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Cellular therapies in acute lymphoblastic leukemia.

ABSTRACT: The majority of adult patients with acute lymphoblastic leukemia (ALL) will die from the disease. Although the prognosis for pediatric patients is significantly better than for adult patients with ALL, the prognosis for patients with relapsed or refractory disease is poor in all cases. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) from a related donor offers a significant therapeutic benefit for pediatric patients, although the benefit of this therapy to adults with ALL is less established. Because most patients lack a suitable related donor, alternative approaches to allo-HSCT, including umbilical cord blood, and unrelated and haploidentical allo-HSCT, have been investigated in the clinical setting. Although treatment with donor-derived T-cells, so-called 'donor lymphocyte infusion', has demonstrated poor outcomes in patients with relapsed ALL following HSCT, modified adoptive T-cell regimens, including the infusion of enriched tumor-targeted donor T-cells and genetically targeted T-cells, are currently under clinical investigation. In addition, the resistance of ALL tumor cell lines to NK-cell-mediated lysis may be overcome by the genetic modification of NK cells to target ALL tumor cell antigens, and this approach will be evaluated in an upcoming clinical trial. Whether these novel adoptive cell therapies will ultimately result in improved clinical outcomes remains to be determined.

SUBMITTER: Brentjens RJ

PROVIDER: S-EPMC4694559 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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Cellular therapies in acute lymphoblastic leukemia.

Brentjens Renier J RJ

Current opinion in molecular therapeutics 20090801 4

The majority of adult patients with acute lymphoblastic leukemia (ALL) will die from the disease. Although the prognosis for pediatric patients is significantly better than for adult patients with ALL, the prognosis for patients with relapsed or refractory disease is poor in all cases. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) from a related donor offers a significant therapeutic benefit for pediatric patients, although the benefit of this therapy to adults with ALL is less ...[more]

PMID: 19649982

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Project description:BackgroundDespite the recent progress that has been made in the understanding and treatment of acute lymphoblastic leukemia (ALL), the outcome is still dismal in adult ALL cases. Several studies in solid tumors identified high expression of WEE1 kinase as a poor prognostic factor and reported its role as a cancer-conserving oncogene that protects cancer cells from DNA damage. Therefore, the targeted inhibition of WEE1 kinase has emerged as a rational strategy to sensitize cancer cells to antineoplastic compounds, which we evaluate in this study.MethodsThe effectiveness of the selective WEE1 inhibitor AZD-1775 as a single agent and in combination with different antineoplastic agents in B and T cell precursor ALL (B/T-ALL) was evaluated in vitro and ex vivo studies. The efficacy of the compound in terms of cytotoxicity, induction of apoptosis, and changes in gene and protein expression was assessed using different B/T-ALL cell lines and confirmed in primary ALL blasts.ResultsWe showed that WEE1 was highly expressed in adult primary ALL bone marrow and peripheral blood blasts (n = 58) compared to normal mononuclear cells isolated from the peripheral blood of healthy donors (p = 0.004). Thus, we hypothesized that WEE1 could be a rational target in ALL, and its inhibition could enhance the cytotoxicity of conventional therapies used for ALL. We evaluated the efficacy of AZD-1775 as a single agent and in combination with several antineoplastic agents, and we elucidated its mechanisms of action. AZD-1775 reduced cell viability in B/T-ALL cell lines by disrupting the G2/M checkpoint and inducing apoptosis. These findings were confirmed in human primary ALL bone marrow and peripheral blood blasts (n = 15). In both cell lines and primary leukemic cells, AZD-1775 significantly enhanced the efficacy of several tyrosine kinase inhibitors (TKIs) such as bosutinib, imatinib, and ponatinib, and of chemotherapeutic agents (clofarabine and doxorubicin) in terms of the reduction of cell viability, apoptosis induction, and inhibition of proliferation.ConclusionsOur data suggest that WEE1 plays a role in ALL blast's survival and is a bona fide target for therapeutic intervention. These data support the evaluation of the therapeutic potential of AZD-1775 as chemo-sensitizer agent for the treatment of B/T-ALL.

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Cellular therapies in acute lymphoblastic leukemia.

Publications

Cellular therapies in acute lymphoblastic leukemia.

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