SARS-CoV-2 Spike-Specific T-Cell Responses in Patients With B-Cell Depletion Who Received Chimeric Antigen Receptor T-Cell Treatments | Targeted and Immune Cancer Therapy | JAMA Oncology | JAMA Network
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Figure.  SARS-CoV-2 Spike-Specific Antibody and T-Cell Responses of Healthy Controls and Patients Treated With CAR T Cells After Spike mRNA Vaccination
SARS-CoV-2 Spike-Specific Antibody and T-Cell Responses of Healthy Controls and Patients Treated With CAR T Cells After Spike mRNA Vaccination

A, Spike RBD-IgG measured with the enzyme-linked immunosorbent assay before and after the primary and booster vaccinations for patients treated with CAR T cells and healthy controls. B, Spike-specific memory CD4+ (mCD4+) T-cell responses measured before and after the primary and booster vaccinations for patients treated with CAR T cells and healthy controls. Dashed horizontal lines indicate the thresholds of positive (top), equivocal (middle), and negative (bottom) reactivity based on clinical laboratory validation data using the same assay. For the CART cohort, brown points and lines represent 4 patients who had strong SARS-CoV-2–specific CD4 T-cell responses despite robust B-cell depletion. AIM indicates activation-induced marker; CAR, chimeric antigen receptor; CART, chimeric antigen receptor T-cell treatment; IgG, immunoglobulin G; mRNA, messenger RNA; OD450, optical density at 450 nm; RBD, receptor binding domain.

Table.  Participant Characteristicsa
Participant Characteristicsa
1.
Goel  RR, Apostolidis  SA, Painter  MM,  et al.  Distinct antibody and memory B cell responses in SARS-CoV-2 naïve and recovered individuals following mRNA vaccination.   Sci Immunol. 2021;6(58):eabi6950. doi:10.1126/sciimmunol.abi6950 PubMedGoogle Scholar
2.
Van Oekelen  O, Gleason  CR, Agte  S,  et al; PVI/Seronet Team.  Highly variable SARS-CoV-2 spike antibody responses to two doses of COVID-19 RNA vaccination in patients with multiple myeloma.   Cancer Cell. 2021;39(8):1028-1030. doi:10.1016/j.ccell.2021.06.014 PubMedGoogle ScholarCrossref
3.
Dhakal  B, Abedin  SM, Fenske  TS,  et al.  Response to SARS-CoV-2 vaccination in patients after hematopoietic cell transplantation and CAR-T cell therapy.   Blood. 2021;blood.2021012769. PubMedGoogle Scholar
4.
Massarweh  A, Eliakim-Raz  N, Stemmer  A,  et al.  Evaluation of seropositivity following BNT162b2 messenger RNA vaccination for SARS-CoV-2 in patients undergoing treatment for cancer.   JAMA Oncol. 2021;7(8):1133-1140. doi:10.1001/jamaoncol.2021.2155 PubMedGoogle ScholarCrossref
5.
Cucchiari  D, Egri  N, Bodro  M,  et al.  Cellular and humoral response after mRNA-1273 SARS-CoV-2 vaccine in kidney transplant recipients.   Am J Transplant. 2021;21(8):2727-2739. doi:10.1111/ajt.16701 PubMedGoogle ScholarCrossref
6.
Bhoj  VG, Arhontoulis  D, Wertheim  G,  et al.  Persistence of long-lived plasma cells and humoral immunity in individuals responding to CD19-directed CAR T-cell therapy.   Blood. 2016;128(3):360-370. doi:10.1182/blood-2016-01-694356 PubMedGoogle ScholarCrossref
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    Research Letter
    November 18, 2021

    SARS-CoV-2 Spike-Specific T-Cell Responses in Patients With B-Cell Depletion Who Received Chimeric Antigen Receptor T-Cell Treatments

    Author Affiliations
    • 1Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
    • 2Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia
    • 3Department of Microbiology, University of Pennsylvania, Philadelphia
    • 4Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia
    • 5Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia
    • 6Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia
    JAMA Oncol. Published online November 18, 2021. doi:10.1001/jamaoncol.2021.6030

    Two messenger RNA (mRNA)-based vaccines, BNT162b2 and mRNA-1273, are currently available for SARS-CoV-2. Both vaccines have been shown to induce protective immunity against SARS-CoV-2 for most healthy individuals.1 Recent studies have demonstrated a substantially lower rate of antibody induction by both SARS-CoV-2 mRNA vaccines among patients with immunosuppression, including individuals with cancer.2-5 However, the immunogenicity of SARS-CoV-2 mRNA vaccines among patients with selective B-cell deficiency is not well known.

    Studies are ongoing to assess vaccine-induced antibody and T-cell responses among patients treated with chimeric antigen receptor (CAR) T cells that lead to substantial B-cell depletion in humans.

    Chimeric antigen receptor T-cell therapies targeting B-cell lineage antigens, most notably CD19 and CD22, have demonstrated remarkable success in inducing the remission of advanced B-cell–derived cancers and have been administered to more than 10 000 patients globally. A successful response to these therapies is often accompanied by substantial B-cell depletion lasting for months to years.6 We previously showed that despite persistent B-cell depletion, some patients maintain preexisting protective humoral immunity.6 However, to our knowledge, their ability to mount new antibody responses and T-cell immunity has not yet been reported. Here, we determined whether patients with hematologic cancers treated with CAR T cells targeting the CD19 and/or CD22 B-cell lineage antigens can mount antibody and T-cell responses to SARS-CoV-2 vaccines.

    Methods

    For this cohort study, written informed consent for participation was obtained from all patients or their guardians according to the Declaration of Helsinki, and the protocols were approved by the institutional review boards of the University of Pennsylvania and Children’s Hospital of Philadelphia. The study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

    We enrolled 12 patients who achieved complete remission after receiving CAR T-cell treatments (CART) that targeted either the CD19 antigen (7 patients) or the CD19 and CD22 combination (5 patients; Table). Eight healthy adults were enrolled as controls. Race and ethnicity were self-reported. All participants received 2 doses of either the BNT162b2 or mRNA-1273 vaccine. We measured the SARS-CoV-2 spike receptor binding domain (RBD) antibodies and spike-specific T-cell responses in blood samples obtained at 5 or fewer time points up to 28 days after the second (booster) dose.

    Statistical analyses were conducted using Prism (version 7.0e, Graphpad Software) and R software (R Core Team) and the nlme package. A Mann-Whitney test was performed as a nonparametric t test and a Kruskal-Wallis test with Dunns test was performed for multiple group comparisons. Mixed-effects model analyses were used to compare longitudinal T-cell responses. A P value of .05 was used as a threshold for statistical significance.

    Results

    All 8 healthy controls produced RBD-immunoglobulin G (IgG) compared with 5 of 12 patients who received CAR T-cell treatments (Figure, A). One month after the booster vaccination when the antibody responses were at the highest levels in both groups (visit 5), the level of RBD-IgG was significantly lower among the CART cohort (median optical density at 450 nm [IQR], 0.47 [0.11-1.36] for CART patients and 1.57 [1.53-1.64] for healthy controls; P <.001). As expected, among the CART cohort, RBD-IgG positivity was associated with higher circulating B-cell levels (mean B-cell count/μL [SD] for RBD-IgG positive, 57.2 [20.2]; for RBD-IgG equivocal, 12.5 [17.7]; for RBD-IgG negative, 9 [10.1]; P < .05 for RBD-IgG positive vs negative). RBD-IgA was detected for 7 of 8 healthy controls compared with 2 of 12 patients in the CART cohort.

    Robust CD4 T-cell responses were detected for all 8 healthy controls, and a comparable T-cell induction was seen for 8 of 12 patients treated in the CART cohort (Figure, B). One month after the booster vaccination, we found no significant difference in the frequency of spike-specific CD4 T cells between the healthy control cohort and the CART cohort (Cohen d effect size, 0.30 [95% CI, 0.04 to 0.45 and 0.06 to 0.31, respectively]; P = .66). In addition, the kinetics of CD4 T-cell responses did not differ between the cohorts over the course of the study, in which predicted slopes of the CD4 T-cell response over time were estimated by the linear mixed-effects model for the healthy control cohort (6.3% per visit) and CART cohort (5.5% per visit) (likelihood ratio test for the difference in slopes, −1.12 [95% CI, −2.30 to 9.22; t value = 0.48, P = .63). Notably, we observed strong SARS-CoV-2–specific CD4 T-cell responses for 4 patients who had robust B-cell depletion by CAR T cells; none had induced SARS-CoV-2–specific antibodies after mRNA vaccination (Figure, B).

    Discussion

    Although this study is limited by its small sample size, we show that immune responses to SARS-CoV-2 mRNA vaccines are induced for the majority of patients who have been treated with CAR T-cell therapies targeting B-cell lineage antigens. An induction of a vaccine-specific antibody was associated with the level of circulating B cells. However, strong CD4 T-cell responses were observed even for some patients with severe humoral immune deficiency. Further refinement of vaccination strategies to promote cell-mediated immunity may enhance immune protection for individuals with B-cell deficiency. Currently, we support SARS-CoV-2 vaccination for all recipients of anti–B-cell CAR T-cell therapies, with close monitoring for immunologic responses to verify our findings in larger cohorts.

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    Article Information

    Accepted for Publication: September 17, 2021.

    Published Online: November 18, 2021. doi:10.1001/jamaoncol.2021.6030

    Corresponding Author: Vijay G. Bhoj, MD, PhD, Department of Pathology and Laboratory Medicine, Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, South Tower Pavilion, 8-111, 3400 Civic Ctr Blvd, Philadelphia, PA 19104 (vbhoj@pennmedicine.upenn.edu).

    Author Contributions: Drs Parvathaneni and Bhoj had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Dr Parvathaneni and Ms Torres-Rodriguez contributed equally to this work.

    Concept and design: Parvathaneni, Frey, Naji, Bhoj.

    Acquisition, analysis, or interpretation of data: Parvathaneni, Torres-Rodriguez, Meng, Hwang, Naji, Bhoj.

    Drafting of the manuscript: Parvathaneni, Meng, Naji, Bhoj.

    Critical revision of the manuscript for important intellectual content: Parvathaneni, Frey, Hwang, Naji, Bhoj.

    Statistical analysis: Parvathaneni, Torres-Rodriguez, Meng, Hwang.

    Obtained funding: Naji, Bhoj.

    Administrative, technical, or material support: Parvathaneni, Meng.

    Conflict of Interest Disclosures: Dr Bhoj reported having a patent (US20170051035A1) with royalties paid from Cabaletta Bio. No other disclosures were reported.

    Funding/Support: This work was supported by the Gift of Life Transplant Foundation (Drs Naji and Bhoj), the National Blood Foundation (Dr Bhoj), and the Burroughs Wellcome Fund (Dr Bhoj).

    Role of the Funder/Sponsor: The Gift of Life Transplant Foundation, the National Blood Foundation, and the Burroughs Wellcome Fund had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Additional Contributions: The authors thank the patients for their participation in this study. The authors also thank members of the University of Pennsylvania Oncology COVID Collaborative Group, including Divyansh Agarwal, MD, PhD; Mary Kaminski, PA; Leticia Kuri-Cervantes, PhD; James J. Knox, PhD; Zheng Zhang, MD, PhD; Xiaoming Xu, MS; Jennifer Trofe-Clark, PharmD; Alfred Garfall, MD; Eline T. Luning Prak, MD, PhD; David L. Porter, MD; Carl H. June, MD; and Michael R. Betts, PhD. In addition, the authors Michela Locci, PhD, and Divij Matthew, PhD, for advice related to the T-cell assays; Scott Hensley, PhD, for providing the RBD antigen; Alessandro Sette, PhD, for generously providing the spike protein peptide pools; Diane Mclaughlin and Sarah Benchimol for administrative assistance; Susan Rostami for assistance with sample processing; and David Miklos, MD, PhD; James Gerson, MD; Daniel Landsburg, MD; Saar Gill, MD, PhD; and Stephen Grupp, MD, PhD, for patient referrals. Finally, the authors thank the following cores for assistance: the Human Immunology Core and the Flow Cytometry Core at the University of Pennsylvania, the Clinical Trials Unit and the Clinical Vaccine Production Facility at the University of Pennsylvania, the Clinical and Translational Research Unit at Stanford University, and the Parker Cancer Institute at the University of Pennsylvania.

    References
    1.
    Goel  RR, Apostolidis  SA, Painter  MM,  et al.  Distinct antibody and memory B cell responses in SARS-CoV-2 naïve and recovered individuals following mRNA vaccination.   Sci Immunol. 2021;6(58):eabi6950. doi:10.1126/sciimmunol.abi6950 PubMedGoogle Scholar
    2.
    Van Oekelen  O, Gleason  CR, Agte  S,  et al; PVI/Seronet Team.  Highly variable SARS-CoV-2 spike antibody responses to two doses of COVID-19 RNA vaccination in patients with multiple myeloma.   Cancer Cell. 2021;39(8):1028-1030. doi:10.1016/j.ccell.2021.06.014 PubMedGoogle ScholarCrossref
    3.
    Dhakal  B, Abedin  SM, Fenske  TS,  et al.  Response to SARS-CoV-2 vaccination in patients after hematopoietic cell transplantation and CAR-T cell therapy.   Blood. 2021;blood.2021012769. PubMedGoogle Scholar
    4.
    Massarweh  A, Eliakim-Raz  N, Stemmer  A,  et al.  Evaluation of seropositivity following BNT162b2 messenger RNA vaccination for SARS-CoV-2 in patients undergoing treatment for cancer.   JAMA Oncol. 2021;7(8):1133-1140. doi:10.1001/jamaoncol.2021.2155 PubMedGoogle ScholarCrossref
    5.
    Cucchiari  D, Egri  N, Bodro  M,  et al.  Cellular and humoral response after mRNA-1273 SARS-CoV-2 vaccine in kidney transplant recipients.   Am J Transplant. 2021;21(8):2727-2739. doi:10.1111/ajt.16701 PubMedGoogle ScholarCrossref
    6.
    Bhoj  VG, Arhontoulis  D, Wertheim  G,  et al.  Persistence of long-lived plasma cells and humoral immunity in individuals responding to CD19-directed CAR T-cell therapy.   Blood. 2016;128(3):360-370. doi:10.1182/blood-2016-01-694356 PubMedGoogle ScholarCrossref
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