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Clinical Trial
. 2021 Sep 23;138(12):1081-1085.
doi: 10.1182/blood.2021010930.

CD19 target evasion as a mechanism of relapse in large B-cell lymphoma treated with axicabtagene ciloleucel

Vicki Plaks  1 , John M Rossi  1 , Justin Chou  1 , Linghua Wang  2 , Soumya Poddar  1 , Guangchun Han  2 , Zixing Wang  1 , Shao-Qing Kuang  2 , Fuliang Chu  2 , Richard E Davis  2 , Francisco Vega  2 , Zahid Bashir  1 , Caron A Jacobson  3 , Frederick L Locke  4 , Patrick M Reagan  5 , Scott J Rodig  6 , Lazaros J Lekakis  7 , Ian W Flinn  8 , David B Miklos  9 , Adrian Bot  1 , Sattva S Neelapu  2
Affiliations
Clinical Trial

CD19 target evasion as a mechanism of relapse in large B-cell lymphoma treated with axicabtagene ciloleucel

Vicki Plaks et al. Blood. .
No abstract available

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Figures

Figure 1.
Figure 1.
Association between CD19 levels at pretreatment or relapse and response. (A) Pretreatment CD19 H-score distribution in ZUMA-1 patients (N = 100) ordered by CD20 H-score: 90% CD19+, 93% CD20+, and 98% CD19+, and/or CD20+. CD19 and CD20 positivity was defined as H-score >5. (B) Association between pretreatment CD19 H-score with engraftment index (CAR T Peak/SPD) and clinical response. (C) Swimmer plot of relapse patients (N = 20) by CD19 status and peak CAR T-cell level. (D) Positron emission tomography scans and tumor biopsies from patient 21 at the indicated time points post–axi-cel. Brown staining shows positive signal from the respective immunohistochemistry marker with ×40 original magnification. Arrows show sites of tumor biopsy. (E) CD19 and CD20 H-scores in paired pretreatment-progression biopsies from relapsed patients (N = 18). CR, complete response; H&E, hematoxylin and eosin; PD, progressive disease; PR, partial response; SD, stable disease; SPD, sum of product of perpendicular diameters.
Figure 2.
Figure 2.
Association between CD19 splice variants at pretreatment or relapse and response. (A) CD19 splicing events scheme. (B) Distribution of CD19 splice variants in pretreatment biopsies by CD19 H-score. (C) Association between pretreatment CD19 gene (transcript per million) and protein expression (left) and their respective relationship with ongoing response (middle and right). (D) Sashimi plots depicting characteristic ASEs in representative biopsies. (E) Prevalence of CD19 splice variants in paired pretreatment-relapse biopsies. (F) CD19 splice variants in relapse biopsies shown in panel E. Numbers denote impacted exons. (G) Response (left) and CD19 H-score (right) of patients shown in panel E. (H) Integrated Genomics Viewer snapshots showing CD19 mutations detected in paired pretreatment-relapse biopsies (representative patient 10). Blank, others; NR, nonresponder; O, ongoing response; Pt., patient; RE, relapsed.
See this image and copyright information in PMC

References

    1. Locke FL, Ghobadi A, Jacobson CA, et al. . Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 2019;20(1):31-42. - PMC - PubMed
    1. Neelapu SS, Locke FL, Bartlett NL, et al. . Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531-2544. - PMC - PubMed
    1. Locke FL, Rossi JM, Neelapu SS, et al. . Tumor burden, inflammation, and product attributes determine outcomes of axicabtagene ciloleucel in large B-cell lymphoma. Blood Adv. 2020;4(19):4898-4911. - PMC - PubMed
    1. Shah NN, Johnson BD, Schneider D, et al. . Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial. Nat Med. 2020;26(10):1569-1575. - PubMed
    1. Gardner R, Wu D, Cherian S, et al. . Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy. Blood. 2016;127(20):2406-2410. - PMC - PubMed

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