Concepts in immuno-oncology: tackling B cell malignancies with CD19-directed bispecific T cell engager therapies

Viardot, Andreas; Locatelli, Franco; Stieglmaier, Julia; Zaman, Faraz; Jabbour, Elias

doi:10.1007/s00277-020-04221-0

Cited by 37 publications

(39 citation statements)

References 92 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In recent years, the application of immunotherapy has become one of the most promising methods of treating haematological malignancies. 1,2 The clinical implementation of therapy directed against the specific B-cell marker CD19 has helped to improve outcomes in patients with relapsed/ refractory (R/R) B-lineage acute lymphoblastic leukaemia (ALL) [3][4][5][6] as well as ALL with a long persistence of leukaemic cells in the bone marrow (BM). 7,8 CD19 is highly expressed on the surface of leukaemic cells in nearly all B-cell malignancies.…”

Section: Introductionmentioning

confidence: 99%

Relative expansion of CD19‐negative very‐early normal B‐cell precursors in children with acute lymphoblastic leukaemia after CD19 targeting by blinatumomab and CAR‐T cell therapy: implications for flow cytometric detection of minimal residual disease

et al. 2021

View full text Add to dashboard Cite

CD19-directed treatment in B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) frequently leads to the downmodulation of targeted antigens. As multicolour flow cytometry (MFC) application for minimal/measurable residual disease (MRD) assessment in BCP-ALL is based on B-cell compartment study, CD19 loss could hamper MFC-MRD monitoring after blinatumomab or chimeric antigen receptor T-cell (CAR-T) therapy. The use of other antigens (CD22, CD10, CD79a, etc.) as B-lineage gating markers allows the identification of CD19-negative leukaemia, but it could also lead to misidentification of normal very-early CD19-negative BCPs as tumour blasts. In the current study, we summarized the results of the investigation of CD19-negative normal BCPs in 106 children with BCP-ALL who underwent CD19 targeting (blinatumomab, n = 64; CAR-T, n = 25; or both, n = 17). It was found that normal CD19-negative BCPs could be found in bone marrow after CD19-directed treatment more frequently than in healthy donors and children with BCP-ALL during chemotherapy or after stem cell transplantation. Analysis of the antigen expression profile revealed that normal CD19-negative BCPs could be mixed up with residual leukaemic blasts, even in bioinformatic analyses of MFC data. The results of our study should help to investigate MFC-MRD more accurately in patients who have undergone CD19-targeted therapy, even in cases with normal CD19-negative BCP expansion.

show abstract

Section: Introductionmentioning

confidence: 99%

Relative expansion of CD19‐negative very‐early normal B‐cell precursors in children with acute lymphoblastic leukaemia after CD19 targeting by blinatumomab and CAR‐T cell therapy: implications for flow cytometric detection of minimal residual disease

et al. 2021

View full text Add to dashboard Cite

show abstract

“…These mutations abolish the binding to Fcγ receptors and to complement component C1q while maintaining neonatal Fc receptor (FcRn) binding, enabling a stable IgG-like PK in vivo with an half-life of around 10 days in NSG mice. This feature is a major differentiation from Blinatumomab, a Tcell bispecific (TCB) antibody targeting CD19 and CD3ε approved in relapsed/refractory Bcell acute lymphoblastic leukemia, which have instead short half-life in vivo of 1-2 hours [7,9] CD20-TCB can redirect the activity of conventional CD4 and CD8 T cells against lymphoma cells by concomitant binding of CD20 on tumor cells and CD3 on T cells (S1b Fig) [7,10]. Previous studies revealed that CD20-TCB has a long half-life and induces selective activation of conventional T cells, resulting in efficient tumor regression of the aggressive DLBCL xenograft model WSU DLCL2 in preclinical animal models in human stem cell humanized (HSC) NSG mice [7].…”

Section: Introductionmentioning

confidence: 99%

Cross-linking of T cell to B cell lymphoma by the T cell bispecific antibody CD20-TCB induces IFNγ/CXCL10-dependent peripheral T cell recruitment in humanized murine model

et al. 2021

View full text Add to dashboard Cite

Diffuse large B cell lymphomas (DLBCL) are a highly heterogeneous subtype of Non Hodgkin Lymphoma (NHL), accounting for about 25% of NHL. Despite an increased progression-free survival upon therapy, 40–50% of patients develop relapse/refractory disease, therefore there remains an important medical need. T cell recruiting therapies, such as the CD20xCD3 T cell bi-specific antibody CD20-TCB (RG6026 or glofitamab), represent a novel approach to target all stages of DLBCL, especially those that fail to respond to multiple lines of treatment. We aimed for a better understanding of the molecular features related to the mode of action (MoA) of CD20-TCB in inducing Target/T cell synapse formation and human T cell recruitment to the tumor. To directly evaluate the correlation between synapse, cytokine production and anti-tumor efficacy using CD20-TCB, we developed an innovative preclinical human DLBCL in vivo model that allowed tracking in vivo human T cell dynamics by multiphoton intravital microscopy (MP-IVM). By ex vivo and in vivo approaches, we revealed that CD20-TCB is inducing strong and stable synapses between human T cell and tumor cells, which are dependent on the dose of CD20-TCB and on LFA-1 activity but not on FAS-L. Moreover, despite CD20-TCB being a large molecule (194.342 kDa), we observed that intra-tumor CD20-TCB-mediated human T cell-tumor cell synapses occur within 1 hour upon CD20-TCB administration. These tight interactions, observed for at least 72 hours post TCB administration, result in tumor cell cytotoxicity, resident T cell proliferation and peripheral blood T cell recruitment into tumor. By blocking the IFNγ-CXCL10 axis, the recruitment of peripheral T cells was abrogated, partially affecting the efficacy of CD20-TCB treatment which rely only on resident T cell proliferation. Altogether these data reveal that CD20-TCB’s anti-tumor activity relies on a triple effect: i) fast formation of stable T cell-tumor cell synapses which induce tumor cytotoxicity and cytokine production, ii) resident T cell proliferation and iii) recruitment of fresh peripheral T cells to the tumor core to allow a positive enhancement of the anti-tumor effect.

show abstract

“…Targeting the pan‐B‐lymphocyte antigen CD19 with the bispecific T‐cell engager blinatumomab is one of the modern ways of treating acute lymphocytic B‐cell precursor leukaemia (BCP‐ALL) 1,2 . This drug has been very successful in treating patients with relapsed/refractory (R/R) disease, 3,4 but it has recently been shown that blinatumomab is also effective in eradicating minimal residual disease (MRD) in patients with relapsed or primary BCP‐ALL 5,6 .…”

Section: Figurementioning

confidence: 99%

Strong expansion of normal CD19‐negative B‐cell precursors after the use of blinatumomab in the first‐line therapy of acute lymphoblastic leukaemia in children

et al. 2021

View full text Add to dashboard Cite

Concepts in immuno-oncology: tackling B cell malignancies with CD19-directed bispecific T cell engager therapies

Cited by 37 publications

References 92 publications

Relative expansion of CD19‐negative very‐early normal B‐cell precursors in children with acute lymphoblastic leukaemia after CD19 targeting by blinatumomab and CAR‐T cell therapy: implications for flow cytometric detection of minimal residual disease

Relative expansion of CD19‐negative very‐early normal B‐cell precursors in children with acute lymphoblastic leukaemia after CD19 targeting by blinatumomab and CAR‐T cell therapy: implications for flow cytometric detection of minimal residual disease

Cross-linking of T cell to B cell lymphoma by the T cell bispecific antibody CD20-TCB induces IFNγ/CXCL10-dependent peripheral T cell recruitment in humanized murine model

Strong expansion of normal CD19‐negative B‐cell precursors after the use of blinatumomab in the first‐line therapy of acute lymphoblastic leukaemia in children

Contact Info

Product

Resources

About