Role of blinatumomab, inotuzumab, and CAR T-cells: Which to choose and how to sequence for patients with relapsed disease

Curran, Emily; O’Brien, Maureen M.

doi:10.1053/j.seminhematol.2020.11.001

Cited by 12 publications

(29 citation statements)

References 64 publications

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“…The choice between CAR-T and BiTE immunotherapy depends on several clinical features that may affect efficacy, including relative disease burden, antigen expression, and T-cell function, as well as patient and disease characteristics. Adverse effects of CD19-targeted immunotherapies, such as cytokine release syndrome and neurotoxicity, still need to be reduced: these events may be more frequent and severe in patients receiving CAR-T [31,32]. Blinatumomab has the advantage to use the same standard drug for every person treated and therapy-associated costs may be lower.…”

Section: Discussionmentioning

confidence: 99%

Cytofluorimetric assay to investigate variability in blinatumomab in vitro response

Braidotti¹,

Franca²,

Granzotto³

et al. 2022

Front. Biosci. (Landmark Ed)

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Background:The T-cell engager antibody blinatumomab (Blincyto T M ) represents a promising rescue therapy for relapsed/refractory CD19 + acute lymphoblastic leukemia (B-ALL), although ~20-30% of patients still do not respond to treatment. Blinatumomab creates a tight synapsis between CD3 + T-lymphocytes and leukemic CD19 + B-cells, resulting in a granzyme B (GzB)-mediated specific lysis of leukemic cells. Methods: Aim of the study was to provide evidence that variability in blinatumomab response could have a genetic basis in PAX5, one of the most often mutated genes in B-ALL, affecting the CD19 surface expression on lymphoblasts, and could be explored in vitro by means of a cytofluorimetric assay, staining both surface antigens (CD45, CD19 and CD3) and intracytoplasmic markers (7AAD, Syto16). Two human immortalized B-ALL cell lines (NALM6 and REH) were chosen for their different PAX5 and CD19 protein levels, as verified by western blot and flow cytometry, respectively. Results: In contrast to NALM6, REH cells do not express the full-length PAX5 protein and show less CD19 on the cell surface (fluorescence peak median intensity: 9155 versus 28895). Co-cultures of CD3 + T-lymphocytes from healthy donors and B-ALL cell lines were seeded at an effector-to-target cell ratio of 1:10 for simulating the condition existing in the bone marrow due to the malignant invasion of blast cells. Co-cultures were exposed in vitro to blinatumomab and the simultaneous increase in blast mortality and T-lymphocytes activation induced by the drug was observed at day +7 (both effects: p < 0.0001 versus untreated, two-way ANOVA, Bonferroni post-test), and was particularly pronounced in REH compared to NALM6 co-cultures (p < 0.05). Surprisingly, daily release of GzB in supernatants, measured by an ELISA assay, was significantly lower in drug-exposed REH co-cultures compared to NALM6 at early time-points (days +3 and +4, p-value < 0.0001, three-way ANOVA), reaching a comparable plateau only towards the end of the incubation period (at day +5). Only 2 out of 5 primary co-cultures of leukemic and mononuclear cells isolated from bone marrow aspirates of B-ALL patients (age: median 10.7 years, interquartile range (IQR) 3.4; males: 60%) responded to the drug in vitro (simultaneous blast mortality and T-lymphocyte activation: both effects: p < 0.0001 versus untreated) and at different drug concentrations. Results were unrelated to the percentages of immature CD19 + B-cells in the diagnostic samples. Conclusions: In conclusion, cytofluorimetric analysis can highlight the different response induced by blinatumomab among co-cultures. Whether and how this difference is affected by PAX5-regulated CD19 expression is unclear and whether it is predictive of in vivo response to therapy remains to be established. Further dedicated studies are required to investigate these issues in detail.

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Section: Discussionmentioning

confidence: 99%

Cytofluorimetric assay to investigate variability in blinatumomab in vitro response

Braidotti¹,

Franca²,

Granzotto³

et al. 2022

Front. Biosci. (Landmark Ed)

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“…Blinatumomab is an anti-CD19/CD3 bispecific antibody. It binds to CD19, which is universally expressed on the surface of both immature and mature B cells, and targets malignant B cells through crosslinking and activation of CD3 T cells, which induces perforin-mediated death of the CD19-expressing B cells [10,17,18,25,26]. The European Medicines Agency (EMA) has approved blinatumomab (Blincyto ® ) for the treatment of relapsed and refractory B-cell precursor ALL in adults [17].…”

Section: Blinatumomabmentioning

confidence: 99%

“…Inotuzumab ozogamicin is an antibody drug conjugate that targets CD22-expressing lymphocytes through an anti-CD22 humanized monoclonal antibody linked to calicheamicin. The binding of the conjugate to the CD22 antigen present on the surface of the cells is followed by the internalization of the compound and the release of calicheamicin, an alkylating agent [10,25,27,41]. In Europe, inotuzumab ozogamicin in the form of Besponsa ® is approved as monotherapy for the treatment of adults with relapsed or refractory CD22-positive B-cell precursor ALL and for adult patients with Ph+ relapsed or refractory B-cell precursor ALL for whom treatment with at least one TKI has failed [19].…”

Section: Inotuzumab Ozogamicinmentioning

confidence: 99%

“…The overall incidence of SID is increasing with societal aging and the advent of new treatment modalities. In the last decade, the increasing use of targeted therapies in the form of monoclonal antibodies, immune checkpoint inhibitors, chimeric antigen receptor (CAR) T cells, and tyrosine kinase inhibitors (TKIs) has led to an increase in the percentage of patients with SID [8][9][10]. These innovative treatments are now widely used in adult patients with hematological malignancies, mainly in chronic lymphocytic leukemia (CLL), multiple myeloma, acute leukemias, and lymphomas [11,12].…”

Section: Introductionmentioning

confidence: 99%

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Secondary Dysgammaglobulinemia in Children with Hematological Malignancies Treated with Targeted Therapies

Tragiannidis

Groll

2021

Pediatr Drugs

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Targeted therapies have emerged as innovative treatments for patients whose disease does not respond to conventional chemotherapy, and their use has widely expanded in the field of pediatric hematologic malignancies in the last decade. While they carry the promise of improved disease control and survival and are currently investigated in first-line treatment protocols for patients with poor prognostic markers, they are associated with a considerable incidence of specific toxicities, including cytokine-release syndrome, neurotoxicity, hepatotoxicity, nephrotoxicity, cardiotoxicity, endocrine adverse events, and infectious complications. Iatrogenic or secondary dysgammaglobulinemia is a main consequence of targeted therapies using monoclonal antibodies and other antibody-derived treatments that target specific antigens on lymphoid cells (blinatumomab, inotuzumab ozogamicin, rituximab), chimeric antigen receptor T cells, tyrosine kinase inhibitors (imatinib, dasatinib, nilotinib) and, to a lesser extent, checkpoint inhibitors (pembrolizumab, nivolumab). This review discusses the diagnosis and incidence of secondary or iatrogenic dysgammaglobulinemia in children treated with targeted therapies for leukemias and lymphomas, and options for monitoring and treatment.

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“…Currently, new immunotherapeutic options have gained approval for patients with adverse prognosis. In view of the availability of innovative therapies, the choice of the most appropriate therapeutic option for a patient with B-ALL constitutes a great challenge [ 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Immunotherapy and Allogeneic Bone Marrow Transplantation in B Acute Lymphoblastic Leukemia: How to Sequence?

et al. 2022

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Long-term disease control is achieved in 80–90% of patients with acute lymphoblastic leukemia of B origin (B-ALL). About half of adult and 10% of pediatric patients develop refractory or relapsed disease, whereas survival after relapse accounts about 10% in adults and 30–50% in children. Allogeneic bone marrow transplantation offers remarkable benefit in cases with unfavorable outcome. Nevertheless, novel immunotherapeutic options have been approved for patients with adverse prognosis. Immunotherapeutic agents, nowadays, are preferred over standard chemotherapy for patients with relapsed or refractory B-ALL The mode of action, efficacy and safety data of immunotherapeutic agents released, indications and sequence of those therapies over the course of treatment, are herein reviewed.

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Role of blinatumomab, inotuzumab, and CAR T-cells: Which to choose and how to sequence for patients with relapsed disease

Cited by 12 publications

References 64 publications

Cytofluorimetric assay to investigate variability in blinatumomab in vitro response

Cytofluorimetric assay to investigate variability in blinatumomab in vitro response

Secondary Dysgammaglobulinemia in Children with Hematological Malignancies Treated with Targeted Therapies

Immunotherapy and Allogeneic Bone Marrow Transplantation in B Acute Lymphoblastic Leukemia: How to Sequence?

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