Cotargeting BCL-2 and BCL-XL for maximal efficacy in ALL

Daver, Naval; Konopleva, Marina

doi:10.1182/blood-2016-07-724948

Cited by 11 publications

(1 citation statement)

References 10 publications

(8 reference statements)

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“…In a similar manner to solid tumor, interferon-γ (IFN-γ) induced PD-L1 expression on AML cells protected them from cytotoxic T cell lysis [27]. In BM aspirates from AML patients, T cell subsets, such as CD4 + effector T cells, CD8 + T cells, and Tregs, had significantly higher PD-1 expression in untreated and relapsed AML patients compared with healthy donors [28]. PD-1 expression on CD4 + and CD8 + T cells was upregulated at relapse after allogeneic stem cell transplantation (allo-SCT) [29].…”

Section: Targeting Immune Checkpoints In Hematologic Malignanciesmentioning

confidence: 99%

Immune checkpoint blockade and CAR-T cell therapy in hematologic malignancies

et al. 2019

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Harnessing the power of the immune system to recognize and eliminate cancer cells is a longtime exploration. In the past decade, monoclonal antibody (mAb)-based immune checkpoint blockade (ICB) and chimeric antigen receptor T (CAR-T) cell therapy have proven to be safe and effective in hematologic malignancies. Despite the unprecedented success of ICB and CAR-T therapy, only a subset of patients can benefit partially due to immune dysfunction and lack of appropriate targets. Here, we review the preclinical and clinical advances of CTLA-4 and PD-L1/PD-1-based ICB and CD19-specific CAR-T cell therapy in hematologic malignancies. We also discuss the basic research and ongoing clinical trials on emerging immune checkpoints (Galectin-9/Tim-3, CD70/CD27, LAG-3, and LILRBs) and on new targets for CAR-T cell therapy (CD22, CD33, CD123, BCMA, CD38, and CD138) for the treatment of hematologic malignancies.

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Section: Targeting Immune Checkpoints In Hematologic Malignanciesmentioning

confidence: 99%

Immune checkpoint blockade and CAR-T cell therapy in hematologic malignancies

et al. 2019

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Treatment of Relapsed/Refractory Acute Myeloid Leukemia

Bose

Vachhani

Cortés

2017

Curr. Treat. Options in Oncol.

197

164

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Approximately 40-45% of younger and 10-20% of older adults with acute myeloid leukemia (AML) will be cured with current standard chemotherapy. The outlook is particularly gloomy for patients with relapsed and/or refractory disease (cure rates no higher than 10%). Allogeneic hematopoietic stem cell transplantation (HSCT), the only realistic hope of cure for these patients, is an option for only a minority. In recent years, much has been learned about the genomic and epigenomic landscapes of AML, and the clonal architecture of both de novo and secondary AML has begun to be unraveled. These advances have paved the way for rational drug development as new "drugable" targets have emerged. Although no new drug has been approved for AML in over four decades, with the exception of gemtuzumab ozogamycin, which was subsequently withdrawn, there is progress on the horizon with the possible regulatory approval soon of agents such as CPX-351 and midostaurin, the Food and Drug Administration "breakthrough" designation granted to venetoclax, and promising agents such as the IDH inhibitors AG-221 and AG-120, the smoothened inhibitor glasdegib and the histone deacetylase inhibitor pracinostat. In our practice, we treat most patients with relapsed/refractory AML on clinical trials, taking into consideration their prior treatment history and response to the same. We utilize targeted sequencing of genes frequently mutated in AML to identify "actionable" mutations, e.g., in FLT3 or IDH1/2, and incorporate small-molecule inhibitors of these oncogenic kinases into our therapeutic regimens whenever possible. In the absence of actionable mutations, we rationally combine conventional agents with other novel therapies such as monoclonal antibodies and other targeted drugs. For fit patients up to the age of 65, we often use high-dose cytarabine-containing backbone regimens. For older or unfit patients, we prefer hypomethylating agent-based therapy. Finally, all patients with relapsed/refractory AML are evaluated for allogeneic HSCT.

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Novel Therapies for Myelofibrosis

Pettit

Odenike

2017

Curr Hematol Malig Rep

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Purpose of Review To provide a contemporary update of novel agents and targets under investigation in myelofibrosis in the JAK inhibitor era. Recent findings Myelofibrosis (MF) is a clonal stem cell disease characterized by marrow fibrosis and a heterogeneous disease phenotype with a variable degree of splenomegaly, cytopenias, and constitutional symptoms that significantly impact quality of life and survival. Overactive JAK/STAT signaling is a hallmark of MF. The only approved therapy for MF, JAK1/2 inhibitor ruxolitinib, can ameliorate splenomegaly, improve symptoms, and prolong survival in some patients. Therapeutic challenges remain, however. Myelosuppression limits the use of ruxolitinib in some patients, eventual drug resistance is common, and the underlying malignant clone persists despite therapy. A deeper understanding of the pathogenesis of MF has informed the development of additional agents. Summary Promising targets under investigation include JAK1 and JAK2, downstream intermediates in related signaling pathways, epigenetic modifiers, pro-inflammatory cytokines, and immune regulators.

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Cotargeting BCL-2 and BCL-XL for maximal efficacy in ALL

Cited by 11 publications

References 10 publications

Immune checkpoint blockade and CAR-T cell therapy in hematologic malignancies

Immune checkpoint blockade and CAR-T cell therapy in hematologic malignancies

Treatment of Relapsed/Refractory Acute Myeloid Leukemia

Novel Therapies for Myelofibrosis

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