Quantification of cell-free DNA for the analysis of CD19-CAR-T cells during lymphoma treatment

Mika, Thomas; Thomson, Julia; Nilius‐Eliliwi, Verena; Vangala, Deepak; Baraniskin, Alexander; Wulf, Gerald; Klein-Scory, Susanne; Schroers, Roland

doi:10.1016/j.omtm.2021.10.009

Cited by 10 publications

(13 citation statements)

References 39 publications

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“…Treatment resulted in a CR at day +30 as confirmed by PET/CT (Figure 2A). In the ddPCR analysis, coincident peaks of the CAR‐T expansion, the t(11;14) signal, and the reference cfDNA were evident at day +10, indicating lymphoma lysis due to CAR‐T cells’cytotoxicity 4 . At first, clearance of the t(11;14) translocation was obvious from day +30 on, but it increased again 3 months after therapy (Figure 1B).…”

Section: Patient 1 Patient 2 Patient 3 Patientmentioning

confidence: 95%

“…Response was assessed by PET/CT according to the Lugano classification 3 . CAR‐T cell expansions were quantified by specific digital droplet‐PCR (ddPCR) from cell‐free DNA (cfDNA) as previously described 4 , 5 . In 1 patient, diagnostic follow‐up was performed by ddPCR analysis of peripheral blood monocytes (PBMC) 6 .…”

Section: Patient 1 Patient 2 Patient 3 Patientmentioning

confidence: 99%

“…In the ddPCR analysis, coincident peaks of the CAR-T expansion, the t(11;14) signal, and the reference cfDNA were evident at day +10, indicating lymphoma lysis due to CAR-T cells'cytotoxicity. 4 At irst, clearance of the t(11;14) translocation was obvious from day +30 on, but it increased again 3 months after therapy (Figure 1B). In a PET/CT scan on day +117, suspect uptake was apparent in the colon with marginal ascites (Figure 2B).…”

mentioning

confidence: 94%

“…Our data emphasizes the need for detailed disease monitoring by MRD in the context of CAR-T cell therapy, to gain further insight into resistance mechanisms in future research. 4,8 (A) Analysis of cell-free DNA of patient 1 displays a moderate increase of the CAR-T signal within the first 14 days, which is not accompanied by a robust increase of total cell-free DNA (reference, bottom). Around day +100, there was an increase of reference DNA for unknown reasons.…”

mentioning

confidence: 99%

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Repeated Infusions of Brexucabtagene-autoleucel in Relapsed/Refractory Mantle Cell Lymphoma

Aydilek,

Klein-Scory,

Thomson

et al. 2023

HemaSphere

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First-line immune-chemotherapy induces long-lasting remissions for most patients with mantle cell lymphoma (MCL). In case of progression, response rates and overall survival decline. 1,2 In 2020, chimeric antigen receptor (CAR)-T cell therapy (Brexucabtagene-autoleucel, brexu-cel; Tecartus) was approved by the FDA and EMA for the treatment of patients suffering from refractory/relapsed (r/r) MCL, who had been previously treated with 2 lines of therapy, including Bruton-tyrosine kinase inhibition. Data on treatment strategies for r/r MCL after CAR-T cell therapy are scarce. Here, we report the clinical courses and molecular observations of 4 patients with r/r MCL, who received a second infusion of the initial CAR-T cell product (second bag infusion) between 4 and 8 months after the irst CAR-T treatment.All patients were treated with brexu-cel at, the University Medicine Göttingen and the Knappschaftskrankenhaus Bochum (Ruhr University Bochum) between 2021 and 2023. Patient characteristics are summarized in Table 1. Before each CAR-T infusion, CD19 + MCL was veriied by low cytometry and/or immunohistochemistry. Lymphodepleting chemotherapy before brexu-cel infusions followed standard protocols applying ludarabine (90 mg/m 2 ) and cyclophosphamide (1.500 mg/ m 2 ). Response was assessed by PET/CT according to the Lugano classiication. 3 CAR-T cell expansions were quantiied by speciic digital droplet-PCR (ddPCR) from cell-free DNA (cfDNA) as previously described. 4,5 In 1 patient, diagnostic follow-up was performed by ddPCR analysis of peripheral blood monocytes (PBMC). 6 Molecular disease monitoring was performed by ddPCR assays for IGH-CCND1 fusions (t11;14), according to the previous reports. 7

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Section: Patient 1 Patient 2 Patient 3 Patientmentioning

confidence: 95%

Section: Patient 1 Patient 2 Patient 3 Patientmentioning

confidence: 99%

mentioning

confidence: 94%

mentioning

confidence: 99%

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Repeated Infusions of Brexucabtagene-autoleucel in Relapsed/Refractory Mantle Cell Lymphoma

Aydilek,

Klein-Scory,

Thomson

et al. 2023

HemaSphere

Self Cite

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“…117 Higher levels of CAR-T-derived DNA were observed in patients responding to axi-cel treatment, indicating a relative expansion of the CAR-T cell population. 120 Similarly, tracking of lymphoma-specific variable, diversity and joining gene segments has shown utility for predicting patient outcomes following CAR T-cell therapy. 119 In this setting, higher pretreatment ctDNA concentrations and the persistence of detectable ctDNA following treatment have been associated with progression after axi-cel infusion.…”

Section: Approaches For Ctdna Detectionmentioning

confidence: 99%

Liquid biopsy approaches to capture tumor evolution and clinical outcomes during cancer immunotherapy

Sivapalan

Murray

Canzoniero

et al. 2023

J Immunother Cancer

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Circulating cell-free tumor DNA (ctDNA) can serve as a real-time biomarker of tumor burden and provide unique insights into the evolving molecular landscape of cancers under the selective pressure of immunotherapy. Tracking the landscape of genomic alterations detected in ctDNA may reveal the clonal architecture of the metastatic cascade and thus improve our understanding of the molecular wiring of therapeutic responses. While liquid biopsies may provide a rapid and accurate evaluation of tumor burden dynamics during immunotherapy, the complexity of antitumor immune responses is not fully captured through single-feature ctDNA analyses. This underscores a need for integrative studies modeling the tumor and the immune compartment to understand the kinetics of tumor clearance in association with the quality of antitumor immune responses. Clinical applications of ctDNA testing in patients treated with immune checkpoint inhibitors have shown both predictive and prognostic value through the detection of genomic biomarkers, such as tumor mutational burden and microsatellite instability, as well as allowing for real-time monitoring of circulating tumor burden and the assessment of early on-therapy responses. These efforts highlight the emerging role of liquid biopsies in selecting patients for cancer immunotherapy, monitoring therapeutic efficacy, determining the optimal duration of treatment and ultimately guiding treatment selection and sequencing. The clinical translation of liquid biopsies is propelled by the increasing number of ctDNA-directed interventional clinical trials in the immuno-oncology space, signifying a critical step towards implementation of liquid biopsies in precision immuno-oncology.

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An IQ Consortium Perspective on Best Practices for Bioanalytical and Immunogenicity Assessment Aspects of CAR‐T and TCR‐T Cellular Therapies Development

Gokemeijer,

Balasubramanian,

Ogasawara

et al. 2023

Clin Pharma and Therapeutics

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CAR‐T therapies have shown remarkable efficacy against hematological malignancies in the clinic over the last decade and new studies indicate that progress is being made to use these novel therapies to target solid tumors as well as treat autoimmune disease. Innovation in the field, including TCR‐T, allogeneic or “off the shelf” CAR‐T, and autoantigen/armored CAR‐Ts are likely to increase the efficacy and applications of these therapies. The unique aspects of these cell‐based therapeutics; patient‐derived cells, intracellular expression, in vivo expansion, and phenotypic changes provide unique bioanalytical challenges to develop pharmacokinetic and immunogenicity assessments. The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) Translational and ADME Sciences Leadership Group (TALG) has brought together a group of industry experts to discuss and consider these challenges. In this white paper, we present the IQ consortium perspective on the best practices and considerations for bioanalytical and immunogenicity aspects toward the optimal development of CAR‐T and TCR‐T cell therapies.

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Quantification of cell-free DNA for the analysis of CD19-CAR-T cells during lymphoma treatment

Cited by 10 publications

References 39 publications

Repeated Infusions of Brexucabtagene-autoleucel in Relapsed/Refractory Mantle Cell Lymphoma

Repeated Infusions of Brexucabtagene-autoleucel in Relapsed/Refractory Mantle Cell Lymphoma

Liquid biopsy approaches to capture tumor evolution and clinical outcomes during cancer immunotherapy

An IQ Consortium Perspective on Best Practices for Bioanalytical and Immunogenicity Assessment Aspects of CAR‐T and TCR‐T Cellular Therapies Development

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