Early Real Time Quantification of CD19. CAR T Cells By Flow Cytometry As a Predictive Biomarker for Response in Patients with R/R LBCL

Blumenberg, Viktoria; Busch, Galina; Baumann, S.; Jitschin, Regina; Winkelmann, Michael; Hellwig, Konstantin; Rejeski, Kai; Frölich, Lisa; Tast, Benjamin; Schmidt, Christian; Hildebrandt, Friederike; Dekorsy, Franziska J.; Schmidkonz, Christian; Bäuerle, Tobias; Kunz, Wolfgang G.; Mueller, Fabian; Mougiakakos, Dimitrios; Bergwelt, Michael von; Bücklein, Veit; Mackensen, Andréas; Voelkl, Simon; Subklewe, Marion

doi:10.1182/blood-2022-168874

Cited by 3 publications

(5 citation statements)

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“…Two patients who achieved long-term remission were PET-negative before CAR-T and had little CAR-T cell expansion. In line with the missing correlation of CAR-T cell expansion and tumor volume (24), the low CAR-T cell count achieved in these long-term survivors was sufficient. On the other hand, six patients with favorable early CAR-T cell expansion relapsed quickly such as the CD19-negative relapse described above.…”

Section: Early Car-t Cell Expansionmentioning

confidence: 68%

“…Monitoring of CAR-T cells was performed as previously described (24). Briefly, peripheral blood mononuclear cells were isolated by density centrifugation, stained with CD19 CAR detection reagent, washed twice and stained with anti-biotin antibody (Miltenyi Biotec), 7-AAD and antibodies against CD45, CD3, and CD8 (all BD Biosciences).…”

Section: Car-t Cell Expansionmentioning

confidence: 99%

“…Early after CAR-T cell infusion, absolute CAR-T cell levels greater than 19 / µl (24)or 20 /µl (25) at day seven to 10 or complete metabolic response at day 30 by PET/CT (PET30-CR) robustly predicted long-term outcome (26)(27)(28). Though PET/CT imaging is the most precise method to evaluate responses in aggressive lymphoma (26), up to 30% of patients do not achieve long-term remission despite PET30-CR (false-negative prediction) and relapse within 12 months from CAR-T cell infusion (28,29).…”

Section: Introductionmentioning

confidence: 99%

“…Though PET/CT imaging is the most precise method to evaluate responses in aggressive lymphoma (26), up to 30% of patients do not achieve long-term remission despite PET30-CR (false-negative prediction) and relapse within 12 months from CAR-T cell infusion (28,29). Similarly, early CAR-T cell expansion produces false-positive and false-negative prediction of PFS (24). Because the reasons for CAR-T failure are diverse and include CD-19 loss, disadvantageous tumor microenvironment, insufficient initial CAR-T cell expansion, or poor CAR-T cell persistence (13,16,30), it is not surprising that a single measurement is not enough to reliably predict response early after CAR-T. With the idea of early immune-modulatory intervention in imminent CAR-T failure as reported in selected cases using checkpoint inhibitors, -imids, bispecific antibodies, or BTK-inhibitors (31)(32)(33)(34)(35), we hypothesized that a combination of biomarkers may more reliably predict early relapse and as such identifies patients in need of novel treatment combinations.…”

Section: Introductionmentioning

confidence: 99%

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Liver-FDG-uptake and CAR T-cell kinetics augment early PET/CT prognostic value for CD19-targeted CAR T-cell therapy in diffuse large B cell lymphoma

Beck,

Blumenberg,

Bücklein

et al. 2024

Preprint

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Despite revolutionary efficacy of CD19.CAR-T cell therapy (CAR-T) in aggressive B cell lymphoma, many patients still relapse mostly early. In early failure, distinct drugs support CAR-T which makes reliable and early prediction of imminent relapse/refractoriness critical. CAR-T cell expansion or negative day 30 PET/CT-scan (PET30-CR) predict PFS but individually fail in a relevant proportion of patients. We aimed to combine early biomarkers to more reliably predict relapse post CAR-T. Sixty-six patients with aggressive B cell lymphoma treated with CD19.CAR-T were retrospectively analyzed. Pre-CAR-T, response to bridging, LDH, total metabolic tumor volume, and international metabolic prognostic index predicted PFS. Post-CAR-T, PET30-CR classified the remission status correctly in 40 of 52 patients (77 %). Adding absolute CAR T-cell counts assessed between day seven and day ten post-infusion to PET30-response improved correct identification to 24 of 29 patients (83 %). Increased liver FDG-uptake from baseline to day30 (delta-Liver-SUVmean) was an independent biomarker for response. The combination of PET30 and delta-liver-SUVmean identified patients at very low, at intermediate and at very high risk of relapse (PFS not reached, 7.5 months, 1.5 months, respectively). Our results may guide early intervention studies aiming to enhance CAR-T particularly in the very high-risk patients.

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Section: Early Car-t Cell Expansionmentioning

confidence: 68%

Section: Car-t Cell Expansionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Liver-FDG-uptake and CAR T-cell kinetics augment early PET/CT prognostic value for CD19-targeted CAR T-cell therapy in diffuse large B cell lymphoma

Beck,

Blumenberg,

Bücklein

et al. 2024

Preprint

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“…In terms of CAR T‐cell kinetics, five centers contributed circulating CAR T‐cell data, locally assessed by flow cytometry, using labeled CD19 protein methodology as previously described 27,37–40 . Peak expansion, days from CAR T‐cell infusion to peak, and area under the curve for the first 28 days after infusion (AUC 0–28 ) were recorded.…”

Section: Methodsmentioning

confidence: 99%

Efficacy and safety of bendamustine‐containing bridging therapy in R/R LBCL patients receiving CD19 CAR T‐cells

Iacoboni,

Sánchez‐Salinas,

Rejeski

et al. 2024

HemaSphere

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Bridging therapy (BT) after leukapheresis is required in most relapsed/refractory (R/R) large B‐cell lymphoma (LBCL) patients receiving chimeric antigen receptor (CAR) T cells. Bendamustine‐containing regimens are a potential BT option. We aimed to assess if this agent had a negative impact on CAR‐T outcomes when it was administered as BT. We included R/R LBCL patients from six centers who received systemic BT after leukapheresis from February 2019 to September 2022; patients who only received steroids or had pre‐apheresis bendamustine exposure were excluded. Patients were divided into two BT groups, with and without bendamustine. Separate safety and efficacy analyses were carried out for axi‐cel and tisa‐cel. Of 243 patients who received BT, bendamustine (benda) was included in 62 (26%). There was a higher rate of BT progressors in the non‐benda group (62% vs. 45%, p = 0.02). Concerning CAR‐T efficacy, complete responses were comparable for benda versus non‐benda BT cohorts with axi‐cel (70% vs. 53%, p = 0.12) and tisa‐cel (44% vs. 36%, p = 0.70). Also, 12‐month progression‐free and overall survival were not significantly different between BT groups with axi‐cel (56% vs. 43% and 71% vs. 63%) and tisa‐cel (25% vs. 26% and 52% vs. 48%); there were no differences when BT response was considered. CAR T‐cell expansion for each construct was similar between BT groups. Regarding safety, CRS G ≥3 (6% vs. 6%, p = 0.79), ICANS G ≥3 (15% vs. 17%, p = 0.68), severe infections, and neutropenia post‐infusion were comparable among BT regimens. BT with bendamustine‐containing regimens is safe for patients requiring disease control during CAR T‐cell manufacturing.

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Mechanisms of Resistance and Treatment of Relapse after CAR T-cell Therapy for Large B-cell Lymphoma and Multiple Myeloma

Rejeski

Jain

Smith

2023

Transplantation and Cellular Therapy

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Early Real Time Quantification of CD19. CAR T Cells By Flow Cytometry As a Predictive Biomarker for Response in Patients with R/R LBCL

Cited by 3 publications

References 0 publications

Liver-FDG-uptake and CAR T-cell kinetics augment early PET/CT prognostic value for CD19-targeted CAR T-cell therapy in diffuse large B cell lymphoma

Liver-FDG-uptake and CAR T-cell kinetics augment early PET/CT prognostic value for CD19-targeted CAR T-cell therapy in diffuse large B cell lymphoma

Efficacy and safety of bendamustine‐containing bridging therapy in R/R LBCL patients receiving CD19 CAR T‐cells

Mechanisms of Resistance and Treatment of Relapse after CAR T-cell Therapy for Large B-cell Lymphoma and Multiple Myeloma

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