Impaired immune response to COVID-19 vaccination in patients with B-cell malignancies after CD19 CAR T-cell therapy

Dahiya, Saurabh; Luetkens, Tim; Lutfi, Forat; Avila, Stephanie V; Iraguha, Thierry; Margiotta, Philip; Hankey, Kim G.; Lesho, Patricia; Law, Jennie Y.; LEE, SEUNG TAE; Baddley, John W.; Kocoglu, Mehmet H.; Yared, Jean A.; Hardy, Nancy M.; Rapoport, Aaron P.; Atanackovic, Djordje

doi:10.1182/bloodadvances.2021006112

Cited by 25 publications

(21 citation statements)

References 11 publications

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“…We postulate that these agents may decrease humoral immunity beyond traditional CD20‐directed therapies. Of note, similar low seroconversion rates have been reported among recipients of CD19‐directed chimeric antigen receptor T‐cell therapy, although, in current practice, that treatment is given to patients with relapsed/refractory lymphomas after multiple lines of immunosuppressive chemotherapy 22 . All of our patients received the bispecific CD20/CD3 antibodies on clinical trials, but many were received as first‐line therapy for diffuse large B‐cell lymphoma.…”

Section: Discussionsupporting

confidence: 66%

Seroconversion and outcomes after initial and booster COVID‐19 vaccination in adults with hematologic malignancies

Ollila

Masel

Reagan

et al. 2022

Cancer

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Background Patients with hematologic malignancies have impaired humoral immunity secondary to their malignancy and its treatment, placing them at risk of severe coronavirus disease‐19 (COVID‐19) infection and reduced response to vaccination. Methods The authors retrospectively analyzed serologic responses to initial and booster COVID‐19 vaccination in 378 patients with hematologic malignancy and subsequently tracked COVID‐19–related outcomes. Results Seroconversion occurred in 181 patients (48%) after initial vaccination; patients who had active malignancy or those who were recently treated with a B‐cell–depleting monoclonal antibody had the lowest rates of seroconversion. For initial nonresponders to vaccination, seroconversion after a booster dose occurred in 48 of 85 patients (56%). The seroconversion rate after the booster was similar for patients on (53%) and off (58%) active therapy (p = .82). Thirty‐three patients (8.8%) developed a COVID‐19 infection, and there were three COVID‐19–related deaths (0.8%). Although no significant association was observed between postvaccination seroconversion and the incidence of COVID‐19 infection, no patient with seroconversion died from COVID‐19, and no patient who received tixagevimab/cilgavimab (N = 25) was diagnosed with a COVID‐19 infection. Conclusions Booster vaccinations can promote seroconversion in a significant proportion of patients who are seronegative after the initial vaccination course regardless of the specific vaccine or on/off treatment status at the time of revaccination. Although postvaccination seroconversion may not be associated with a decrease in any (including asymptomatic) COVID‐19 infection, the authors' experience suggested that effective vaccination (including a booster), supplemented by passive immunization using tixagevimab/cilgavimab in case of lack of seroconversion, effectively eliminated the risk of COVID‐19 death in the otherwise high‐risk population. Lay summary Patients with hematologic malignancy, especially lymphoma, have an impaired response to coronavirus disease 2019 (COVID‐19) vaccination. In this single‐institution review, less than one half of the patients studied made detectable antibodies. For those who did not make detectable antibodies after initial vaccination, over one half (65%) were able to produce antibodies after booster vaccination. By the end of February 2022, 33 of the original 378 patients had a documented COVID‐19 infection. The only deaths from COVID‐19 were in those who had undetectable antibodies, and no patient who received prophylactic antibody therapy developed a COVID‐19 infection.

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Section: Discussionsupporting

confidence: 66%

Seroconversion and outcomes after initial and booster COVID‐19 vaccination in adults with hematologic malignancies

Ollila

Masel

Reagan

et al. 2022

Cancer

View full text Add to dashboard Cite

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“…This is consistent with Dahiya et al, which reported that antibody responses to common pathogens such as Epstein-Barr virus and in uenza were preserved despite their lower seroconversion rate against SARS-CoV-2 in CD19-directed CAR-T recepients. 13 Conversely, BCMA-targeting therapies eliminate mature plasma cells that are responsible for longterm immunity 35 . As such, while targeting BCMA may eliminate preexisting immunity from vaccinations before CAR-T therapy, it may be less disruptive to developing post-treatment immunity compared to CD19-directed treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Four studies included humoral responses to a third or fourth dose of either the BNT162b2 or mRNA1273 vaccines in a total of 55 patients. 7,[11][12][13] The Roche Elecsys anti-SARS-CoV-2 S enzyme immunoassay was the most common humoral response assessment platform (6 studies) [14][15][16][17][18] , whereas 5 studies utilized the AdviseDx SARS-CoV-2 IgG II assay 11,[19][20][21][22] . Other commercial assays included the EUROIMMUN ELISA, Meso Scale discovery electrochemiluminescence assay, COVID-SeroKlir Kantaro SARS-CoV-2 IgG assay, and Atellica IM SARS-CoV-2 IgG (sCOVG) assay 12,23,24 .…”

Section: Study Characteristicsmentioning

confidence: 99%

“…Other commercial assays included the EUROIMMUN ELISA, Meso Scale discovery electrochemiluminescence assay, COVID-SeroKlir Kantaro SARS-CoV-2 IgG assay, and Atellica IM SARS-CoV-2 IgG (sCOVG) assay 12,23,24 . Dahiya et al and Parvathaneni et al utilized an unspeci ed ELISA for S1-and RBD-IgG or only RBD-IgG respectively 13,25 . Haggenburg et al employed a bead-based multiplex assay involving S1 and RBD spike protein subunits and nucleoprotein coupled to microspheres (Table 1) 26,27 .…”

Section: Study Characteristicsmentioning

confidence: 99%

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Efficacy of SARS-CoV-2 primary and booster vaccine doses in CAR-T recipients

Abid

Uyemura

et al. 2022

Preprint

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While multiple studies have demonstrated diminished humoral response to vaccinations against COVID-19 in immunocompromised patients, data are limited in chimeric antigen receptor T-cell (CAR-T) recipients. In this systematic review, we identified 18 studies through a manual search of key databases that reported SARS-CoV-2 vaccine responses in 236 CAR-T recipients. This included data from 184 recipients of CD19-directed CAR-T and 29 BCMA- or CD138-directed CAR-T therapy. The pooled humoral response rate across 18 studies was 25.8% (61/236), irrespective of number of vaccine doses. The vaccine response rate among patients who only completed their primary vaccine series with 2 doses, was 27.6% across 15 studies (50/181). The pooled seroconversion rate after receiving a third or fourth dose of vaccine was 20% in 4 studies (11/55). Recipients of CD19-directed CAR-T products had a seroconversion rate of 19.2% (25/130) compared to 71.4% (20/28) among those who received BCMA- or CD138-directed therapies after completion of a primary course of vaccination. Given a high COVID-19 attributable mortality and blunted seroconversion rates in CAR-T recipients, these results provide guidance to cellular therapy centers in terms of identifying higher risk patients. In the setting of ongoing highly transmissible variants of concern, the results are hypothesis-generating in terms of potential for earlier utilization of novel strategies such as the use of monoclonal antibodies in those CAR-T recipients less likely to respond to vaccines.

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“…However, emerging data suggests that despite these vaccines inducing high levels of immunity in the general population, patients with hematologic malignancies have lower rates of seroconversion as defined by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 ) spike antibody (anti-S antibody) titers [12,13]. Evidence has also suggested that specific therapies, such as anti-CD20 antibodies, BTKinhibitors and stem cell transplantation (SCT) have an association with lower rates of seroconversion [14][15][16]. We previously published preliminary results of a study defining notable impacts of a 3 rd booster dose of vaccine, demonstrating a more than 50% seroconversion rate amongst patients remaining seronegative after primary vaccinations [17].…”

Section: Introductionmentioning

confidence: 99%

Efficacy and longevity of immune response to 3^rd COVID-19 vaccine and effectiveness of a 4^th dose in severely immunocompromised patients with cancer

Thakkar

Pradhan

Duva

et al. 2022

Preprint

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Cancer patients show increased morbidity with COVID-19 and need effective immunization strategies. We demonstrate that a 3rd dose of COVID-19 vaccine leads to seroconversion in 57% of patients that were seronegative after primary vaccination. The immune response is durable as assessed by anti-S antibody titers, T-cell activity and neutralization activity against wild-type SARS-CoV2 and BA1.1.529 at 6 months of follow up. A subset of severely immunocompromised hematologic malignancy patients were unable to mount adequate immune response after the 3rd dose and were treated with a 4th dose in a prospective clinical trial which led to adequate immune-boost in 67% of patients. Low baseline IgM levels and CD19 counts were associated with inadequate seroconversion. Booster doses induced limited neutralization activity against the Omicron variant. These results indicate that vaccine booster-induced immunity is durable in cancer patients and additional doses can further stimulate immunity in a subset of hematologic malignancy patients.Statement of significanceWe demonstrate that a 3rd dose of vaccine leads to seroconversion in 57% of negative patients with durable immune responses at 6 months. A 4th dose of vaccine can seroconvert hematologic malignancy patients with higher baseline IgM and CD19 levels.

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Impaired immune response to COVID-19 vaccination in patients with B-cell malignancies after CD19 CAR T-cell therapy

Cited by 25 publications

References 11 publications

Seroconversion and outcomes after initial and booster COVID‐19 vaccination in adults with hematologic malignancies

Seroconversion and outcomes after initial and booster COVID‐19 vaccination in adults with hematologic malignancies

Efficacy of SARS-CoV-2 primary and booster vaccine doses in CAR-T recipients

Efficacy and longevity of immune response to 3^rd COVID-19 vaccine and effectiveness of a 4^th dose in severely immunocompromised patients with cancer

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Impaired immune response to COVID-19 vaccination in patients with B-cell malignancies after CD19 CAR T-cell therapy

Cited by 25 publications

References 11 publications

Seroconversion and outcomes after initial and booster COVID‐19 vaccination in adults with hematologic malignancies

Seroconversion and outcomes after initial and booster COVID‐19 vaccination in adults with hematologic malignancies

Efficacy of SARS-CoV-2 primary and booster vaccine doses in CAR-T recipients

Efficacy and longevity of immune response to 3rd COVID-19 vaccine and effectiveness of a 4th dose in severely immunocompromised patients with cancer

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Product

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Efficacy and longevity of immune response to 3^rd COVID-19 vaccine and effectiveness of a 4^th dose in severely immunocompromised patients with cancer