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. 2024 Apr 10;78(4):1022-1032.
doi: 10.1093/cid/ciad708.

Cytomegalovirus (CMV) Reactivation and CMV-Specific Cell-Mediated Immunity After Chimeric Antigen Receptor T-Cell Therapy

Eleftheria Kampouri  1 , Sarah S Ibrahimi  1 , Hu Xie  2 , Elizabeth R Wong  1 , Jessica B Hecht  1 , Mandeep K Sekhon  1 , Alythia Vo  1 , Terry L Stevens-Ayers  1 , Damian J Green  3   4 , Jordan Gauthier  2   4 , David G Maloney  2   4 , Ailyn Perez  5 , Keith R Jerome  1   5 , Wendy M Leisenring  2   6 , Michael J Boeckh  1   2   4 , Joshua A Hill  1   2   4
Affiliations

Cytomegalovirus (CMV) Reactivation and CMV-Specific Cell-Mediated Immunity After Chimeric Antigen Receptor T-Cell Therapy

Eleftheria Kampouri et al. Clin Infect Dis. .

Abstract

Background: The epidemiology of cytomegalovirus (CMV) after chimeric antigen receptor-modified T-cell immunotherapy (CARTx) is poorly understood owing to a lack of routine surveillance.

Methods: We prospectively enrolled 72 adult CMV-seropositive CD19-, CD20-, or BCMA-targeted CARTx recipients and tested plasma samples for CMV before and weekly up to 12 weeks after CARTx. We assessed CMV-specific cell-mediated immunity (CMV-CMI) before and 2 and 4 weeks after CARTx, using an interferon γ release assay to quantify T-cell responses to IE-1 and pp65. We tested pre-CARTx samples to calculate a risk score for cytopenias and infection (CAR-HEMATOTOX). We used Cox regression to evaluate CMV risk factors and evaluated the predictive performance of CMV-CMI for CMV reactivation in receiver operator characteristic curves.

Results: CMV was detected in 1 patient (1.4%) before and in 18 (25%) after CARTx, for a cumulative incidence of 27% (95% confidence interval, 16.8-38.2). The median CMV viral load (interquartile range) was 127 (interquartile range, 61-276) IU/mL, with no end-organ disease observed; 5 patients received preemptive therapy based on clinical results. CMV-CMI values reached a nadir 2 weeks after infusion and recovered to baseline levels by week 4. In adjusted models, BCMA-CARTx (vs CD19/CD20) and corticosteroid use for >3 days were significantly associated with CMV reactivation, and possible associations were detected for lower week 2 CMV-CMI and more prior antitumor regimens. The cumulative incidence of CMV reactivation almost doubled when stratified by BCMA-CARTx target and use of corticosteroids for >3 days (46% and 49%, respectively).

Conclusions: CMV testing could be considered between 2 and 6 weeks in high-risk CARTx recipients.

Keywords: CAR; CMV; chimeric antigen receptor; cytomegalovirus; immunotherapy.

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Conflict of interest statement

Potential conflicts of interest. E. K. reports travel support from Merck to attend the International Immunocompromised Host Society (ICHS) symposium 2022. D. J. G. has served as an advisor and has received research funding and royalties from Juno Therapeutics, a Bristol-Myers Squibb company; has served as an advisor and received research funding from Seattle Genetics; has served as an advisor for GlaxoSmithKline, Celgene, Ensoma, Janssen Biotech, and Legend Biotech; and has received research funding from SpringWorks Therapeutics, Sanofi, and Cellectar Biosciences. J. G. has served as ad hoc consultant and has received honoraria from Sobi, Legend Biotech, Janssen, Kite Pharma, and MorphoSys; has received research funding from Sobi, Juno Therapeutics (a Bristol-Myers Squibb company), Celgene (a Bristol-Myers Squibb company), and Angiocrine Bioscience; and has participated in the independent data review committee for Century Therapeutics. D. G. M. has served as ad hoc consultant and has received honoraria from BMS, Celgene, Genentech, Juno Therapeutics, and Kite. D. G. M.'s institution, Fred Hutchinson Cancer Center, has received research funding, including salary support, from the following companies for clinical trials on which D. G. M. is a principal investigator or subinvestigator: Kite Pharma, Juno Therapeutics, Celgene, Legend Biotech, and BMS. D. G. M. has the rights to royalties from the Fred Hutchinson Cancer Center for patents licensed to Juno Therapeutics/BMS; has stock options from A2 Biotherapeutics and Navan Technologies; has served as member with compensation for A2 Biotherapeutics, Navan, and Chimeric Therapeutics (member of the Scientific Advisory Board), Genentech (member and chair of the Lymphoma Steering Committee), BMS (member of the JCAR017 EAP-001 Safety Review Committee), BMS (member of the CLL Strategic Council), ImmPACT Bio (member of the Clinical Advisory Board and the CD19/CD20 bispecific CAR-T Cell Therapy Program), Gilead Sciences (member of the Scientific Review Committee and Research Scholars Program in Hematologic Malignancies), and Interius (member of Clinical Advisory Board); has served as member without compensation for BMS (member of the JCAR017-BCM-03 Scientific Steering Committee). M. J. B has served as consultant and has received research funding from Merck; has served as consultant for Symbio, Helocyte, Moderna, and Allovir; and has served as a consultant and had option to acquire stock for EvrysBio. J. A. H. has served as a consultant for Moderna, Allovir, Gilead, SentiBio, Modulus, and Allogene and received research funding from Allovir, Gilead, and Merck. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Graphical Abstract
Graphical Abstract
This graphical abstract is also available at Tidbit: https://tidbitapp.io/tidbits/cmv-reactivation-and-cmv-specific-cell-mediated-immunity-after-chimeric-antigen-receptor-t-cell-therapy
Figure 1.
Figure 1.
CONSORT flow diagram. Between 1 August 2021 and 17 November 2022, a total of 146 chimeric antigen receptor (CAR)–T-cell infusions were administered in 141 patients with B-cell hematologic cancer, excluding 6 patients who did not sign general consent and were excluded. Among 89 cytomegalovirus (CMV)–seropositive patients, 14 declined, 4 were not approached, and 2 withdrew after enrollment, leading to a total of 72 CAR–T-cell infusions in 69 patients analyzed; consent to follow-up for 12 weeks was obtained in 61 infusion events, and consent to follow-up for up to 4 weeks in 11 infusion events.
Figure 2.
Figure 2.
Cumulative incidence and kinetics of cytomegalovirus (CMV) reactivation within 12 weeks after chimeric antigen receptor (CAR) T-cell infusion. A, Cumulative incidence curve of any CMV reactivation within 12 weeks: 27% (95% confidence interval; 17%–38% (depicted by shading). B, Heat map of CMV reactivation kinetics. Each row represents a patient, and each square a plasma sample. The intensity of color represents the viral load (negative samples are depicted as white). BCMA-CARTx recipients are depicted at the bottom, and CD19/CD20 CARTx recipients at the top of the heat map.
Figure 3.
Figure 3.
Comparison of cytomegalovirus (CMV)–specific cell-mediated immunity (CMV-CMI) (T-cell responses to IE-1 and pp65) at time points before and 2 and 4 weeks after chimeric antigen receptor–modified T-cell immunotherapy (CARTx), overall and among patients with versus without CMV reactivation. A, B, Box plots of CMV-CMI at each time point in all participants for IE-1 (A) and pp65 (B). C, D, Box plots of CMV-CMI at each time point stratified by subsequent development of CMV reactivation or not (relative to each time point) for IE-1 (C) and pp65 (D); patients with CMV reactivation before each time point are not depicted. Horizontal lines and the boxes represent median values and upper and lower quartiles, respectively; circles represent all values. Wilcoxon rank sum and Wilcoxon signed rank tests were used as appropriate. *P < .001. Abbreviation: SPCs, spot counts.
Figure 4.
Figure 4.
Forest plots of multivariable Cox regression models for cytomegalovirus (CMV) reactivation within 12 weeks after chimeric antigen receptor (CAR) T-cell therapy. Forest plot of 4 models incorporating unique sets of variables. A, B, Data on participants with available CMV-specific cell-mediated immunity (CMV-CMI) results (69 infusions in 66 participants). C, D, Data on all studied infusions (72 infusions in 69 participants). CMV-CMI and corticosteroids were evaluated as time-dependent variables. Abbreviations: CI, confidence interval; CRS, cytokine release syndrome; HR, hazard ratio; ICANS, immune effector cell–associated neurotoxicity syndrome; SPCs, spot counts.
Figure 5.
Figure 5.
Cumulative incidence of cytomegalovirus (CMV) reactivation by week 12 after chimeric antigen receptor (CAR)–modified T-cell therapy (CARTx), stratified by key clinical characteristics. A, Stratification by CAR–T-cell therapy target: BCMA (46% [95% confidence interval (CI), 17%–72%]) versus CD19/CD20 (23% [12%–35%]). B, Stratification by receipt of corticosteroids for cytokine release syndrome (CRS)/immune effector cell–associated neurotoxicity syndrome (ICANS) for >3 days: 49% (95% CI, 21%–73%) versus no steroids or steroids for <3 days: 20% (10%–33%). Curves start at day 11, after corticosteroid onset for CRS/ICANS (onset of corticosteroids >3 days by day 11 in all patients but 3, who were excluded from this plot; all CMV events occurred after day 11). C, Stratification by CARTx target and receipt of corticosteroids: BCMA with or without (w/o) corticosteroids for >3 days, 100% and 38%, respectively; CD19/20 with or without corticosteroids, 41% and 18%. Curves start at day 11 after corticosteroid onset for CRS/ICANS (onset by day 11 in all but 3 patients, who were excluded from this plot; all CMV events occurred after day 11). D, Stratification by presence of low CMV-specific cell-mediated immunity (CMV-CMI) at week 2 (defined as IE-1 and/or pp65 below median): high CMV-CMI, 14% (95% CI, 4%–30%) versus low CMV-CMI: 38% (22%–53%). Curves start at week 2 and include data on 69 patients with available CMV-CMI results. Abbreviation: SPCs, spot counts.
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