CD19: A multifunctional immunological target molecule and its implications for Blineage acute lymphoblastic leukemia

Weiland, Judith; Elder, Alex; Forster, Victoria J.; Heidenreich, Olaf; Koschmieder, Steffen; Vormoor, Josef

doi:10.1002/pbc.25462

Cited by 23 publications

(16 citation statements)

References 63 publications

(87 reference statements)

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“…The consequence of CD19 deficiency was previously described in knockout murine models and in humans (10). In one report, a primary immunodeficiency syndrome associated with loss of CD19 expression due to homozygous mutations resulting in deletion of the cytoplasmatic domain was described, perhaps pointing to potential toxicities of CD19-targeted therapies.…”

Section: Cd19 As a Targetmentioning

confidence: 95%

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Blinatumomab for the Treatment of Philadelphia Chromosome–Negative, Precursor B-cell Acute Lymphoblastic Leukemia

Wolach

Stone

2015

Clinical Cancer Research

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Blinatumomab is a CD19/CD3 bispescific antibody designed to redirect T cells toward malignant B cells and induce their lysis. It recently gained accelerated approval by the FDA for the treatment of relapsed or refractory Philadelphia chromosomenegative B-cell acute lymphoblastic leukemia (RR-ALL). In the phase II trial that served as the basis for approval, blinatumomab demonstrated significant single-agent activity and induced remission [complete remission (CR) and CR with incomplete recovery of peripheral blood counts (CRh)] in 43% of 189 adult patients with RR-ALL; the majority of responders (82%) also attained negative minimal residual disease (MRD À ) status that did not generally translate into long-term remissions in most cases. Additional studies show that blinatumomab can induce high response rates associated with lasting remissions in patients in first remission treated for MRD positivity, suggesting a role for blinatumomab in the upfront, MRD-positive setting. Blinatumomab infusion follows a predictable immunopharmacologic profile, including early cytokine release that can be associated with a clinical syndrome, T-cell expansion, and Bcell depletion. Neurologic toxicities represent a unique toxicity that shares similarities with adverse effects of other T-cell engaging therapies. Further studies are needed to clarify the optimal disease setting and timing for blinatumomab therapy. Additional insights into the pathogenesis, risk factors, and prevention of neurologic toxicities as well as a better understanding of the clinical consequences and biologic pathways that are associated with drug resistance are needed.

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Section: Cd19 As a Targetmentioning

confidence: 95%

“…Furthermore, CD19 is B-cell lineage-specific, and thus targeting this protein does not generally compromise other tissues. There is evidence to suggest a role for CD19 in enhancing malignant pathways (10). For example, high levels of CD19 expression were shown to correlate with Akt activation and overexpression of c-Myc (12,13).…”

Section: Cd19 As a Targetmentioning

confidence: 99%

Blinatumomab for the Treatment of Philadelphia Chromosome–Negative, Precursor B-cell Acute Lymphoblastic Leukemia

Wolach

Stone

2015

Clinical Cancer Research

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“…Clinical trials of CD19-CAR T cell therapy have shown high complete responses in hematological malignancies patients [30,31]. CD19-CAR engineered NK cells are expected to exert better anti-tumor effect due to the advantages of CAR-NK cell therapy in hematological malignancies.…”

Section: Hematological Malignanciesmentioning

confidence: 98%

Chimeric antigen receptor (CAR)-modified NK cells against cancer: Opportunities and challenges

Wang

Dou

et al. 2019

International Immunopharmacology

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“…Initial poor results have hampered the development of naked anti-CD19 compounds. 17 Denintuzumab mafodotin (SGN-CD19A) is a humanized anti-auristatin F, a microtubule-disrupting agent, which has recently been investigated in a phase I study in R/R BCP-ALL patients. A preliminary analysis showed a 30% response and achievement of complete MRD responses.…”

Section: Anti-cd19 Monoclonal Antibodiesmentioning

confidence: 99%

Updates in Adult Acute Lymphoblastic Leukemia—Current Status of Antigen-targeted Treatments and Immunotherapy

Thomas¹

2017

Oncology &Amp; Hematology Review (US)

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T he outcomes of adult acute lymphoblastic leukemia (ALL) remain inferior to those observed in pediatric populations. Targeted therapy with monoclonal antibodies and immunotherapy represents the most promising new way to fight ALL without significant additive toxicity. Since the use of rituximab in combination chemoimmunotherapy for treatment of B cell lineage ALL, a number of other monoclonal antibodies are under investigation for the treatment of this disease. Deep molecular remissions with anti-CD19-and anti-CD22-directed therapy have been shown in relapsed/refractory (R/R) disease, allowing for the opportunity to transplant. Blinatumomab is the first antigen-directed treatment approved for use in R/R ALL. Adoptive cellular therapy with human T cells genetically engineered to express CD19 redirected chimeric antigen receptors (CARs) has also recently demonstrated efficacy in patients with B cell lineage ALL. In this article, we review the therapeutic implications, primary results, and current status of antigen-targeted treatments and immunotherapy in adult B cell lineage ALL. KeywordsAcute lymphoblastic leukemia, monoclonal antibodies, prognosis, blinatumomab, chimeric antigen receptor (CAR) T cells, inotuzumab ozogamicin, rituximab, epratuzumab Disclosure: Xavier Thomas has nothing to declare in relation to this article. No funding was received in the publication of this article. Compliance with Ethics:This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors.Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. One approach to improving outcomes in adult ALL involves intensification of existing chemotherapy combinations or the addition of chemotherapeutic agents. 2 The results of allogeneic hematopoietic stem cell transplantation (HSCT) for adults with ALL in first-line therapy have also improved significantly over time, 3 but it is unlikely that the sole intensification of regimens can continue to improve prognosis substantially. Intensifying chemotherapy may reduce the incidence of resistance, but at the cost of increased toxicities. Outcomes remain particularly poor in relapsed/refractory (R/R) patients. Response rates after salvage treatment range from 18-45% and median survival times from 2-8 months, with less than 10% survival after 5 years. [4][5][6][7][8][9] In this setting, allogeneic HSCT is the only curative option, but this can only be achieved in a subgroup of patients. 4,5,8 A retrospective analysis of 1,706 adult patients with Philadelphia chromosome-neg...

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CD19: A multifunctional immunological target molecule and its implications for Blineage acute lymphoblastic leukemia

Cited by 23 publications

References 63 publications

Blinatumomab for the Treatment of Philadelphia Chromosome–Negative, Precursor B-cell Acute Lymphoblastic Leukemia

Blinatumomab for the Treatment of Philadelphia Chromosome–Negative, Precursor B-cell Acute Lymphoblastic Leukemia

Chimeric antigen receptor (CAR)-modified NK cells against cancer: Opportunities and challenges

Updates in Adult Acute Lymphoblastic Leukemia—Current Status of Antigen-targeted Treatments and Immunotherapy

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