraria; Miltenyi Biomedicine: Honoraria; Celgene/BMS: Honoraria. Kröger: Novartis: Research Funding; Riemser: Honoraria, Research Funding; Sanofi: Honoraria; Neovii: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Gilead/Kite: Honoraria; Celgene: Honoraria, Research Funding; AOP Pharma: Honoraria. Kersten: Celgene: Research Funding; Miltenyi Biotec: Consultancy, Honoraria, Other: Travel support; Roche: Consultancy, Honoraria, Other: Travel support, Research Funding; BMS/Celgene: Consultancy, Honoraria; Takeda: Research Funding; Novartis: Consultancy, Honoraria, Other: Travel support; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support, Research Funding. Mielke: DNA Prime SA: Speakers Bureau; Immunicum: Other: Data safety monitoring board; Novartis: Speakers Bureau; Miltenyi: Other: Data safety monitoring board; Gilead/KITE: Other: Travel support, Expert panel ; Celgene/BMS: Speakers Bureau.