How to integrate CD19 specific chimeric antigen receptor T cells with other CD19 targeting agents in diffuse large B‐cell lymphoma?

de Ramon Ortiz, Carmen; Wang, Sisi; Stathis, Anastasios; Bertoni, Francesco; Zenz, Thorsten; Novak, Urban; Simonetta, Federico

doi:10.1002/hon.3237

Cited by 2 publications

(1 citation statement)

References 105 publications

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“…8 Therapies targeting CD19 include CAR-T cell therapy, monoclonal antibodies, bispecific antibodies, and targeted antibody-drug couplings. 9 Among them, the impressive clinical reactions of resistant B-cell cancers to the transfer of anti-CD19 CAR-engineered T cells have emphasized the crucial function of CD19 protein in the treatment of different tumors. 10 Consequently, it is necessary to investigate the different levels of CD19 expression in all types of cancers and their impact on the immune system.…”

Section: Introductionmentioning

confidence: 99%

The Pan-Cancer Analysis Uncovers the Prognostic and Immunotherapeutic Significance of CD19 as an Immune Marker in Tumor

Wei,

Meng,

Xiang

et al. 2024

IJGM

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Background:The specific cytotoxic effects of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy have led to impressive outcomes in individuals previously treated for B-cell malignancies. However, the specific biological role of CD19(+) target cells, which exert antitumor immunity against some solid tumors, remains to be elucidated. Methods: We collected information regarding the level of CD19 mRNA and protein expression from various databases including The Cancer Genome Atlas (TCGA), Tumor Immune Estimation Resource (TIMER), Genotype-Tissue Expression (GTEx), and Human Protein Atlas (HPA) for both tumor and normal samples. To evaluate the patient's prognosis according to CD19 expression, a Kaplan-Meier (KM) analysis and univariate Cox regression were performed. Furthermore, using the Estimation of Stromal and Immune Cells in Malignant Tumor Tissues Using the Expression Data (ESTIMATE) algorithm, we estimated the ratio of immune cells infiltrating malignant tumor tissues. Afterward, the GSCALite repository was employed to evaluate the vulnerability of tumors expressing CD19 to drugs used in chemotherapy. To validate the results in clinical samples of certain cancer types, immunohistochemistry was then performed. Results: Most tumor types exhibited CD19 expression differently, apart from colon adenocarcinoma (COAD). The early diagnostic value of CD19 has been demonstrated in 9 different tumor types, and the overexpression of CD19 has the potential to extend the survival duration of patients. Multiple tumors showed a positive correlation between CD19 expression and tumor mutation burden (TMB), microsatellite instability (MSI), and ESTIMATE score. Furthermore, a direct association was discovered between the expression of CD19 and the infiltration of immune cells, particularly in cases of breast invasive carcinoma (BRCA). Moreover, CD19 is highly sensitive to a variety of chemotherapy drugs. Conclusion:The study reveals the potential of CD19 as both a predictive biomarker and a target for different cancer immunotherapies.

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Section: Introductionmentioning

confidence: 99%

The Pan-Cancer Analysis Uncovers the Prognostic and Immunotherapeutic Significance of CD19 as an Immune Marker in Tumor

Wei,

Meng,

Xiang

et al. 2024

IJGM

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Targeting CD19-positive lymphomas with the antibodydrug conjugate loncastuximab tesirine: preclinical evidence of activity as a single agent and in combination therapy

Tarantelli,

Wald,

Munz

et al. 2024

haematol

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Antibody-drug conjugates (ADCs) represent one of the most successful therapeutic approaches introduced in clinical practice in the last few years. Loncastuximab tesirine (ADCT-402) is a CD19 targeting ADC, in which the antibody is conjugated through a protease cleavable dipeptide linker to a pyrrolobenzodiazepine (PBD) dimer warhead (SG3199). Based on the results of a phase 2 study, loncastuximab tesirine was recently approved for adult patients with relapsed/refractory large B-cell lymphoma. We assessed the activity of loncastuximab tesirine using in vitro and in vivo models of lymphomas, correlated its activity with CD19 expression levels, and identified combination partners providing synergy with loncastuximab tesirine. Loncastuximab tesirine was tested across 60 lymphoma cell lines. Loncastuximab tesirine had strong cytotoxic activity in B-cell lymphoma cell lines. The in vitro activity was correlated with CD19 expression level and intrinsic sensitivity of cell lines to the ADC’s warhead. Loncastuximab tesirine was more potent than other anti-CD19 ADCs (coltuximab ravtansine, huB4-DGN462), albeit the pattern of activity across cell lines was correlated. Loncastuximab tesirine activity was also largely correlated with cell line sensitivity to R-CHOP. Combinatorial in vitro and in vivo experiments identified the benefit of adding loncastuximab tesirine to other agents, especially BCL2 and PI3K inhibitors. Our data support the further development of loncastuximab tesirine as a single agent and in combination for patients affected by mature B-cell neoplasms. The results also highlight the importance of CD19 expression and the existence of lymphoma populations characterized by resistance to multiple therapies.

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How to integrate CD19 specific chimeric antigen receptor T cells with other CD19 targeting agents in diffuse large B‐cell lymphoma?

Cited by 2 publications

References 105 publications

The Pan-Cancer Analysis Uncovers the Prognostic and Immunotherapeutic Significance of CD19 as an Immune Marker in Tumor

The Pan-Cancer Analysis Uncovers the Prognostic and Immunotherapeutic Significance of CD19 as an Immune Marker in Tumor

Targeting CD19-positive lymphomas with the antibodydrug conjugate loncastuximab tesirine: preclinical evidence of activity as a single agent and in combination therapy

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